Seminars in Cancer Biology 35 (2015) S5S24 [613402]

Seminars in Cancer Biology 35 (2015) S5–S24
Contents lists available at ScienceDirect
Seminars in Cancer Biology
j o ur na l ho me page: www.elsevier.com/locate/semcancer
Review
Genomic instability in human cancer: Molecular insights and
opportunities
for therapeutic attack and prevention through
diet
and nutrition
Lynnette R. Fergusona,∗, Helen Chenb, Andrew R. Collinsc, Marisa Connellb,
Giovanna Damiad, Santanu Dasguptae, Meenakshi Malhotraf, Alan K. Meekerg,
Amedeo Amedeih, Amr Amini,j, S. Salman Ashrafk, Katia Aquilanol, Asfar S. Azmim,
Dipita
Bhaktan, Alan Bilslando, Chandra S. Boosanip, Sophie Chenq, Maria Rosa Ciriolol,
Hiromasa Fujiir, Gunjan Guhan, Dorota Halickas, William G. Helfericht, W. Nicol Keitho,
Sulma I. Mohammedu, Elena Niccolaih, Xujuan Yangt, Kanya Honokir,
Virginia R. Parslowa, Satya Prakashf, Sarallah Rezazadehm, Rodney E. Shackelfordv,
David Sidranskyw, Phuoc T. Tranx, Eddy S. Yangy, Christopher A. Maxwellb,∗∗
aDiscipline of Nutrition, University of Auckland, Auckland, New Zealand
bDepartment of Pediatrics, University of British Columbia, Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute,
Vancouver,
Canada
cDepartment of Nutrition, Faculty of Medicine, University of Oslo, Oslo, Norway
dDepartment of Oncology, Instituti di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
eDepartment of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, United States
fSchool of Pharmacy, University College Cork, Cork, Ireland
gDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States
hDepartment of Experimental and Clinical Medicine, University of Florence, Florence, Italy
iDepartment of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
jFaculty of Science, Cairo University, Cairo, Egypt
kDepartment of Chemistry, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
lDepartment of Biology, Università di Roma Tor Vergata, Rome, Italy
mDepartment of Biology, University of Rochester, Rochester, United States
nSchool of Chemical and BioTechnology, SASTRA University, Thanjavur, Tamil Nadu, India
oInstitute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
pDepartment of BioMedical Sciences, Creighton University, Omaha, NE, United States
qDepartment of Research & Development, Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey, United Kingdom
rDepartment of Orthopaedic Surgery, Nara Medical University, Kashihara, Nara, Japan
sNew York Medical College, Valhalla, NY, United States
tDepartment of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Champaign, IL, United States
uDepartment of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, United States
vDepartment of Pathology, Louisiana State University Health Shreveport, Shreveport, LA, United States
wDepartment of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
xDepartments of Radiation Oncology & Molecular Radiation Sciences, Oncology and Urology, The Sidney Kimmel Comprehensive Cancer Center,
Johns
Hopkins School of Medicine, Baltimore, MD, United States
yDepartment of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United States
a r t i c l e i n f o
Article history:
Available
online 11 April 2015
Keywords:Genomic instability
Cancer
therapya b s t r a c t
Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the
affected patient. Genomic instability arises from many different pathways, such as telomere damage,
centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous
sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both
enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a
∗Corresponding author at: Discipline of Nutrition, University of Auckland, Private Bag 92019, Auckland, New Zealand.
∗∗Corresponding author at: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada. Tel.: +1 6048752000×4691.
E-mail addresses: l.ferguson@auckland.ac.nz (L.R. Ferguson), cmaxwell@cfri.ca (C.A. Maxwell).
http://dx.doi.org/10.1016/j.semcancer.2015.03.005
1044-579X/© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ ).

S6 L.R. Ferguson et al. / Seminars in Cancer Biology 35 (2015) S5–S24
Cancer prevention
DNA
damage
Nutraceuticalglobal scale but it is accepted that personalized treatments, those that are tailored to the particular patient
and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic
instability arises and can lead to cancer, as well as treatments and measures that prevent genomic insta-
bility or take advantage of the cellular defects caused by genomic instability. In particular, we identify and
discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement
of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition
of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors,
resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized tar-
get sites and approaches were cross validated to identify potential synergistic effects on a number of
important areas of cancer biology.
© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/ ).
1. Cellular mechanisms that prevent or promote genomic
instability
Genomic instability plays critical roles in both cancer initiation
and progression. This instability can manifest itself genetically on
several different levels, ranging from simple deoxyribonucleic acid
(DNA) sequence changes to structural and numerical abnormali-
ties at the chromosomal level. This section will briefly outline the
mechanisms that maintain the stability of nuclear and mitochon-
drial DNA and how these mechanisms may become corrupted in
cancer cells.
1.1. Telomeres foster chromosomal stability and can inhibit or
promote
malignant transformation
The chromosome stabilizing role of intact telomeres was rec-
ognized as early as the 1930s from independent research by
McClintock [1] and Muller [2] and more recent work has further
strengthened the connection between telomere dysfunction and
chromosomal instability (CIN) [3,4] . Telomeres, which are located
at the ends of each chromosome, consist of approximately 5–10 kbp
of specialized, tandem repeat, noncoding DNA complexed with a
variety of telomere associated proteins [5,6] . These elements create
a protective cap that prevents the recognition of the chromosomal
termini as DNA double strand breaks (DSBs) and their consequent
aberrant repair via nonhomologous end joining (NHEJ) or homol-
ogous recombination (HR) [7–10] . Due to the inability of DNA
polymerase to fully replicate the ends of linear DNA molecules, in
the absence of compensatory mechanisms, telomeric DNA is lost
at the rate of approximately 100 base pairs (bp) per telomere per
cell division [11–17] . In normal somatic cells, this telomere erosion
is used by the cell to monitor its division history, with moderate
telomere shortening triggering either irreversible cell cycle arrest,
termed replicative senescence, or apoptosis [18–21] . This block to
continued proliferation is thought to have evolved to prevent the
development of cancer in long-lived organisms by restricting the
uncontrolled outgrowth of transformed cell clones, and also by pre-
venting further telomere erosion which would accompany such
abnormal growth and eventually destabilize the telomeres leading
to CIN [13,22] .
A current popular model for the involvement of telomere short-
ening in carcinogenesis posits that increasing numbers of cells
experience telomere shortening as a person ages, which increases
the pool size of cells that are in danger of experiencing eventual
telomere dysfunction and prooncogenic CIN. In the vast majority of
such cells, the senescence and apoptotic blocks are strictly enforced
[23–28] . However, this process eventually fails in rare cells which
continue to replicate and eventually experience CIN due to crit-
ical telomere shortening [15,29–37] . Notably, such cells may be
more tolerant of rampant genomic instability due to their previous
abrogation of the tumor suppressive telomere length checkpoints.
However, if left unchecked, this instability will eventually reachlethal levels in the transforming cells, thereby presenting a sec-
ond block to the development of cancer [37–40] . This escalating
telomere driven CIN creates a strong selective pressure for telo-
mere maintenance in incipient cancer cell populations; a problem
that is solved in one of two ways: activation of telomerase or
alternative lengthening of telomeres (ALT). In the majority of
human cancers, the telomere specific reverse transcriptase telo-
merase, which is stringently repressed in normal somatic cells,
is activated, thereby restabilizing the telomeres, although can-
cer telomeres on average seem to remain very short [32,41–45] .
Whereas most cancers use telomerase to maintain telomere length,
a significant minority of cancers (typically non-carcinomas) utilize
ALT, a telomerase independent, homologous recombination based
mechanism [46–48] . This mode of telomere maintenance results in
extreme telomere length heterogeneity and, interestingly, better
patient survival compared to their telomerase positive counter-
parts in several tumor types [49–52] . These observations suggest
that cancer cells utilizing ALT may have compromised their vital-
ity in exchange for the unlimited replicative potential conferred by
this telomere maintenance mechanism.
