Biology Reference
In-Depth Information
CHAPTER
12
Personalized Cancer Medicine: DNA Repair
Alterations Are Promising Predictive
Bi
omarkers in Canc
er
Christina Perry, Rebeka Sultana, Srinivasan Madhusudan
University of Nottingham, UK
INTRODUCTION
DNA single and double-strand breaks, DNA cross-
linking or mismatch base pairing. To counteract this
insult to genomic integrity, highly conserved DNA
damage sensor mechanisms have evolved in mamma-
lian cells that initiate cellular responses such as: (a)
induction of apoptosis to remove extensively damaged
cells; (b) initiation of DNA damage checkpoints and
interruption of cell cycle progression to allow time
for cellular repair; (c) transcriptional response that
promote cell survival; (d) damage tolerance; and (e)
activation of DNA repair pathways to remove DNA
damage. These complex mammalian responses there-
fore determine whether a cancer cell survives cytotoxic
insult or whether programmed cell death/apoptosis
occurs. For example, DNA repair mechanisms that
operate in cancer cells to rectify DNA damaging
lesions induced by cytotoxic agents, contribute to ther-
apeutic resistance. On the other hand, suboptimal
DNA repair in normal tissue may negatively impact
on normal tissue tolerance (
Figure 12.1
). Given the
broad range of DNA-damaging lesions induced by
cytotoxic agents, it is perhaps not surprising that
multiple DNA repair pathways have evolved within
cells to deal with DNA damage (
Figure 12.2
). These
pathways include: (a) repair of base damage and
single-strand breaks by base excision repair (BER);
(b) repair of bulky DNA adducts by nucleotide exci-
sion repair (NER); (c) direct repair of alkyl adducts
by methylguanine methyl transferase (MGMT); (d)
repair of mismatches and insertion/deletion loops by
DNA mismatch repair (MMR); and (e) repair of
double-strand breaks by homologous recombination
(HR), non-homologous end joining (NHEJ) and
single-strand annealing (SSA).
7
e
20
The overall prognosis for patients with advanced
cancer is poor. Although systemic chemotherapy and
radiotherapy remain important treatment options, their
narrow therapeutic index, wherein slight alterations in
dosing lead to dramatic changes in responses (poten-
tially sub-therapeutic or unacceptable toxicity) signifi-
cantly limit their application. A common clinical
observation is that some cancer patients get an excellent
response to a treatment with minimal toxicity, whereas
others develop unpredictable and even life-threatening
side effects despite very little antitumor activity. The
mechanisms for interindividual variability in drug
response are complex and influenced by background
genetic (germ line) factors
1,2
as well as tumor specific
(somatic) factors.
2
e
6
Predictive biomarkers are measures
that help determine which patients do well with partic-
ular types of treatment whereas prognostic biomarkers
are measurements available at the time of diagnosis or
surgery that are associated with recurrence, death or
other clinical outcomes and determine how patients
will fare irrespective of treatment. Clinical utility of
a predictive biomarker is critically dependent on its reli-
ability, ready availability, and easy detectability by
reasonably acceptable laboratory technology. The role
of predictive biomarkers in solid tumor therapeutics is
rapidly advancing and guiding the emerging field of
personalized cancer medicine.
The cytotoxicity of chemotherapy and radiation is
predominantly dictated by their ability to induce
DNA damage in cancer cells. Cytotoxic agents can
cause a broad range of DNA damaging lesions
including oxidation, alkylation of bases, depurination,
