Genetic Variation in Genes for the Xenobiotic-Metabolizing Enzymes CYP1A1, EPHX1, GSTM1, GSTT1, and GSTP1 and Susceptibility to Colorectal Cancer in Lynch Syndrome

Lynch syndrome, commonly known as hereditary nonpolyposis colorectal cancer, is caused by an inherited pathogenic germline mutation in one of the DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6, or PMS2 (1). The mutations have an autosomal dominant pattern of inheritance and result in deficient MMR, predisposing individuals with these mutations to early onset of cancers of the colon, the endometrium, and, less frequently, the stomach, ovaries, small intestine, biliary and uroepithelial tracts, skin, and brain (2).

Wide variation in disease expression both within and between families, particularly in age at onset (3), has been observed among individuals with Lynch syndrome, suggesting that other genetic and environmental factors may modify the effect of the inherited single-gene mutations. Evidence for the role of other genetic factors may also lie in the fact that 25% to 30% of colorectal cancer cases that occur annually are considered familial (4). Of these cases, about 5% to 14% are attributable to known inherited deleterious mutations (5). The remaining familial component of incident colorectal cancers is likely due to the effect of variation in common low-penetrance genes or “modifier” genes (4). Therefore, it is of interest to examine low-penetrance genes as potential modifiers of risk for cancer onset in individuals with Lynch syndrome.

Cancer risk resulting from human exposure to exogenous chemicals (xenobiotics), like polycyclic aromatic hydrocarbons (PAH), which are ubiquitous environmental, dietary, and tobacco carcinogens, may vary according to the ability to clear the xenobiotics from the body. Polymorphisms in the genes that encode enzymes involved in the metabolism of PAHs (xenobiotic-metabolizing enzymes), such as the cytochrome P450 group (CYP), the microsomal epoxide hydrolase group (EPHX), and the glutathione S-transferase group (GST), result in varying activity levels of these enzymes, which can then influence xenobiotic clearance. The metabolism of PAHs involves both activation (phase I) and detoxification (phase II) reactions by these enzymes. During activation, reactive intermediates are formed that can bind to DNA and result in adducts that cause mutations if not repaired, thereby initiating carcinogenesis (6). It is likely that the expression and activity levels of the xenobiotic-metabolizing enzymes determine the relative level of activation and detoxification of carcinogens. These levels are important because increased levels of activation, decreased detoxification, or both may increase cancer risk. Therefore, we hypothesize that the variation in enzyme activity due to polymorphisms in metabolic genes may explain some of the differences seen in disease risk for colorectal cancer in individuals with Lynch syndrome. We identified several candidate metabolic genes that display variation in activity levels of their expressed enzymes and selected common polymorphisms in these genes (with a minor allele frequency >5%) to test our hypothesis.

The CYP group of enzymes is involved in the oxidation of many xenobiotics. CYP1A1 encodes the principal enzyme that metabolizes PAHs. In the phase I reaction, PAHs are metabolically activated, which may generate highly reactive mutagenic metabolites. Two common single nucleotide polymorphisms (SNP) in CYP1A1, a noncoding Msp1 polymorphism in the 3′-untranslated region (nucleotide T to C) and an exon 7 polymorphism Ile462Val, (nucleotide A to G), which are in linkage disequilibrium (7), have been commonly examined for cancer risk. The functional significance of the Msp1 polymorphism is uncertain, but the I462V polymorphism results in higher enzyme activity compared with the homozygous wild-type genotype and the enzyme is expressed in the colon (8). de Jong et al. (9) found little evidence that polymorphic variants of CYP1A1 influence the risk for sporadic colorectal cancer; however, Slattery et al. (10) have suggested that these variant alleles increase the risk for sporadic colorectal cancer among smokers. Similarly, Talseth et al. (11) found an association of the CYP1A1 Msp1 variant with an increased colorectal cancer risk in Lynch syndrome.

EPHX1 plays an important role in both activation and detoxification of PAHs. Two EPHX1 polymorphisms, Tyr113His and His139Arg, result in reduced and increased enzyme activity, respectively. Gsur et al. (12) showed that genetically reduced microsomal epoxide hydrolase activity may be protective against lung cancer, but these same EPHX1 polymorphisms have not been implicated in risk for sporadic colorectal cancer (13, 14). We were unable to find any prior studies evaluating their role in the risk for colorectal cancer in individuals with Lynch syndrome.