1.2. Centrosomes, the spindle assembly checkpoint, and
tumorigenesis
The centrosome is the primary microtubule organizing center
in dividing mammalian cells and is composed of a pair of centri-
oles surrounded by a cloud of proteins that promote microtubule
nucleation [53,54] . The centrosome is duplicated in a semicon-
servative fashion with one daughter centriole formed next to a
preexisting mother centriole, and this process only occurs once in
every cell cycle [53,55] . Centrosome amplification, the presence of
greater than two centrosomes during mitosis, is a common char-
acteristic of most solid and hematological tumors that may induce
multipolar mitoses, chromosome missegregation, and subsequent
genetic imbalances that promote tumorigenesis [54,56] .
Centrosome amplification may be caused by diverse mecha-
nisms, including centrosome overduplication [53,57–59] , de novo
assembly, [60–62] and mitotic failure downstream from mono- [63]
or multipolar division [64–69] . The end result of these structural
abnormalities is often cytokinesis failure, which can give rise to
tetraploid binucleated cells and genome instability downstream.
Over time, the net result is a small population of cells that harbor
the ability to manage extra centrosomes, which could account for
the accumulation of cancer cells with centrosome amplification and
aneuploidy.
Catastrophic aneuploidy and nonviable daughter cells are a
possible tumor suppressive consequence for centrosome abnor-
malities [70] . However, cancer cells have developed mechanisms
that overcome this fate by clustering multiple centrosomes into
a “pseudobipolar” state [59,70–72] . Cancer cells may utilize
this mechanism to dampen high level aneuploidy and extreme
CIN, leading to better prognostic outcomes [73,74] . Centrosome

L.R. Ferguson et al. / Seminars in Cancer Biology 35 (2015) S5–S24 S7
clustering in tumor cells is not completely understood, but it
is likely to rely on microtubule associated proteins and motor
proteins that bundle together microtubules and centrosomes [71] .
Given that centrosome clustering may be advantageous for cancer
cell survival, this process may be an attractive and specific ther-
apeutic target [71,75,76] . In theory, the induction of multipolarity
through declustering of supernumerary centrosomes will selec-
tively target cancer cells without affecting healthy cells [71,75–77] .
Bipolar chromosome attachment during mitosis is ensured by a
quality control mechanism known as the spindle assembly check-
point. The assembly checkpoint senses tension across kinetochores
as a measure of bipolar attachment of chromosomes, and pre-
vents the onset of anaphase in the presence of unattached and/or
misattached chromosomes [78] . Any failures to sense errors will
compromise the checkpoint and, potentially, induce instability.
The assembly checkpoint relies upon kinase signaling to delay
cell cycle progression and correct attachment errors. Aurora kinase
B, for example, detects misattached chromosomes [79,80] and
overexpression of the kinase is sufficient to disrupt the checkpoint
and promote tetraploidy [81] . Moreover, mutations or expres-
sion changes in other checkpoint gene products may compromise
the checkpoint and favor tumorigenesis [82–85] . Lastly, oncogenic
cues, such as overexpression of Aurora kinase A, may override a
functioning checkpoint and enable cells to enter anaphase despite
misattached chromosomes [86] . Cancer cells may take advantage
of the checkpoint for their own benefit. For example, checkpoint
mediated delay provides time for centrosome clustering [71] ,
which can be manipulated by disabling or restoring assembly
checkpoint function [77] . The ability to manipulate or hijack the
cell’s innate quality control mechanism may act as a selection pres-
sure, and cancer cells that possess this ability may have a growth
advantage over others.
Correlation between aberrant centrosome numbers and aber-
rant chromosome numbers dates back over 100 years [87] , yet there
is still a debate whether supernumerary centrosomes are the cause
or the result of genomic instability, or vice versa [54] . One interest-
ing phenomenon that may shed light on this debate is the presence
of a transient tetraploid state during tumorigenesis [88] .
Tetraploidy arises after cytokinesis failure following prolonged
activation of the assembly checkpoint, regardless of the reason for
checkpoint activation [54] . Depending on the status of tumor pro-
tein 53 (TP53), a tumor suppressor, the aborted postmitotic cells
will either undergo apoptosis after prolonged cell cycle arrest or
continue to cycle [56,89–92] . In p53 null cells, a postmitotic check-
point is compromised, which enables the cell to progress through
a subsequent cell cycle with double the amount of centrosomes
and genetic material [57,89] . Consequently, each subsequent divi-
sion for these tetraploid cells will be more error prone, generating
more unstable and detrimental aneuploidy [88] . A TP53-dependent
postmitotic checkpoint is frequently mutated during early stages
of tumorigenesis [88,90–92] , which suggests that the tetraploid
state serves as an intermediate for the aneuploid state observed
in cancer cells [88] . In patients with Barrett’s oesophagus, the
presence of tetraploid cells is detected before aneuploid cells and
correlates with early loss of TP53 [93] . Tetraploid cells were also
isolated from p53-/−mouse mammary epithelial cells, and these
cells formed tumors in nude mice and showed increased aberrant
mitoses and genomic instability in culture [94] . Therefore, regard-
less of how centrosome amplification or genomic instability occurs
in this “chicken or egg” argument, it is clear that either event is
positively enhanced by the other in promoting tumorigenesis.
1.3. Epigenetic mechanisms contributing to genomic instability
A plethora of studies, including more recent genome-wide pro-
filing, have demonstrated that epigenetic changes direct differentcellular phenotypes in both normal and cancer cells [95–97] .
Epigenetics refer to all heritable changes that may modify gene
expression without changing the primary DNA sequence, such as
DNA methylation and chromatin remodelling. Epigenetic modifica-
tions are established during differentiation and are stably inherited
and maintained through multiple rounds of cell division. Epigenetic
processes that lead to genomic instability and ultimately malignant
transformation constitute heritable changes that modulate gene
expression and can also affect DNA repair dynamics [95–97] .
DNA methylation consists of the addition of a methyl group at
the carbon 5 position of the cytosine pyrimidine ring or the num-
ber 6 nitrogen of the adenine purine ring [98,99] . Most cytosine
methylation occurs in the context of cytosine-phosphate-guanine
(CpG) dinucleotides, and occurs via a group of DNA methyl-
transferase enzymes resulting in silencing of gene transcription
[100,101] . Aberrant changes in DNA methylation were among the
first events to be recognized in cancer [102] . Global hypometh-
ylation in repetitive sequences of the genome can occur early
during tumorigenesis and may initially predispose premalignant
cells to repetitive sequence genomic instability [103] . Furthermore,
hypomethylation of the promoter of oncogenes can increase their
expression [104] and lead to genomic instability [105,106] . Simi-
larly, aberrant sequence specific hypermethylation in cancer cells
can lead to further genomic instability by the silencing of genes
involved in cell cycle regulation and DNA repair [107] . A prominent
example is the aberrant methylation of CpG islands in the promoter
regions of DNA mismatch repair (MMR) genes that result in cancer
cells with a “mutator phenotype” [108,109] .
In addition to DNA methylation, histone molecules that form
the primary protein component of chromatin also regulate genome
stability as well as gene transcription [110] . A number of post-
translational modifications such as acetylation, deacetylation,
methylation, phosphorylation and ubiquitination have been identi-
fied that alter the function of histones [111] . Various combinations
of these posttranslational histone modifications have been hypoth-
esized to form a “histone code” that dictate distinct chromatin
structures that can affect genome stability pathways and tran-
scription [95,97,98,112] . Acetylation of the lysine residues at the
amino (N) terminus of histone proteins removes positive charges,
thereby reducing the affinity between histones and DNA to facili-
tate access by ribonucleic acid (RNA) polymerase and transcription
factors to gene promoter regions [112] . Therefore, in most cases,
histone acetylation enhances transcription while histone deacety-
lation represses transcription. In addition, histone acetylation can
affect DNA repair by promoting histone dynamics that stimulate a
DNA damage response in response to ionizing radiation [113–118] .
Similarly, histone ubiquitination can also modify DNA repair capac-
ity [119–123] . Briefly, ubiquitinated histones can lead to chromatin
structures that are conducive to the assembly of nucleotide exci-
sion repair complexes on damaged DNA [124] , as well as both
types of DSB repair pathways and cell cycle checkpoint factors
critical for the DNA damage response [119–126] . Monoubiquitina-
tion of histones H2A and H2B prevents chromatin compaction and
facilitates assembly of the repair machinery at the damaged sites
[126] . Polyubiquitination of histone H2A and H2AX is important
for the retention of repair proteins, such as TP53 binding protein
1 (53BP1) and breast cancer 1 (BRCA1), at damaged loci [120,127] .
