Biology Reference
In-Depth Information
DOUBLE-STRAND BREAK REPAIR
(
TABLE 12.4
)
as the BRCA2 gene). RAD52 is required not only in HR
but also for SSA.
Chemotherapeutic agents (such as bleomycin, etopo-
side) and ionizing radiation induce double-strand
breaks (DSBs). In addition, when a replication fork
encounters an SSB in the DNA template DSBs are gener-
ated. DSBs are sensed by the the MRE11
e
RAD50
e
NBS1
complex (MRN) and Ku proteins. The early response
phosphoinositide-3-kinase-related protein kinases,
such as ataxia telangiectasia-mutated kinase (ATM)
and ATM- and Rad3-related kinase (ATR), get activated
and phosphorylate a wide range of substrates. Regu-
lator and mediator proteins (e.g. BRCA1 and p53) coor-
dinate DNA repair, cell cycle, and apoptotic responses.
The DSB DNA repair process includes non-homologous
end joining (NHEJ), homologous recombination (HR),
and single-strand annealing (SSA) pathways. The
molecular mechanisms of these pathways are complex.
Outside the S-phase of the cell cycle, NHEJ is the
primary repair pathway whereas HR is the central
pathway for the DSBs generated during S-phase.
NHEJ components include the Ku70
e
80 heterodimer,
DNA-dependent protein kinase catalytic subunit
(DNA-PKcs), and the XRCC4
e
DNA ligase IV hetero-
dimer. The components of HR include RAD51 and its
paralogs (RAD51B-D, XRCC2, and XRCC3), RAD52,
RAD54, and BRCA2. Fanconi anemia proteins may
also have a role in HR (FANCD1 was recently identified
BRCA1 and BRCA2
BRCA1 and BRCA2 proteins are essential for HR.
215
BRCA-mutated tumors are therefore less able to repair
DNA double-strand breaks by HR and are very sensitive
to inhibition of DNA single-strand break repair which
can be achieved by the inhibition of the enzyme
poly(ADP)ribose polymerase. This is the principle of
synthetic lethality, whereby mutation in either of two
genes alone has no effect, but mutations in both lead
to cell death. In the context of cancer treatment this
refers to the mutational loss of one gene and the inhibi-
tion of the second gene, resulting in a treatment that is
selectively lethal to the tumor cell but spares normal
cells.
216
A large body of evidence confirms that cancers asso-
ciated with BRCA1 mutations have increased chemo-
sensitivity
217
and are promising predictive biomarkers
in breast cancer (reviewed in
218
). Retrospective studies
in breast cancer patients have shown that tumors arising
in BRCA1 mutation carriers respond better to chemo-
therapy or radiotherapy compared to breast cancer in
non-carrier patients. However, one study has shown
no difference in the relative risk reduction associated
with adjuvant chemotherapy between non-carriers and
carriers of either BRCA1 or BRCA2 mutations. A lower
TABLE 12.4 Double-Strand Break Repair as a Predictive Marker in Human Cancers
Cancer type
Treatment
Repair enzyme
Results
Reference
Breast
Cx, TAM
BRCA1 and 2
No difference in relative risk reduction between carriers and
non-carriers. Benefit of TAM only seen in non-mutation carriers
219
Ovary
Cx
BRCA
Carriers had higher tumor RR
220
Bladder
Cisplatin-based
BRCA1
response with low/intermediate mRNA levels
221
[
NSCLC
Docetaxel-based
BRCA1
High mRNA expression associated with
PFS
222
[
NSCLC
Cisplatin-based
BRCA1
High expression associated with
[
RR and survival if
223
antitubulin agent included
MM
Autologous BMT
XRCC3
Carriers of variant T allele Thr241Met have
time to treatment
failure compared to homozygous wild type carriers
[
169
NSCLC
Cisplatin/gemcitabine
XRCC3
[
survival with 241 Met/Met versus Thr/Met or Thr/Thr
225
รพ
Breast
HD
autologous SCT
XRCC1, XRCC3
[
DFS and PFS with XRCC1 Arg399Gln and XRCC3 Thr241Met
polymorphisms
116
NSCLC
Daunorubicin
ATM
Polymorphisms not associated with resistance
98
Rectum
RT
Ku
Expression pattern correlates with radiosensitivity and DFS
228
Rectum
RT
Ku70
Expression correlates with radiosensitivity
229
Abbreviations: NSCLC, non-small-cell lung cancer; MM, multiple myeloma; RT, radiotherapy; Cx, chemotherapy; BMT, bone marrow transplant; TAM, tamoxifen;
HD, high-dose chemotherapy; SCT, stem cell transplant; RR, response rate; DFS, disease-free survival; PFS, progression-free survival, OS, overall survival;
[
increased;
Y
decreased.