GSTs are a superfamily of proteins that perform the phase II detoxification reactions of PAHs and other xenobiotics. GSTs catalyze the conjugation of reduced glutathione to a variety of potentially carcinogenic electrophilic and hydrophobic compounds. This detoxification reaction inactivates the compounds and renders them water-soluble, so they can be readily excreted through urine or bile (15). GSTs include GSTT1, GSTM1, and GSTP1. Null alleles exist as a common polymorphism for the GSTT1 and GSTM1 genes. Total or partial deletion of these genes results in no enzyme being produced (16, 17). An overall increased risk for sporadic colorectal cancer has been described for the GSTT1-null allele, in a report by de Jong et al. based on 11 studies (9), but their report was inconclusive for the association, or lack thereof, between colorectal cancer and GSTM1 or GSTP1. In a recent study examining Lynch syndrome individuals, Felix et al. (18) reported that males with the GSTM1- and GSTT1-null genotype were at a 3-fold increased risk for an earlier age at onset of colorectal cancer compared with those with no deletion of the genes. Another study reported a 6-year shift in the median age at onset among 150 MLH1 mutation carriers with an earlier onset age associated with the null alleles of both GSTM1 and GSTT1 (19). However, two earlier studies found no influence on age at colorectal cancer onset for either GSTM1 (20, 21) or GSTT1 (21) polymorphism. In our study, we report on some of the participants previously examined by Jones et al. (20), but our study includes substantially more subjects.

Although many of the genes encoding xenobiotic-metabolizing enzymes have been examined for their influence on the age at onset for colorectal cancer in Lynch syndrome, the results have not been consistent. This inconsistency might be due to the limited sample size or heterogeneous populations used in previous studies. A major strength of this study is the larger, predominantly White study population, consisting of a cohort of known carriers of pathogenic MMR gene mutations from many different families. Therefore, we are reporting on a population that is a unique resource for examining possible variation in disease expression associated with metabolic genes in this high-risk group. Specifically, we assessed the association between common polymorphisms in genes involved in xenobiotic-metabolism—CYP1A1 (rs4646903:g.6235T>C and rs1048903:c.1384A>G p.I462V), EPHX1 (rs1051740:c.339T>C p.Y113H and rs2234922:c.418A>G p.H139R), GSTM1 (deletion), GSTT1 (deletion), and GSTP1 (rs1695:c.330A>G p.I105V and rs1138272:c.343C>T p.A114V)—and age at onset of colorectal cancer to determine if genetic variation in any of these candidate metabolic genes modifies the age at onset of colorectal cancer in individuals with Lynch syndrome.

The study population, which consisted of a cohort of individuals with Lynch syndrome, has been described previously (22, 23). Briefly, most Lynch syndrome probands were recruited from The University of Texas M. D. Anderson Cancer Center gastrointestinal and other clinics from September 1994 to July 2007. Through the probands (n = 119), other first-degree relatives (n = 74) and more distantly related family members (n = 64) carrying the inherited mutation were recruited to the study. Study participants were from 130 families. The size of the families varied between 1 and 10 members of which 80 (31%) were singletons, 150 (58%) were between 2 and 7 members per family, and the remaining were single families with 8, 9, and 10 members each. Criteria for mutation testing for Lynch syndrome were young age at onset of colorectal cancer (<45 years), presence of a strong family history (met Amsterdam or relaxed Amsterdam criteria; ref. 24), and suggestive tumor characteristics (defined as presence of microsatellite instability and loss of staining for a MMR protein). A total of 260 confirmed carriers of a MMR gene mutation were recruited. We excluded 3 subjects with mutations in MSH6 because MSH6 is associated with a variant form of Lynch syndrome with later age at colorectal cancer onset (25). We also did not include any individuals who tested positive for variants of unknown significance in the MMR genes because the pathogenicity of these mutations is not known. Among the remaining 257 study participants, there were 81 different MMR mutations, which included deletions (25.7%), insertions (4.3%), nonsense (20.6%), splice site (27.2%), and missense mutations (22.2%). We confirmed that all of these mutations were pathogenic, particularly the missense mutations. They were either reported to be pathogenic by a Clinical Laboratory Improvement Act certified laboratory or confirmed to be pathogenic from the International Collaborative Group-HNPCC InSight database⁵

For most participants (65%), information about demographic characteristics and medical history was obtained from a self-administered health, habits, and history questionnaire. Where questionnaire data were not available (when individuals were deceased or lost to follow-up), information was abstracted from the subjects' medical records. Colorectal cancer date of diagnosis was confirmed for the cases by review of pathology reports. Dates of diagnosis for adenoma or other cancers were similarly confirmed from medical records, pathology reports, or both.