Finally, histone phosphorylation is an early event following DNA
damage and required for efficient DNA repair. Upon introduction
of a DSB, hundreds of histone molecules become phosphorylated
within minutes at the chromatin flanking the break site, thus pro-
viding a rapid and highly amplified detection system and a focus
for the accumulation of many other proteins involved in DNA repair
and chromatin remodelling [128] . These examples, and numerous
other observations, suggest that a vast array of epigenetic mecha-
nisms contribute to the genomic instability in cancer cells.

S8 L.R. Ferguson et al. / Seminars in Cancer Biology 35 (2015) S5–S24
1.4. Mitochondrial DNA alteration in human cancers
Mitochondrial genetic reprogramming and energy balance
within cancer cells play a pivotal role in tumorigenesis and are
duly regarded as one of the hallmarks of human cancer [129] . In
1927, Otto Warburg [130,131] identified mitochondrial dysfunc-
tion as a key component of tumorigenesis and numerous studies
have since elaborated upon the role of mitochondrial DNA (mtDNA)
alterations in different human cancers [132] .
Mitochondria are the key component of the oxidative phos-
phorylation system to generate cellular adenosine triphosphate.
They uniquely possess their own DNA and generate reactive oxygen
species (ROS) [132] . Most human cells contain hundreds of nearly
homoplasmic (identical) copies of mtDNA, which are maternally
inherited [132] . Compared to the nuclear DNA, the mutation rate
of mtDNA is nearly 10 times higher and alterations are much easier
to detect due to their high copy number in cancer cells.
A substantial number of studies identified somatic mtDNA
mutations involving coding and noncoding mtDNA regions in var-
ious cancers [132–136] . Among the noncoding mtDNA mutations,
a poly C mononucleotide repeat (known as D310) was frequently
altered in numerous cancers and appeared to be a mutational hot
spot [132] . Notably, coding mtDNA mutations targeting respiratory
complex I, III, IV or V were frequent in a variety of human can-
cers [132–138] . Moreover, alteration of mtDNA copy number could
potentially be associated with mitochondrial dysfunction leading
to disease progression [132,133] . In recent studies, a correlation
between mutations in mtDNA and epidermal growth factor receptor ,
or prostate-specific antigen expression, was established in lung and
prostate cancer, respectively [134,135] . These results suggest cross
talk between mitochondria and nuclear genomes maintain tumor
growth.
In order to understand their role, a number of studies introduced
mtDNA mutations in cancer cells. Introduction of a mitochondrial
mutant adenosine triphosphate 6 (ATP6 ) (complex V) or cyclooxy-
genase 1 (COXI ) (complex IV) increased the growth of prostate
cancer cells [136,139] or induced cancer cell proliferation and
altered reactive oxygen and nitrogen species [140] , respectively.
In a bladder cancer study, introduction of a mutant mitochon-
dria encoded cytochrome B (CYTB ) induced bladder cancer growth
and invasion, accompanied with increased ROS, lactate produc-
tion and oxygen consumption [141] . Moreover, the ROS-producing
CYTB mutant tumor cells efficiently killed normal splenic immune
effector cells, which may provide tumor cells with an immune eva-
sion mechanism [141] . In addition, mutant CYTB overexpression
in nontumorigenic bladder epithelial cells triggered an increased
mitochondrial proliferation and inhibition of apoptosis [142] . As
these mutations in mtDNA were detected in human patients, the
preceding studies suggest a causative role for mtDNA alterations in
tumorigenesis.
2. Repair pathways responsible for genetic fidelity and
tumor suppression
DNA is replicated with extreme fidelity in normal cells with a
mutation rate of 10−10per base pair per cell division. DNA dam-
age typically occurs through the following: (1) exposure to agents
such as ultraviolet irradiation, genotoxic chemicals, and ionizing
radiation; (2) spontaneous DNA damaging events, such as a basic
site formation; and (3) failure in normal cellular DNA processing
and replication events, such as stalled replication forks. These pro-
cesses induce oxidation, alkylation, crosslinking, dimerization, and
strand breaks in DNA, which must be resolved. As such, repair of
this DNA damage is essential to preserving genome integrity and
preventing cancer.2.1. Excision repair pathways
Three excision repair pathways can repair single stranded DNA
damage: nucleotide excision repair (NER), base excision repair
(BER), and DNA mismatch repair (MMR).
2.2. Nucleotide excision repair
Fidelity of genetic information transmission depends on NER,
which serves to repair DNA damage caused by ultraviolet irradi-
ation, alkylating and oxidizing agents, or chemotherapeutic drugs
that form bulky, helix distorting adducts. Two sub-pathways have
been identified. Global genome NER repairs damage in both strands
of the DNA regardless of whether the gene is being actively
transcribed [143–145] . Transcriptionally coupled NER, however,
repairs transcriptionally active genes [143–145] . The two path-
ways are similar in that they use many of the same pathways, but
global genome NER uses xeroderma pigmentosum complementa-
tion group C (XPC)-RAD23 homolog B (HR23B) and DNA damage
binding protein 1 (DDB1)-DDB2/XPE proteins to recognize distort-
ions in the double helix while transcriptionally coupled NER occurs
at regions where RNA Polymerase II has stalled [146–150] . Genetic
polymorphisms of NER gene products associate with human dis-
eases, including xeroderma pigmentosum, which can lead to severe
cases of skin cancer.
2.3. Base excision repair
The BER pathway fixes damaged DNA bases (reviewed in [151] ).
These lesions are recognized and removed by specific DNA glycosyl-
ases, which cleave the glycosidic bond between the damaged base
and the sugar of the DNA backbone. In more complex lesions, prolif-
erating cell nuclear antigen (PCNA), flap endonuclease 1 (FEN1), and
DNA polymerase (POL) /H9252, with or without POL/H9254//H9255, act to repair the
lesion. This complex set of events in BER is facilitated by poly (ADP-
ribose) polymerase 1 (PARP1), which recruits proteins involved in
the DNA repair response, such as X-ray repair cross-complementing
protein (XRCC)1, DNA ligase, and DNA polymerase [152,153] .
Because cells are constantly subjected to DNA damaging condi-
tions, the BER pathway is crucial to preserving genome integrity.
This is exemplified by the embryonic lethality of mice that possess
knockouts of key components of this pathway [154–156] . A bial-
lelic germline defect within a DNA glycosylase, mutY Homology
(MUTYH) , was initially found in families that had excess colorec-
tal tumors with somatic mutations in the adenomatous polyposis
coli gene [157] . A subsequent larger study revealed that bial-
lelic germline MUTYH defects conferred 93 fold excess risk of
colon cancer with penetrance by age 60 [158,159] and may also
confer increased risk for endometrial cancer [160] . Mutations in
another glycosylase, 8 Oxoguanine (OGG1) , have been associated
with laryngeal cancers [161] while gastric cancers harbor inacti-
vating mutations in glycosylase nei endonuclease VIII-like 1 (NEIL1)
[162] . Taken together, these studies confirm the importance of BER
in the suppression of carcinogenesis.
2.4. DNA mismatch repair
Some evidence suggests that proofreading activity of replicative
DNA polymerases and MMR machinery act in series in mam-
malian cells [163–166] . MMR targets could generally be classified
into base/base mispairs and large insertion–deletion loops. At
the forefront of error recognition, MutS protein homolog (Msh)
2 pairs with Msh6 or Msh3, to form MutS/H9251 (Msh2/Msh6) and
MutS/H9252 (Msh2/Msh3). Whereas the former is mostly responsible
for base/base mispairs, the latter targets large insertion–deletion
loops. To initiate the repair process, MutL homolog 1(Mlh1)/Pms2

L.R. Ferguson et al. / Seminars in Cancer Biology 35 (2015) S5–S24 S9
heterodimers (MutL homologues), in the presence of exonuclease1,
interact with MutS complexes to create nicks in the 3/primeand 5/primeof
the nascent strand containing the mismatch. Following nick cre-
ation, enzymes required to repair the damage site are recruited
and resynthesis of the DNA is carried out by POL/H9254//H9255. As a nexus
for DNA damage sensing and cell death, MMR machinery play an
important role in recognizing damaged DNA and relaying signals
downstream to activate a G2/M cell cycle checkpoint.
