Biology Reference
In-Depth Information
cancer treated with oxaliplatin/5-fluorouracil chemo-
therapy found no association between the Arg399Gln
polymorphism and prognosis.
111
Among other polymorphisms of XRCC1, Arg280His
polymorphism appears to impair cellular BER/SSBR
activity
112
and a polymorphism at locus 1196 carrying
the AA genotype may be associated with reduced risk
of recurrence or death in patients with primary invasive
breast cancer treated with adjuvant doxorubicin/cyclo-
phosphamide or cyclophosphamide/methotrexate/
5-fluorouracil chemotherapy.
113
In patients with pancre-
atic cancer the Arg194Trp polymorphismwas associated
with a significantly reduced survival in the homozygous
state.
95
Increased risk of diffuse large B-cell lymphoma
(DLBCL) has been observed in carriers of variant geno-
types of XRCC1 194. However, in patients treated
with R-CHOP chemotherapy no association was
seen between these variant genotypes and therapy
outcome.
114
Another study in patients with advanced
gastric cancer treated with a taxane and cisplatin
demonstrated that the XRCC1 194 CT genotype was
associated with poorer overall survival than XRCC1
194 CC homozygotes.
115
In patients with metastatic
breast cancer enrolled into one of five prospective clin-
ical trials of high-dose chemotherapy and autologous
stem-cell transplantation, Arg399Gln polymorphism
demonstrated increased breast cancer-free survival and
progression-free survival.
116
polymorphisms did not show an association with
survival. However, in the subgroup of patients treated
with radiotherapy a significant association with median
survival was observed with XRCC1 haplotype. In this
subgroup of patients median survival was 11.8 years
with the R399Q AA/R194WCC haplotype and 12.2 years
for patients with the R399Q AG/R194W CC haplotype,
compared with 6.7 years and 6.2 years for the R399Q
AG/R194W CT and R399Q GG/R194W CT haplotypes,
respectively.
117
In combination, but not separately, XRCC1 and
ERCC1 polymorphisms (XRCC1 codon 399A/G and
ERCC1 codon 118C/T) are significantly associated
with disease control rate and median survival time in
patients with metastatic colorectal cancer treated with
oxaliplatin-based chemotherapy.
118
Although it is too early to draw firm conclusions, and
some individual studies have produced conflicting
results, the preponderance of evidence suggests that
BER gene SNPs, particularly those within XRCC1 and
APE1 protein expression, may be important predictive
factors in cancer.
NUCLEOTIDE EXCISION REPAIR
(
TABLE 12.2
)
Platinum-based chemotherapy has been used for the
treatment of a wide variety of solid tumors including
lung, head and neck, ovarian, cervical, and testicular
cancer for over three decades.
119
Cisplatin interacts
with DNA to form predominantly intrastrand crosslink
DNA adducts that trigger a series of intracellular events
that ultimately result in cell death. DNA intrastrand
crosslinks can distort the DNA double helix thereby
interfering with DNA base pairing, replication, and
transcription and are repaired by the nucleotide excision
repair (NER) pathway in mammalian cells.
120,121
NER is
a complex molecular mechanism involving several
proteins with distinct functions and interacting partners.
Although detailed discussion is beyond the scope of this
chapter a brief summary of NER will be provided to aid
discussion of clinical studies. Two NER sub-pathways
have been described: the transcription-coupled nucleo-
tide excision repair (TCR) pathway that targets lesions
specifically in the transcribed strand of expressed genes
and the global genome nucleotide excision repair (GGR)
pathway that deals with lesions in the rest of the
genome. The essential steps of GGR are DNA damage
recognition by XPC-HR23B complex, lesion demarcation
and verification by TFIIH complex (cdk7,cyclin H,
MAT1, XPB, XPD, p34, p44, p52 and p62), assembly of
a pre-incision complex (RPA, XPA and XPG), DNA
opening by XPB and XPD helicases, dual incision by
ERCC1-XPF and XPG endonucleases usually a few bases
Other BER Factors
Polymorphisms in DNA Pol
b
(A165G and T2133C)
were strongly associated with overall survival in a study
of patients with pancreatic cancer.
95
The median
survival time was 35.7 months for patients carrying at
least one of the two homozygous variant DNA Pol
b
GG or CC genotypes, compared with 14.8 months
for those carrying the AA/AG or TT/TC genotypes.
The same study found a weak but significant association
between the 8-oxo-guanine DNA glycosylase (hOGG1)
G2657A polymorphism and overall survival.
95
A study
of 210 patients with esophageal cancer examined the
impact of BER polymorphisms (hOGG1 Ser326Cys,
APE1 Asp148Glu, PARP1 Val762Ala and XRCC1
Gln399Arg) on clinical outcomes.
106
Possession of the
variant (Gln) alleles at codon 399 of XRCC1 was associ-
ated with a significantly increased risk of death
compared with the wild-type (Arg) genotype. Among
NER, BER, and DSB repair gene SNPs only XRCC1
Arg399Gln was significantly associated with patholog-
ical complete response in that study.
106
A study of patients with castrate-resistant prostate
cancer found that the XRCC1 R399Q (1301G
A), ERCC1
>
N118N (500C
T), XPD K751Q (2282A
C), XRCC1
>
>
R194W (685C
T),
and PARP1 V762A (2446T
C)
>
>