All participants provided 10 mL samples of blood from which DNA was extracted using the AUTOPURE LS Automated DNA Purification Instrument (Gentra Systems) according to the manufacturer's instructions. Genotyping of SNPs, with the exception of GSTM1 and GSTT1 deletions, was done using the PCR and pyrosequencing methods described by Chen et al. (22). The primers used in these procedures are listed in Supplementary Table S1 available at the journal Web site online. The PCR mixture was initially incubated at 95°C for 6 min followed by 45 cycles at 95°C for 15 s, 59°C for 30 s for both CYP1A1 SNPs, 59°C for 30 s for both EPHX1 SNPs, 59°C for 30 s for the GSTP1 A114V SNP, 61.5°C for 30 s for the GSTP1 I105V SNP, and 56°C for 30 s for GSTM1/GSTT1 followed by 72°C for 15 s and then an extension of 72°C for 5 min. A multiplex PCR method was used for the GSTM1 and GSTT1 deletions, and the genotypes were ascertained on a 1.2% agarose gel by examining the gels for bands of the appropriate sizes as described by Abdel-Rahman et al. (30). Positive and negative controls were included and 5% of the samples were run in duplicate for each genotyping assay with 100% concordance.

We estimated the genotype frequencies for each of the candidate metabolic gene polymorphisms and tested them for Hardy-Weinberg equilibrium. We used the Kaplan-Meier product limit method to assess the probability that subjects with a particular genotype would remain free of colorectal cancer. Thus, we defined colorectal cancer as the failure event; data for all other subjects were censored on the date of last contact for those remaining free of colorectal cancer, on the date of diagnosis of adenoma or cancer other than colorectal cancer, or on the date of death due to other causes. Total analysis time at risk for all participants consisted of the period from the date of birth to the time of the first colorectal cancer event for cases or the date of censoring for the rest. The disease-free survival curves by genotype were compared using the log-rank test. The median age at onset was defined as the age at which 50% of the participants remained cancer-free. We did Cox proportional hazards regression analysis to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for risk of colorectal cancer at any age, comparing the polymorphic with the wild-type genotype. Gender, ethnicity (White or other), and MMR gene mutated (MLH1 or MSH2) were included in the Cox model as potential confounding factors. We obtained unadjusted and adjusted HRs for the main effect of each of the candidate metabolic genes. We further did stratified analysis (using Kaplan-Meier plots and Cox regression) for the SNPs that had a significant main effect by levels of the other variables, such as gender, ethnicity, and gene mutated, to examine whether the effect of the SNP varied within these variables. We also generated interaction terms for SNPs significantly associated with colorectal cancer risk with each of the other gene polymorphisms (dichotomized as homozygous wild-type = 0; heterozygous and homozygous variant = 1; or nondeleted = 0 and deleted = 1 for GSTM1 and GSTT1) and tested for multiplicative interaction in the Cox model by including each of the main effect terms and the term for interaction. We used the Huber-White robust variance correction as applied in Stat 8.0 (StataCorp) to correct for any correlations in time to onset of colorectal cancer among family members (31, 32). The robust variance estimator adjusts for within-cluster correlation (data not independent within groups but independent across groups) appropriately correcting for within-family correlation of the age of onset. We tested whether the HRs were proportional using the method described by Grambsch and Therneau (33).

Of the 257 participants, 120 (46.7%) developed colorectal cancer as the first cancer. We found no differences in the colorectal cancer-free survival time or the median age at onset of colorectal cancer by gender, ethnicity, or MMR gene mutated (log-rank test P > 0.05 for each of the variables; Table 1). All of the SNPs analyzed were in Hardy-Weinberg equilibrium (exact P > 0.05; Table 2). The allele frequencies were close to those described in the literature (we compared allele frequencies in our patients with those reported for White populations because our study participants were predominantly non-Hispanic Whites). We compared the genotypic frequencies for each of the gene SNPs between subjects with and without colorectal cancer using Pearson's χ² tests and found no difference in the frequencies of EPHX1 and GST genotypes (data not shown). For CYP1A1, the genotype frequencies for both Msp1 [χ²₍₂₎ 6.23; P = 0.04] and I462V [χ²₍₂₎ 7.63; P = 0.02] SNPs were significantly different between the patients with and without colorectal cancer (however, the endpoint of our study was the time to onset of colorectal cancer by genotype).