2.5. Double strand break repair and cancer predisposition
The DSB is the most lethal form of DNA damage, as it can
lead to significant DNA damage by multiple genomic changes,
including translocation formation, deletions, and amplifications,
resulting in heritable cellular genomic instability/damage that can
lead to malignancy [167–169] . DSBs are repaired by both HR
and NHEJ repair pathways. NHEJ repair occurs throughout the
cell cycle, while HR prevails in S and G2 phase cells (reviewed,
[167–169] ). NHEJ repair joins broken DNA ends without identify-
ing DNA sequence homology and is therefore highly error prone
[169] . HR repair is dependent upon DNA sequence homology and
therefore is relatively error free [168–170] .
Errors in the NHEJ pathway may generate inappropriate dicen-
tric chromosomes that are covalently joined (reviewed, [171,172] ).
These dicentric chromosomes may break during anaphase, produc-
ing new dicentric chromosomes through further NHEJ [171,172] .
This process is known as the breakage fusion bridge (BFB) cycle,
which is important in telomere related genome instability [172] .
Damaged telomeres will be processed by NHEJ, unless the bro-
ken ends are healed by a new telomere, and continuation of the
BFB cycle can result in complex chromosomal rearrangements
that include gene loss, gene amplification and unbalanced translo-
cations [171,172] . BFB cycles are self-perpetuating and result in
genetic heterogeneity in a variety of cancers [173] .
HR repair involves multiple gene products some of which are
involved in repair of stalled replication forks [170] . The DSB is rec-
ognized by a Mre11-Rad50-NBS1 complex which recruits many
different proteins, including proteins with topoisomerase, endonu-
clease, and helicase activity. Eventually a “synaptic complex” is
formed which allows homologous single strand DNA (ssDNA) to
invade and anneal to complementary DNA. DNA polymerase then
fills in the ssDNA gap and the synaptic complex is resolved. Both
crossover and non-crossover products can be created by this pro-
cess [167–170] . Interestingly, loss or mutation of many of these
gene products is associated with specific cancer prone diseases.
BRCA1 and BRCA2 are key players in the HR repair pathway and
act as tumor suppressors by maintaining genome stability. Link-
age studies in families with early onset breast cancer detected the
presence of a breast cancer susceptibility gene, BRCA1 [174] . Subse-
quently, mutations in BRCA1 were confirmed in families with early
onset breast and ovarian cancer [175–178] . Later, a novel locus,
encoding BRCA2 , was discovered and linked to breast cancer sus-
ceptibility [179–181] . In one meta-analysis, cumulative breast and
ovarian cancer risks for BRCA1 mutation carriers are 57 and 40%,
respectively, while, for carriers of BRCA2 mutations, these risks
are 49 and 18%, respectively [182] . Furthermore, hereditary BRCA
mutations have been also linked to pancreatic, prostate, and colon
cancers [183] . Of interest, germline mutations in BRCA1 versus
BRCA2 associate with different subtypes of breast cancer. BRCA1
associated cancers are of the more aggressive triple negative sub-
type and appear at an earlier age than sporadic tumors. In contrast,
BRCA2-associated tumors relate mostly with hormone receptor
positive breast cancers.
Like BRCA1 and BRCA2, partner and localizer of BRCA1 (PALB2)
promotes genome integrity through its role in DSB repair. It binds
and colocalizes with BRCA2 in the nucleus to stabilize BRCA2 fociand facilitate the intra S phase checkpoint and HR repair [184] .
Germline mutations in PALB2 confer a 2–5 fold increase in breast
cancer risk [185,186] and germline mutations have been recently
found in African American breast cancer patients [187,188] . PALB2
mutations have also been observed in 1% of Chinese women with
early onset breast cancer [189] . Interestingly, exome sequencing
identified PALB2 as a pancreatic cancer susceptibility gene [190]
and PALB2 mutations have been found in patients with familial
pancreatic cancers [191,192] .
Fanconi anemia (FA) is an autosomal recessive disorder char-
acterized by congenital defects, CIN, hypersensitivity to DNA
crosslinks, bone marrow failure, and predisposition to cancer
[193,194] . Fifteen FA or FA-like genes have been identified, all
of which are involved in coordinating DNA repair through the
FA/BRCA pathway. Interestingly, two of these genes are BRCA2
(FANCD1) and PALB2 (FANCN) , thus revealing interplay between FA
and HR [195,196] . Patients with FA have increased susceptibility to
breast, ovarian, and oral cancers. Additionally, heterozygote carri-
ers of germline mutations in FA genes may also harbor an increased
risk to develop cancer. Importantly, unlike the BRCA-associated
cancers, tumors from FA patients, or with acquired FA defects,
may be hypersensitive to crosslinking agents such as cisplatin and
mitomycin C, and also are hypersensitive to radiation [197–199] .
Finally, biallelic loss of ataxia telangiectasia mutated (ATM) results
in ataxia telangiectasia, a disease characterized by a roughly 1000
fold increased lymphoma incidence [200,201] .
3. Therapeutic targeting of genomic instability
Current standard therapies for cancer often involve agents or
strategies that damage the DNA, which can also damage noncancer-
ous tissues. New treatments that target genomic instability (Fig. 1)
may minimize these off target toxicities to normal tissues.
3.1. Targeting DNA repair pathways in cancer therapy
Drugs that target DNA repair proteins have shown preclinical
and/or clinical efficacy in potentiating DNA damage (reviewed in
[202] ). Synthetic lethality, whereby deficiencies in parallel path-
ways are only cytotoxic when both pathways are defective, is a
novel strategy that may selectively target cancerous cells defec-
tive in DNA repair [203] . Synthetic lethality was illustrated in BRCA
deficient cells, which exhibited profound sensitivity to inhibition
of PARP [204,205] . This was due to conversion of unrepaired sin-
gle strand breaks into DSBs during DNA replication due to the
BRCA deficiency. Persistence of the unrepaired DSBs led to pro-
found cellular cytotoxicity. The potential efficacy of PARP inhibitors
in patients with BRCA-associated cancers has been reported in
multiple clinical trials [206–211] . Perhaps more important is the
high therapeutic index of these compounds, since noncancerous
cells in this patient population still maintain one wild type allele
and thus remain HR proficient. Natural products have also been
shown to act on PARP, such as isothiocyanates, which are found
in Brassica vegetables. Isothiocyanates stimulate the proteolytic
cleavage of PARP [212] . Recent work implicates vitamin D as a pos-
sible treatment mechanism to supplement PARP treatment [213] .
BRCA1-deficient cells bypass growth arrest by activating cathep-
sin L (CTSL)-mediated degradation of 53BP1. Vitamin D depletes or
inhibits CTSL leading to increased genomic instability and compro-
mised cancer cell proliferation after irradiation and treatment with
PARP inhibitors [213] . Selenocysteine can induce ROS formation,
which can lead to DSBs in cancer cells but not in normal human
fibroblasts [214] . Thus, DSB repair deficient cancers may be sensi-
tive to treatment with selenium compounds.
In addition to defective DSB repair, inappropriate HR often
results in a significant predisposition to cancer development

S10 L.R. Ferguson et al. / Seminars in Cancer Biology 35 (2015) S5–S24
Fig. 1. Genome stability is dependent on faithful DNA repair and chromosome segregation during cell division. During S phase, the centrosome and genomic material are
replicated concurrently, and replication errors are repaired prior to mitotic entry (1). During mitosis, equal segregation of chromosomes requires a bipolar mitotic spindle,
telomere
preservation and the completion of the spindle assembly checkpoint. Ectopic amplification of centrosomes (2), telomerase dysfunction (3) and failure of the spindle
assembly
checkpoint (4) may result in aborted mitosis. Mitotic failure gives rise to a single tetraploid cell (4 N) instead of two diploid cells (2 N). This tetraploid cell can
progress
through the cell cycle should the TP53-dependent post mitotic checkpoint fail to induce apoptosis or senescence (4). Thus, genomic instability is propagated in
subsequent
cell cycles.
