Genetic effect of ERCC1 codon 118 polymorphism and confounding factors.

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.