Kaplan-Meier survival curves, comparing colorectal cancer-free survival by genotype, were significantly different for the CYP1A1 I462V SNP (comparing AA, AG, and GG, log-rank test P = 0.018; for AG and GG genotypes combined, log-rank test P = 0.036) and marginally so for the CYP1A1 T>C SNP (comparing genotypes TT, TC, and CC, log-rank test P = 0.059; Fig. 1). Colorectal cancer-free survival did not differ by genotype for any of the other polymorphisms or gene deletions (P > 0.05). The median age at onset for colorectal cancer was 39 years for patients with the CYP1A1 I462V AG genotype compared with 43 years for those with the wild-type AA genotype. Using Cox proportional hazards regression analysis, we also found an increased risk of early-onset colorectal cancer associated with the AG genotype compared with the AA genotype (HR, 1.81; 95% CI, 1.19-2.75; P = 0.005). Because of the rarity of the CYP1A1 homozygous variant genotypes for both Msp1 and I462V, we did not analyze them separately (risk estimates were unstable and have been omitted) but did combine them with the heterozygous genotypes to calculate the risk estimates (Table 2). On stratified analysis for the effects of various CYP1A1 genotypes by gender and gene mutated on risk of early disease, we found that female gender and presence of the MSH2 mutation were significantly associated with the risk of early onset colorectal cancer (Table 3). Although the direction of association was the same among males and females and among MLH1 and MSH2 mutation carriers, the magnitude of effect was smaller among males and MLH1 mutation carriers and the results did not achieve statistical significance perhaps due to smaller numbers in those categories. Furthermore, because our study population was predominantly White, we analyzed the non-Hispanic Whites versus others and found that a significant association persisted with an increased risk related to the AG genotype compared with the AA (HR, 1.73; 95% CI, 1.08-2.77; P = 0.021) among the non-Hispanic Whites (Table 3). Although gender, ethnicity, or gene mutated did not have significant effects at the α = 0.05 level in the Cox model, we retained them as covariates as per convention for their role as potential confounders of the modifier gene-colorectal cancer association. The crude and adjusted HRs are listed in Table 2. We tested for and found no evidence of multiplicative interaction by gender, ethnicity, or gene mutated in the Cox model (Wald χ² test P > 0.05). All the estimates were obtained by applying robust correction using the cluster function in Stata.

In analyzing the CYP1A1 Msp1 SNP, which was in significant linkage disequilibrium with the CYP1A1 I462V SNP (D′ = 0.97; R² = 0.44; P < 0.0001), we found that the TC genotype was associated with an increased hazard for earlier onset of colorectal cancer compared with the TT genotype (adjusted HR, 1.62; 95% CI, 1.06-2.45; P = 0.02) and that this was more evident among MSH2 mutation carriers, as in the case of the CYP1A1 I462V. The proportional hazards assumption was tested using the Schoenfeld residuals and was not violated for either of the CYP1A1 SNPs (P > 0.05 for the global test).

None of the other SNPs analyzed was associated with an earlier age at onset or a difference in risk by genotype. However, we found evidence for multiplicative interaction between CYP1A1 I462V and EPHX1 Y113H (Wald χ² P = 0.036; likelihood ratio test P = 0.044) with a greater than multiplicative HR for the combined effect of having a variant allele of both these SNPs (HR, 3.09; 95% CI, 1.58-6.04; P = 0.001). Further, on stratified analysis (Fig. 2), we found that, in the presence of any polymorphic allele of the EPHX1 Y113H SNP (genotypes TC and CC), having any polymorphic allele of CYP1A1 I462V (genotypes AG and GG) was associated with a significantly earlier median age of colorectal cancer onset at 37 years compared with 42 years (log-rank test P = 0.002) for having the CYP1A1 I462V homozygous wild-type allele (AA genotype). We did not detect interaction of CYP1A1 I462V SNP with any of the other polymorphisms (P for interaction term > 0.05).