[200,201] . Many human malignancies with HR deficiency show
increased sensitivity to chemotherapy agents that cause DSBs, such
as ionizing radiation, bleomycin, and cisplatin. Additionally, agents
which inhibit DNA replication, such as bifunctional alkylating
agents and topoisomerase inhibitors, also preferentially inhibit
the growth of HR deficient malignant cells [170,215,216] . There
has been intense interest in identifying HR deficiencies in human
tumors and targeting these tumors with DSB-inducing chemother-
apeutic agents. Since ∼25% of human malignancies show HR defects
[170] , targeted treatment could eventually play a significant role
in chemotherapy. As tumors often overexpress specific proteins
involved in HR, this approach might also preferentially target tumor
over normal tissue [170,215–217] . A major challenge in this area is
the efficient and accurate identification of HR deficiency in human
malignancies.
Some of the proteins that have been proposed as useful tar-
gets to inhibit HR include ATM, checkpoint kinase (CHK)1&2, ataxia
telangiectasia and Rad3 related (ATR), and the FA pathway proteins
[170] . Many inhibitors that target these enzymes are either in pre-
clinical development or in the early phases of clinical development
[218,219] . Resveratrol may activate sirtuin 1 (Sirt1) activity [220] ,
which is a nicotinamide adenine dinucleotide-dependent deacety-
lase that is known to activate DNA repair. Studies in mice have
shown that Sirt1+/−; p53+/−mice develop tumors in many different
tissue types but mice treated with resveratrol display a reduced
amount of tumorigenesis [221] , indicating that resveratrol could act
to prevent and/or treat cancers in patients that have reduced Sirt1
function. Although in early development, therapies that specifically
alter HR are a promising area of research and may contribute totargeted chemotherapy regimens that are more personalized and
effective.
3.2. Targeting microsatellite instability
MMR inactivation is associated with the lack of repair of repli-
cation errors leading to an increase in spontaneous mutation rate
[222] . A marker of defective MMR is microsatellite instability (MSI),
or numerous alterations in the lengths of microsatellites [223,224] .
Tumors displaying MSI are said to exhibit a “mutator phenotype”,
with a dramatic predisposition to somatic mutations.
The critical role of MMR pathways in tumorigenesis is exem-
plified by the fact that germline mutations in the genes involved
in MMR predispose to cancer development [225] . In the case of
colorectal cancer (CRC), MMR deficiency is estimated to be present
in 15 to 17% of all primary cancers, including both sporadic CRC
and Lynch syndrome (then called hereditary nonpolyposis colorec-
tal cancer), though through different mechanisms [223,226,227] .
Lynch syndrome is characterized by inactivating germline muta-
tions to MSH2, MSH6, PMS2, or MLH1 , whereas MLH1 expression
is silenced due to biallelic hypermethylation in sporadic CRC
[228–232] . MLH1 methylation results from extensive aberrant pro-
moter methylation [233,234] . The 3/primeend of the MLH1 promoter,
proximal to the start codon, is most commonly methylated [227] .
Methylation of the 5/primeend of the MLH1 promoter can also occur,
however, the methylation pattern must extends to the 3/primeend to be
deleterious [227] . Loss of MLH1 expression increases with age and
protein expression is lost by ∼50% in patients who are 90 years or
older [235] . The exact mechanism(s) behind MLH1 silencing remain

L.R. Ferguson et al. / Seminars in Cancer Biology 35 (2015) S5–S24 S11
unknown, but may result from abnormal methylation [236] , struc-
tural chromatin changes that increase accessibility to promoter
regions [237] , or genomic damage [238] . Tumors with mutations
in the MLH1 gene are rare, which suggests that hypermethylation
of the MLH1 promoter is an important event in neoplastic transfor-
mation in sporadic CRC [234] .
The extent of MSI in CRC has been classified as MSS
(microsatellite–stable), MSI-H (with high level of instability), and
MSI-L (with low level of instability) [239] . Classification between
MSI-H and MSI-L depends on which MSI markers are present and
their proportions [240] . These markers include mononucleotide
repeats, such as BAT25, BAT26, and BAT40, and the dinucleotide
repeats D5S346, D2S123, and D17S250 [241–244] . Dinucleotide
markers are present in both MSI-H and MSI-L cancers, whereas
mononucleotide markers are specific for MSI-H cancers [241] . In
MSI-H tumors, more than 30% of these markers are unstable, while
in MSH-L tumors, 10–40% of these markers are unstable, and MSS
tumors demonstrate no unstable markers [241,245–248] . MSI-L
and MSS tumors are frequently grouped together due to similar-
ities in their clinical features and gross abnormalities [248] . MSI-H
is most prevalent in sporadic CRC, observed in 10–15% of all cases
[240,248] .
The predictive value of MMR status as a marker of response to 5
fluorouracil, irinotecan and other drugs is still controversial [249] .
Recently, two large retrospective analyses from several random-
ized trials confirmed the detrimental effect of a 5 fluorouracil-based
adjuvant therapy in stage II colorectal patients [250] , not applicable
to stage III patients [251] . These latter authors, however, reported
that MSI stage III tumors harboring genetic mutation in the MMR
genes seem to benefit from the 5 fluorouracil adjuvant therapy.
These data imply that molecular differences within the MSI sub-
group influence the response to 5 fluorouracil.
The CRC MSI subgroup represents a cancer with a defined molec-
ular etiology, a characterized mutational profile and an established
genotype–phenotype relationship, which may enable synthetic
lethal approaches that target MMR deficiency. High through-
put experiments revealed synthetic lethal interactions between
MSH2 and POLB , between MLH1 and Polymerase G gene [252] ,
between RAD54B and FEN1 [253,254] , between MLH1/MSH2 and
PTEN-induced putative kinase 1 gene [255] , and the preferential
effect of methotrexate in MMR deficient systems [256] . These syn-
thetic interactions may induce or accumulate ROS [257,258] . A
phase II randomized clinical trial in MLH2-deficient metastatic
CRC (NTC00952016) is currently underway [256] . Combination
therapy with methotrexate and PARP inhibitors may be effective
against tumors with MMR mutations. Methotrexate elevates ROS
and DSBs and the combination of MMR mutation and PARP inhi-
bition may attenuate repair and induce growth arrest or apoptosis
[259–261] .
3.3. Targeting gene expression of cell cycle and DNA repair
components
RNA interference (RNAi) may enable personalized antitumor
therapies. A number of RNAi-based studies have silenced genes
responsible for tumor cell growth, metastasis, angiogenesis, and
chemoresistance [262] . For example, siRNA targeting of Cyclin E
suppressed tumor development [263] . Epigenetic regulation of
gene expression is an alternative approach. Resveratrol, a phy-
toalexin produced by plants such as the Japanese knotweed,
prevents hypermethylation of the BRCA1 promoter [264] , and may
be effective for triple negative or basal subtype breast cancers.
Other natural compounds, like genistein and lycopene, can alter
DNA methylation of the glutathione S transferase p1 (GSTP1 ) tumor
suppressor gene [265] .3.4. Targeting centrosome abnormalities
Centrosome amplification is an important process during early
stages of cancer development (see Section 1.2). Though the
mechanism(s) behind centrosome amplification remain elusive,
TP53 negatively regulates centrosome amplification through a
TP53-p21-CDK2 signaling loop [266,267] . Moreover, TP53 induces
apoptosis through transactivation of proapoptotic genes and
transrepression of antiapoptotic genes [268] . Thus, TP53 pro-
vides an interesting link between two major cancer processes,
centrosome amplification and apoptosis dysregulation [268] . In
one study, the loss of TP53, or treatment with 5 fluorouracil,
promoted centrosome amplification in HCT116 cells and those
cells with supernumerary centrosomes were more acutely sen-
sitive to resveratrol [268] . However, TP53 defective cancer cells
that resist 5 fluorouracil treatment are prone to centrosome
amplification and downstream genome instability [269] . The
presence of supernumerary centrosome can also be problem-
atic for cancer cells. Clustering excess centrosomes may be a
necessary prosurvival pathway for cancer cells and thus an attrac-
tive target [70] . Griseofulvin, an antifungal drug that suppresses
proliferation in tumor cells without affecting non-transformed
cells, declusters centrosome, although the precise mechanisms
behind the drug’s action remain unknown [71] . In a similar
fashion, depletion of a kinesin-like motor protein can selec-
tively kill tumor cells with supernumerary centrosomes [77] .
