Genetic Effect of ERCC1 Codon 118 Polymorphism and Confounding Factors

Abstract

To the Editor: Viguier et al. (1) reported that the ERCC1 codon 118 polymorphism has a predictive value in colorectal cancer patients treated with platinum combination chemotherapy. However, there are contradictory reports on the effects of this polymorphism on the survival of cancer patients. Although Viguier et al. suggested that cancer patients carrying a variant genotype survived for a longer period, we found that the wild genotype favored a better survival (2). On the other hand, there are some reports showing no association between the ERCC1 codon 118 polymorphism and survival (3, 4). These inconsistencies make the prognostic or predictive relevance of this marker unsuitable for clinical practice. Similar observations were also reported for other polymorphisms of the MDR1 gene, such as C3435T and G2877T, where contradictory genetic effects were also noted.There is increasing evidence suggesting that environmental factors modulate the genetic effect of these polymorphisms. For example, a case-control study showed the presence of a gene-smoking interaction with the ERCC1 polymorphism (5). This interaction was also observed in our recent study (6). Prognostic significance was observed only in those patients with non -small cell lung cancer who were heavy smokers (z50 pack-years; P = 0.03, using the log-rank test).The apparent conflicting information regarding the ERCC1 codon 118 polymorphism might be explained by the coexistence of major confounding factors, such as ethnicity, environmental factors (smoking or diet), the number of patients enrolled, or some linkage to other polymorphisms, which might mask the relatively minor gene effect associated with a single genetic polymorphism. Moreover, there was no direct or clear evidence for the functional significance of the ERCC1 codon 118 polymorphism.In addition to a functional study, further research will be needed to verify which confounding factors have the most significant results.

ERCC1 codon 118 polymorphism is a useful prognostic marker in patients with pancreatic cancer treated with platinum-based chemotherapy

“…Which genotype is associated with higher mRNA levels and/or better prognosis with the patients that received platinum compound is still a controversial topic (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Some reported environmental factors such as smoking interaction might modulate and mask the genetic effect of polymorphism (35)(36)(37).…”

<em>ERCC1</em> and <em>XRCC1</em> but not <em>XPA</em> single nucleotide polymorphisms correlate with response to chemotherapy in endometrial carcinoma

“…Similarly, Viguier et al29 showed that the expressions of ERCC1 protein were changed when ERCC1 codon 118 C (rs11615) was transferred to T, reducing the ability of DNA repair and weakening the impact of ERCC1 on DNA damage caused by platinum drugs. Besides, the data also indicated that the patients with ERCC1 codon 118 T/T genotype were more sensitive to platinum-based chemotherapy than the patients with C/T and C/C genotype 29,30. All the results revealed that the patients with wild-type C/C were more sensitive to chemotherapeutic drugs than heterozygous C/T and mutant T/T in ERCC1 118.…”

Role of Pharmacogenetics in Gastrointestinal Cancer

“…In this retrospective study including 91 patients, response rate was 61.9%, 42.3%, and 21.4% in T/T, C/T, and C/C groups, respectively (P= 0.018). However, the results of the www.intechopen.com studies regarding the ERCC1 codon 118 polymorphism are somewhat contradictory, likely due to a variety of factors such as ethnicity, environment (smoking or diet), the number of patients enrolled and/or linkage to other polymorphisms (Ryu, 2006). A SNP in codon 751 of the ERCC2 gene which leads to glutamine instead of lysine, was associated with a reduced response rate (Park et al, 2001, Stoehlmacher et al, 2004.…”