This study investigated eight polymorphisms in five candidate genes involved in the metabolism of xenobiotics to determine if they had any effect on the age at onset of colorectal cancer as an indicator of phenotypic variation in individuals with Lynch syndrome. The modifying effect of these genes was examined among individuals with a common background for increased susceptibility to colorectal cancer due to an inherited deleterious mutation resulting in deficient MMR. Our most prominent finding was an observed shift in the median age at onset of colorectal cancer to 4 years earlier among CYP1A1 I462V heterozygotes compared with those with the homozygous wild-type genotype. In addition, subjects with the heterozygous genotype had an ∼80% higher risk for colorectal cancer each year than subjects with the homozygous wild-type genotype. A similar trend in risk was observed for the CYP1A1 Msp1 variant, although the risk estimates were lower. Because the CYP group of enzymes is predominantly involved in activation reactions and the CYP1A1 I462V polymorphism results in higher enzyme activity, it is reasonable to assume that the increased CYP1A1 activity may be associated with an increase in the level of activated metabolites that have the potential to cause DNA damage and initiate carcinogenesis.

Comparing our results with evidence in the literature, we found that in a recent study, Talseth et al. (11) examined four of the same polymorphisms we did—CYP1A1 Msp1, GSTP1 I105V, and GSTM1 and GSTT1 deletions—in a mixed Australian (n = 86) and Polish (n = 134) population of MMR gene mutation carriers. The researchers did not find a statistically significant difference between the age at diagnosis of colorectal cancer by genotype for any of the genes tested, although they did detect a nonsignificant difference of up to 8 years in the median age at onset of colorectal cancer for three of the SNPs (authors did not specify which SNPs). Talseth et al. also found that only the CYP1A1 Msp1 mutant genotype was present significantly more in the colorectal cancer-affected subjects than in those without colorectal cancer (P = 0.03). This finding was confirmed by our results that showed a significant excess of Msp1 heterozygotes among the colorectal cancer affected (P = 0.04). Similarly, for the I462V SNP, there were significantly more subjects with the heterozygous genotype among the colorectal cancer cases (P = 0.02) than among the cancer free. However, Talseth et al. did not examine the CYP1A1 I462V, which is the SNP that we also found to be most strongly associated with an earlier onset of colorectal cancer.

The GSTM1 and GSTT1 deletion polymorphisms have been extensively examined in individuals with Lynch syndrome (18-21). In a Finnish population of 150 MLH1 mutation carriers, the null alleles of GSTM1 and GSTT1 each shifted the median age of onset of colorectal cancer to 6 years earlier; the authors, however, did not report whether these differences were statistically significant (19). Another recent study examining a homogeneous cohort of 129 South African individuals carrying a single predisposing mutation in MLH1 reported that men who were carriers of both GSTM1- and GSTT1-null alleles had a 3-fold increase in risk of developing colorectal cancer compared with men who had neither null allele (18). There are likely to be inherent genetic differences and differences in environment and lifestyle factors between the two study populations that could explain why we did not find similar results. Nevertheless, our null results for GSTM1 and GSTT1 do corroborate the findings of two previous studies on MMR gene mutation carriers; neither one of which found an association between GSTM1 and GSTT1 deletions and early onset of colorectal cancer (18, 19). Of these, the study by Jones et al. was on a smaller subset of our population (104 MMR gene mutation carriers from 59 families) and a similar analysis detected no association of GSTM1 with age at onset of colorectal cancer. (20). Although GSTM1 deletion is common, being present in almost 50% of the general population, the enzyme is not expressed in the colonic mucosal cells (34); hence, it may play a very limited role in the metabolism of xenobiotics in the colon. This could perhaps explain why most studies have not found an association of GSTM1 with risk for sporadic or hereditary cases of colorectal cancer. The putative influence of GSTT1, however, is biologically plausible because this gene is abundantly expressed in the colon (34) and variation in GSTT1 enzyme levels could influence xenobiotic detoxification in the colon. Although our study did not find a modification of risk for colorectal cancer by GSTT1 in individuals with Lynch syndrome, compiled evidence appears to indicate that those with the gene deletion (that is, those lacking the GSTT1 enzyme) are likely to be at an increased risk for sporadic colorectal cancer (9, 35, 36). Our study could have detected a HR of ∼1.6 for this polymorphism with 80% power at a significance level of 5%, but a larger sample size would be needed to detect less penetrant effects of this (or other) variants on risk.