Finally, the PARP inhibitor PJ34 also declusters supernumerary
centrosomes without deleterious effects on spindle morphology,
centrosome integrity, mitosis, or cell viability in normal cells
[270] .
4. Prevention of genomic instability and human cancer
There is no question that optimizing nutrient intake plays a sig-
nificant role in stabilizing the genome. In recent years, an increasing
number of biomarkers of genome integrity, including telomere
length and mtDNA deletions, have been utilized in establishing
recommended daily intakes for nutrients [271] . In several cases,
such an approach has led to substantial changes in the levels of
various nutrients that populations had been previously advised to
consume. These findings highlight the need to better optimize an
individual’s diet to their personal genetic makeup, which in turn
has prompted the emergence of nutrigenomics, a new field that
aims to determine how a particular genotype or expression pro-
file correlates to nutrient metabolism, absorption, etc. (reviewed
in [272,273] ).
4.1. Vitamins–carotenoids
Since Peto et al. [274] concluded that the evidence pointed to
a cancer preventive role for /H9252 carotene, many placebo-controlled
carotenoid intervention trials have been carried out with disease
and mortality as outcomes. Early findings were that, in subjects
who were smokers and/or asbestos workers, there was a signifi-
cant increase in lung cancer incidence [275] . A recent meta-analysis
confirmed that a significant increase in mortality is associated with
vitamin A, /H9252 carotene or vitamin E supplements [276] . When deter-
mining the effects that dietary supplements and other compounds
have on cancer prevention, it is important to take into account
the different types of data: conventional intervention studies, ani-
mal experiments, cell culture studies, or human intervention trials
based on biomarkers. This is important because of the nature of
each type of experiment and the information that can be obtained
from them.

S12 L.R. Ferguson et al. / Seminars in Cancer Biology 35 (2015) S5–S24
4.1.1. Human biomarker trials with molecular endpoints
Human trials with carotenoids [277–286] were mostly cross
sectional or case control studies, with a few intervention trials. In
general, a negative correlation was seen between blood carotenoid
levels and various biomarkers of DNA damage, and intervention
trials tended to show a decrease in DNA damage or no effect.
4.1.2.
Animal experiments
Most animal experiments [287–300] involved treatment of
rats or ferrets with genotoxic agents during or after carotenoid
supplementation, and generally decreased levels of DNA dam-
age were reported. Another study [301] looked at base oxidation
in leukocytes and oxidation products in urine, reporting a
carotenoid-induced decrease in the former (but no effect on urinary
biomarkers). There was a decrease in endogenous DNA oxidation
in liver of mice fed tomato paste (rich in lycopene) [302] .
4.1.3. Cell culture experiments
We found eleven cell culture studies [287,303–312] with provi-
tamin A carotenoids (/H9251 and /H9252 carotene, /H9252 cryptoxanthin, retinoic
acid, retinal and retinol), and eight with nonvitamin A carotenoids
(lycopene, lutein, astaxanthin or zeaxanthin) [294,304,313–318] .
Experiments in most cases involved cotreatment with DNA dam-
aging agent and carotenoid. Concentrations of carotenoid varied
widely, from less than 1–100 /H9262M. Here we found a very clear
pattern in the results, depending on the type of carotenoid and
the concentration: while the non-vitamin A carotenoids invariably
resulted in a decrease in DNA damage, the provitamin A carotenoids
at low concentrations either had no effect or decreased DNA dam-
age, while at concentrations above about 5 /H9262M, increases in damage
were the norm. Potential prooxidant effects of carotenoids can
probably be ruled out as a cause of this DNA damage, since there is
no obvious reason why provitamin A carotenoids should be more
likely to act as prooxidants. Instead, we should perhaps be look-
ing at downstream effects of vitamin A itself, on transcription, via
retinoic acid and retinoic acid receptors binding to retinoic acid
response elements present in the regulatory sequence of many
genes.
In a review of effects of carotenoids on DNA repair [319] , we
found relatively few reports. Cells from the spleen of rats sup-
plemented with carotenoids (plus nicotinamide and zinc) showed
accelerated repair of DSBs induced by radiation, and lympho-
cytes from human subjects given the same supplement mix were
faster at rejoining hydrogen peroxide induced breaks [184] . Mixed
carotenes plus /H9251 tocopherol as a supplement in humans had no
effect on DNA repair [320] . DSB rejoining was faster in Molt 17 cells
in the presence of /H9252 carotene, lutein or /H9252 cryptoxanthin [321] , and
in HeLa and Caco2 cells with /H9252 cryptoxanthin [306] ; but no effect
was seen in lymphocytes incubated with /H9252 carotene or lycopene
[322] or with vitamin A [311] .
Lung cells from ferrets supplemented with /H9252 carotene were
tested for BER capacity with an in vitro comet-based assay, and
showed an increase in activity [323] . B cryptoxanthin enhanced
BER of 8 oxoguanine in HeLa and Caco2 cells [306] , but no effect of
carotenoids was seen in Molt 17 cells [321] or lymphocytes [320] .
The pattern that emerges from this survey of carotenoid effects
on DNA damage is that, in cell culture at least, while nonvitamin
A carotenoids tend to decrease damage (whether endogenous or
induced), at whatever concentration, the provitamin A carotenoids
show a clear tendency to cause or increase damage at high concen-
trations. Whether this can account for the apparent harmful effects
of /H9252 carotene as seen in the human clinical trials is not possible to
answer at present.
Glutathione is another important antioxidant that can improve
outcomes for patients with cancer and can help reduce treat-
ment toxicity. Some studies have shown that supplementation withglutathione can reduce the toxicity of chemotherapy agents such
as cisplatin and cyclophosphamide during treatment [324,325] .
Interestingly, while the antioxidant properties of glutathione may
reduce treatment toxicity, the same properties can make tumor
cells resistant to chemotherapy when glutathione is present in
high levels in the cells [326,327] . A GSTP1 polymorphism (GSTP1
Ile105Val), which has a seven fold higher efficiency, has been linked
to a reduced survival rate in cancer patients further emphasizing
that while glutathione may be able to reduce treatment toxicity, it
can potentially also confer an advantage to the tumor cells as well
[328,329] .
An additional aspect that may lead to conflicting results
regarding the efficacy of antioxidants in cancer treatment is the
oxidative stress that tumor cells experience in their microenviron-
ment. Tumor cells have been shown to undergo the Warburg effect,
which is where they produce energy primarily through glycolysis
rather than through aerobic respiration ([131] ; reviewed in [330] ).
The production of lactate in tumor cells rather than pyruvate, an
antioxidant, increases the load of ROS and increases oxidative stress
in the cancer cells. Recent work has suggested that cancer cells
might be targeted by using 3 bromopyruvate, an inhibitor of the
glycolysis enzyme hexokinase II, to amplify the Warburg effect in
cells [331] .
4.2. Other vitamins
A range of B vitamins, including niacin (vitamin B3), folate (vita-
min B9), and vitamin B12, significantly interact to maintain the
stability of both nuclear and mitochondrial genomes. For example,
a niacin deficiency, common in certain populations, impairs the
function of the PARP family of enzymes, identified above as criti-
cal to DNA repair. A folate deficiency, especially in the presence of
suboptimal levels of vitamin B6 and vitamin B12, may have signifi-
cant effects on the expression of chromosomal fragile sites, leading
to chromosome breaks, micronuclei and deletions of mtDNA. It
may also lead to reduced telomere length. There are consider-
able interindividual differences in people’s capacity to absorb and
metabolize these vitamins, dependent upon genotype and epigeno-
type [332] .
Vitamin C is considered an antioxidant, and is present at high
concentrations (mM) in certain tissues such as the eye. Effects on
various markers of genome stability were shown to depend on indi-
vidual diet-derived vitamin C concentrations, and also on exposure
to xenobiotics or oxidative stress [333] . Vitamin D is also critical
in the maintenance of genome stability, possibly through protec-
tion against oxidative stress, chromosomal aberrations, telomere
shortening and inhibition of telomerase activity [334] .
4.3. Minerals
While a number of minerals are typically considered as tox-
icants, there are several that are essential micronutrients, albeit
usually with a narrow window of efficacy as compared with toxic-
ity. These include iron [335] , selenium [336] , and zinc [337] .
Selenium provides a useful illustration of the complexities of
reaching agreement on optimal population levels. The population
as a whole shows a “U” shaped curve for functionality, where low
and high selenium levels both increase genomic instability. Optimal
levels of selenium may protect against DNA or chromosome break-
age, chromosome gain or loss, damage to mtDNA, and detrimental
effects on telomere length and function. One example of how sele-
nium can function is by protecting genome stability through a
BRCA1-dependent mechanism [338] . When cells are supplemented
with selenium, there is reduced DNA breakage and the number of
aneuploid cells is reduced when compared to control cells. Unfor-
tunately, these optima differ among individuals and according to

L.R. Ferguson et al. / Seminars in Cancer Biology 35 (2015) S5–S24 S13
Table 1
Cross-validation
for priority targets against genomic instability.
Other cancer hallmarks Priority targets for genomic instability
Prevent DNA
damageEnhance DNA
repairTarget deficient
DNA
repairBlock
centrosomeclusteringInhibit
telomerase
Sustained proliferative signaling 0 0 0 0 +
[432,433]
Tumor-promoting inflammation −
[434–436]−
[434–436]−
[434–436]+
[437,438]+
[439,440]
Evasion of anti-growth signaling +
[441,442]+
[441–443]+
[444]+
[445,446]+
[447]
Resistance to apoptosis ±
[448]±
[448]±
[448]0 +
[449]
Replicative immortality +
[450,451]0 0 +
[452]n/a – same
target
Dysregulated
metabolism ±
[453]±
[453]±
[453]+
[454]+
[455,456]
Immune system invasion +
[352]+
[352]+
[352]0 0
Angiogenesis −
[457–461]−
[457–461]0 +
[462]+
[463–465]
Tissue invasion and metastasis +
[466,467]+
[466,467]+
[466,467]+
[468,469]+
[470–474]
Tumor microenvironment + +
[475]+
[476]+
[437]+
[477]
Priority targets that were not only relevant for genomic instability, but also relevant for other aspects of cancer’s biology (i.e., anticarcinogenic) were noted as having
complementary
effects (+). Those targets that were found to have procarcinogenic actions were noted as having contrary effects (−). In instances where reports on relevant
actions
in other aspects of cancer biology were mixed (i.e., reports showing both procarcinogenic potential and anticarcinogenic potential), the designation (±) was used.
Finally, we indicate (0) in instances where no literature support was found to document the relevance of a target in a particular aspect of cancer’s biology.
the form of selenium in the diet [336,339] . Various genetic poly-
morphisms have been shown to affect the uptake and utilization of
selenium among individuals.
4.4. Other dietary factors
Diets high in plant-based foods have been associated with
decreased cancer risks [340] . Lim and Song [341] discuss how cer-
tain dietary components, common in plant foods, can alter DNA
methylation levels, affecting genome stability and transcription
of tumor suppressors and oncogenes. Much of the available data
exist for folate, since this is a well-recognized nutritional factor
in one-carbon metabolism, acting to supply the methyl units for
DNA methylation. This has been shown to be especially important
in the maternal diet as a lack of folate can lead to hypomethyla-
tion of some genes in their offspring. One well studied example
of this is the Agouti mutation in mice, which affects coat color,
as well as making the offspring more susceptible to cancer and
obesity [342,343] . The Agouti mutation has been shown to be a
lack of methylation at the promoter of the Agouti gene [344] .
Pregnant mice that were fed bisphenol A had offspring that exhib-
ited hypomethylation of the Agouti gene but, by feeding them
dietary supplements of folate, methylation status was rescued
[345] . This data demonstrates the importance of the maternal diet
during development to outcomes even later in life for their off-
spring. In other systems, folate supplements during pregnancy have
also been shown to be protective against neuroectodermal brain
tumors [346] .
Alcohol, various polyphenols, phytoestrogens and lycopene
also have demonstrable effects. Indeed, there is compelling evi-
dence that a considerable range of plant polyphenols may stabilize
genomic DNA, through various processes, including effects on DNA
methylation [347] . Duthie [340] suggested that the evidence is par-
ticularly strong for berry phytochemicals, specifically anthocyanins
(a class of flavonoids), which modulate various biomarkers of DNA
damage and carcinogenesis, in both in vitro and in vivo animal
studies. However, evidence for cancer preventive effects in human
studies is currently weak.Accumulating evidence shows that genome integrity is highly
sensitive to nutrient status, and that optimal levels may differ
among individuals. Many investigations to date are limited by
considering only the effects of single nutrients, without looking
at the potential interactions among these, and of nutrients with
toxicants in the diet. Many currently available studies also suffer
from a failure to consider the effects of genetic susceptibility. In
subsequent work, it will be critical to consider modifying and inter-
active effects with deficiencies in nutrients required for effective
DNA damage response, and DNA repair.
Hyperglycemia and a high fat diet have been shown to be pos-
itively correlated with an increased risk of cancers, such as breast
and endometrial cancers. Hyperglycemic diets have been shown
to increase the levels of many signaling molecules [348] . Rats that
were fed high fat diets had an increased risk of breast cancer in
their progeny [349] . These results were similar to those seen when
mice are treated with estradiol. In addition to an increased risk
of developing cancer, hyperglycemia, diabetes, and obesity have
been linked to a worse prognosis. Advanced breast cancer patients
with high blood glucose levels had a lower rate of survival than
those with normal sugar levels [350] and obese adolescents with
pediatric acute lymphoblastic leukemia had a higher likelihood of
relapse than a normal cohort [351] .
5. Complementary effects on the enabling characteristics
of cancer while targeting genomic instability
Treatments that are less cytotoxic but can also act on multiple
different cancers and pathways that contribute to cancer forma-
tion is an important goal (Table 1). Work focusing on the effects
of vitamin D, vitamin B, selenium, carotenoids, PARP inhibitors,
resveratrol, and isothiocyanates has shown promising results
(Table 2).
During cancer formation, genetic instability interacts with many
other pathways that are integral to the survival and proliferation of
the cancer cells, such as inflammation, immune system evasion, or
apoptosis resistance. Preventing and/or treating genomic instabil-
ity can cause tumor cells to lose: (1) their replicative immortality;

S14 L.R. Ferguson et al. / Seminars in Cancer Biology 35 (2015) S5–S24
Table 2
Cross-validation
for priority approaches against genomic instability.
Other cancer hallmarks Priority approaches for genomic instability
Vitamin D Vitamin B Selenium Carotenoids PARP inhibitor Resveratrol Isothiocyanates
Sustained proliferative signaling +
[478]±
[259,426]±
[357,479]+
[480–482]+
[358,483,484]+
[354,355]+
[485,486]
Tumor-promoting inflammation +
[487,488]+
[393,394]−
[395–397]+
[398,399]+
[400,401]+
[402,489]+
[403,404]
Evasion of anti-growth signaling +
[490–492]0 +
[493,494]±
[366,495]+
[358]+
[496,497]+
[360,361,364]
Resistance to apoptosis +
[380]0 +
[378]+
[377]+
[498]+
[382]+
[379]
Replicative immortality +
[369,370,374]0 +
[182]+
[369,372,373]+
[368,499]+
[375,376]+
[364,371]
Dysregulated metabolism 0 0 0 +
[500]0 +
[268,501–508]+
[364,383,509]
Immune system invasion +
[406]0 0 +
[405]0 +
[407,510–513]0
Angiogenesis +
[514]±
[408–410,412,414]±
[411,413,415,417]+
[416]+
[418]+
[515] , [516]+
[419]
Tissue invasion and metastasis +
[517]+
[425,426]+
[351,427,428]+
[429,431,518]+
[484]+
[519]+
[363,420,430]
Tumor microenvironment +
[520]0 +
[395]+
[521]+
[476]+
[522]+
[523]
Approaches that are not only relevant for genomic instability, but also relevant for other aspects of cancer’s biology were noted as having complementary effects (+). Those
approaches
that were found to have procarcinogenic actions were noted as having contrary effects (−). In instances where reports on relevant actions in other aspects of
cancer
biology were mixed, the designation (±) was used. Finally, we indicate (0) in instances where no literature support was found to document the relevance of an
approach in a particular aspect of cancer’s biology.