One of the limitations of our study was a lack of complete data on different sources of exposure to PAHs, which include smoking and consumption of well-done meat. It is likely that the influence of the genetic polymorphisms is dependent on the level of xenobiotic exposure (the risk associated with the metabolic genes could be further modified by the level of the substrates on which they act). As shown by Slattery et al. (10), the effect of smoking on sporadic colorectal cancer risk is modified by the CYP1A1 genotype. Further, we had limited power to test the joint effects of the various genes or gene-gene interaction in our Cox model. Although we found that the adverse effect of the CYP1A1 I462V variant allele was further increased among individuals with the EPHX1 Y113H variant allele, showing a 5-year earlier shift in median age at onset and a 3-fold increased risk by year compared with having the CYP1A1 homozygous wild-type allele, these results are based on small numbers and would require validation in larger studies. It is pertinent to note that the interaction effect seen between EPHX1 and CYP1A1 is biologically plausible because both these enzymes are sequentially involved in the biotransformation of PAHs. In the initial phase I reaction, CYP1A1 converts benzo(a)pyrene to the active benzo(a)pyrene 7,8 epoxide. This is hydrated by EPHX1 to a transhydrodiol derivative benzo(a)pyrene 7,8 diol that is less toxic (37), but the diol derivative is a primary substrate for CYP enzymes that further oxidize it to the highly reactive benzo(a)pyrene 7,8 dihydrodiol 9,10 epoxide, a potent mutagen capable of reacting with DNA to form adducts. Thus, these and other genes may interact to play a more complex role in carcinogenesis. Future studies on larger numbers of mutation carriers using statistical tools such as Random Forest and CART analysis may be useful in determining the presence of gene-gene interactions and allow risk predictions to be made based on a combination of genotypes.

It is important to note that although we found an earlier age at colorectal cancer onset associated with two SNPs in the CYP1A1 gene that are in linkage disequilibrium, it is possible that neither one of these is the causative SNP. The increased risk may be due to genetic variation at another locus that happens to be in further linkage disequilibrium with the CYP1A1 SNPs examined in our study. Within CYP1A1, a reduced risk for sporadic colorectal cancer has been described for two other CYP1A1 SNPs, T461N and -1738A>C (13). The T461N SNP has a very low minor allele frequency (<5%) and the functional relevance of the -1738A>C SNP is still unknown, but it would be of interest to examine these two CYP1A1 SNPs in future studies on individuals with Lynch syndrome.

Although we had limited power to examine the association of the SNPs with age at onset by different ethnic subgroups, our results were consistent whether we analyzed the overall population or restricted the analysis to non-Hispanic Whites alone. Further, although we examined genetic variation at eight different loci, we do not believe that our results could be due to type I error as a consequence of multiple testing because the polymorphisms examined were in candidate metabolic genes that were selected a priori based on biological or epidemiologic evidence for their role in affecting colorectal cancer risk. Besides, the univariate P value for CYP1A1 I462V (P = 0.005) meets the stringent threshold P < 0.00625 (0.05 / n = 8 tests) on applying the Bonferroni correction for multiple testing.

There is a possibility that some degree of selection bias may have influenced the results of our study because hospital-identified probands are likely to be younger than Lynch syndrome cases identified from the general population. This may be mitigated to some extent in our study by the inclusion of family members with Lynch syndrome, both colorectal cancer-affected and nonaffected, to the analysis that perhaps restores the age at onset distribution closer to that in the population. Additionally, because the participants were not enrolled based on their genotype, selection bias would not falsely indicate an association, although there may be an earlier shift in the age at onset.

Finally, the results of our study indicate that, among MMR gene mutation carriers, the age at onset of colorectal cancer may be modified by the CYP1A1 I462V and Msp1 polymorphisms, the I462V polymorphism increasing risk for an earlier onset age by 4 years on average. Therefore, combining the knowledge of an individual's CYP1A1 genotype along with other genetic markers and environmental factors that influence colorectal cancer risk in MMR gene mutation carriers may improve risk estimates and help identify genetically susceptible high-risk subgroups with Lynch syndrome that could benefit most from intensive screening and chemopreventive or surgical interventions.

No potential conflicts of interest were disclosed.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Haidee Chancoco and Domitila Patenia for technical assistance.