(2) their ability to evade the immune system; and/or, (3) their abil-
ity to evade antigrowth signaling (Table 1). For example, in MSI-H
CRCs, the immune response can be evaded by mutations in the
neoantigens caused by defects in DNA repair machinery [352] . In
this case, by preventing genomic instability, it could be possible to
minimize the mutations that lead to immune system evasion.
Sustained proliferative signaling is required for cancer cell
growth and vitamin D and resveratrol are able to inhibit this
signaling [353–355] . There are no known interactions for the other
compounds, except selenium, which inhibits growth in some cases
while inducing it in others [356,357] . In a related characteristic of
cancer cells, evasion of antigrowth signaling, all compounds are
able to inhibit growth except vitamin B, which shows no relation-
ship, and carotenoids, which have mixed results [255,358–366] .
Similarly, all of the compounds are able to prevent replicative
immortality by impairing telomerase activity or inducing senes-
cence [364,367–376] and increasing cell death except for vitamin
B, which has no known relationship to apoptosis [377–382] . Dys-
regulated metabolism also contributes to cancer cell growth and all
of the compounds had complementary effects on metabolic path-
ways except vitamin D and PARP inhibitors, which have no known
link [268,338,364,383–386] .
Cancer cells use inflammatory agents in the microenviron-
ment to promote their proliferation and survival. One important
inflammatory signaling molecule is nuclear factor kappa-light-
chain-enhancer of activated B cells (NF/H9260B), a transcription factor
whose aberrant regulation has been linked to cancer [387,388] .
Inflammatory signaling, including that of NF/H9260B, can be affected
by the diet. It has been shown that compounds found in crucifer-
ous vegetables can reduce NF/H9260B signaling in pancreatic cancer cells
[389] . Polyphenols have also been shown to suppress transcription
factors upstream of NF/H9260B [390] . Inflammation, in general, is also
inhibited by all of the compounds, except vitamin B [354,391–404] ,
while only vitamin D, carotenoids, and resveratrol prevent the
tumor cells from evading the immune system [405–407] .
Tumors need specialized environments to grow and thrive in.
As the tumor grows, new blood vessels need to form to providethe cells with oxygen and all of the treatment options selected
are able to inhibit angiogenesis, except vitamin B and selenium,
both of which show mixed results [408–419] . Interestingly though,
in regards to other factors that contribute to the tumor microen-
vironment, all compounds are able to provide therapeutic value
[395,420–424] .
Effective treatments to prevent tissue invasion and metastasis
are important as these stages of cancer are associated with poor
outcomes. It has been found that all of the targeted treatments
are able to inhibit/prevent these pathways except for resver-
atrol and PARP inhibitors, which have no known relationship
[363,420,421,425–431] . Further work and clinical trials will have
to be performed to understand the full benefit of these compounds
in regards to cancer treatment.
6. Conclusion
Genomic instability plays a critical role in cancer initiation and
progression. The fidelity of the genome is protected at every stage
of the cell cycle. In cancer, the presence of aneuploid or tetraploid
cells indicates the failure of one or many of these safety nets. The
resultant genomic heterogeneity may offer the cancer “tissue” a
selection advantage against standard of care and emerging thera-
pies. Understanding these safety nets, and how they are bypassed
in cancer cells, may highlight new and more specific mechanisms
for cancer prevention or therapeutic attack.
The therapeutic targeting of genomic instability may dampen
other enabling characteristic of tumors cells, such as replicative
immortality, evasion of antigrowth signaling, and tumor promot-
ing inflammation. To this end, vitamins, minerals, and antioxidants,
such as vitamin D, vitamin B, selenium, and carotenoids, as well as
nutraceuticals, such as resveratrol, have shown remarkable plas-
ticity in elucidating antitumor responses. In addition to alleviating
genomic instability, these compounds are known to inhibit pro-
liferative signaling [353–355] , attenuate oncogenic metabolism
[268,338,364,383–386] , and block inflammation [354,391–404] .

L.R. Ferguson et al. / Seminars in Cancer Biology 35 (2015) S5–S24 S15
However, caution must be applied as certain antioxidants, such
/H9252 carotene, may promote carcinogenic processes in a dose- and
context-dependent manner.
While mortality rates associated with heart disease and stroke
have been reduced ∼70% in the last 50 years, mortality rates asso-
ciated with cancer remain largely unchanged. This is likely due to
our ability to manage the risk factors for heart disease and stroke
and our inability to detect and prevent genomic instability and can-
cer. However, diet and lifestyle are two of our great hopes in this
area. In particular, antioxidants are critical for the prevention of
DNA damage that enables cancer initiation and growth. Growing
evidence shows that vitamins, minerals, and other dietary factors
have profound and protective effects against cancer cells, whether
they are grown in the lab, in animals, or studied in human popu-
lations. A better understanding of the effects and synergy of these
dietary factors in the prevention and treatment of genomic insta-
bility is critical to the future reduction of mortality associated with
cancer.
Author’s contributions
The following authors composed the indicated sections: HC,
CAM, AKM (Mechanisms underlying genomic instability), PTT (epi-
genetic mechanisms), SD and DS (Mitochondrial genetics), GD, ESY,
SR (DNA repair pathways), ARC and LRF (cancer prevention), SP and
MM (targeting with RNAi). AA, AA, SSA, KA, ASA, DB, AB, CSB, SC,
MC, MRC, HJ, GG, DH, BH, WNK, SM, EN, XY and KH (cross vali-
dation in Tables 1 and 2). LRF, MC, and CAM integrated and edited
the sections.
Conflict of interest statement
The following authors declare that there are no conflicts of
interest: LRF, HC, ARC, MC, GD, SD, MM, AKM, AA, AA, SSA, KA,
ASA, DB, AB, CSB, SC, MRC, HF, GG, DH, WGH, WNK, SIM, EN, XY,
KH, VRP, PR, SR, RS, DS, PTT, and CAM. ESY has material transfer
agreements with AbbVie, Eli Lilly, Bristol Myers Squibb, and Cerion
NRx.
Acknowledgments
The following funding agencies supported the research: Ital-
ian Ministry of University and Research and the University of
Florence (A. Amedia); Terry Fox Foundation, UAEU Program for
Advanced Research, Al-Jalila Foundation and Zayed Center for
Health Sciences (A. Amin); Italia Ministry of Education, University
and Research- Miur, PRIN 20125S38FA 002 (K. Aquilano); Uni-
versity of Glasgow, Beatson Oncology Centre Fund, CRUK grant
C301/A14762 (A. Bilsland and W.N. Keith); Child and Family
Research Institute PhD studentship (H. Chen); Michael Cuccione
childhood cancer research foundation fellowship (M. Connell);
Ovarian Prostate Cancer Research Trust Laboratory (S. Chen); Uni-
versity of Oslo (A.R. Collins); Italian Association for Cancer Research
AIRC IG 10636 (M.R. Ciriolo); Elsa U Pardee Foundation (S. Das-
gupta); Auckland Cancer Society Research Centre, University of
Auckland (L. Ferguson and V. Parslow); National Institutes of
Health (H.D. Halicka); Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan, No. 24590493 (K. Honoki); CIHR, in
partnership with the Avon Foundation for Women, OBC 134038
(C.A. Maxwell); NIH/NCI RO1CA172380, DOD W81WH1210545,
DOD W81XWH12PCRPTIA, NIH/NCI P30CA006973, NIH/NCI RCI
RFA0D09009, NIH/NCI 5R01 CA132996-03 (A. Meeker); Italian Min-
istry of University and University of Italy (E. Niccolai); CIHR MOP
64308 (S. Prakash); Department of Biology, University of Rochester
(S. Rezazadeh); Patrick C. Walsh Prostate Cancer Research Fund, theDepartment of Defense (W81XWH-11-1-0272 and W81XWH-13-
1-0182), Commonwealth Foundation, Uniting Against Lung Cancer,
a Sidney Kimmel Translational Scholar award (SKF-13-021), an
ACS Scholar award (122688-RSG-12-196-01-TBG) and the NIH
(1R01CA166348) (P.T. Tran); Susan G. Komen Foundation, AACR,
Gabrielle’s Angel Foundation, Eli Lilly, and Bristol Myers Squibb (E.S.
Yang).
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