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Genome-wide association studies have identified 16 germline single-nucleotide polymorphisms (SNPs) that are associated with colorectal cancer (CRC) incidence. We examined the relationship between these SNPs and survival of 2611 individuals with CRC, enrolled in 5 cohort studies. We used Cox regression analysis to associate SNPs with overall and CRC-specific survival times. The minor allele in rs4939827 (SMAD7) was associated with reduced overall survival (hazard ratio, 1.16; 95% confidence interval, 1.06–1.27; P = .002) and disease-specific survival (hazard ratio, 1.17; 95% confidence interval, 1.05–1.30; P = .005). Other SNPs were not associated significantly with survival. Common germline variations might be prognostic factors for patients with CRC. A variant in SMAD7 could affect progression of CRC.
Recent genome-wide association studies (GWAS) have identified at least 16 single-nucleotide polymorphisms (SNPs) at 14 loci that are associated statistically significantly with risk of incident colorectal cancer (CRC).1,2 Common genetic variation also may play a role in CRC prognosis. To date, however, most studies evaluating genetic variation in relation to CRC survival have focused on polymorphisms in candidate genes involved in putative pathways of action for cancer therapeutics,3–5 mismatch repair,6 or oncogenes (eg, cyclooxygenase-2 [COX-2]7), and have reported null or only marginally significant associations that have been replicated inconsistently. A small number of studies have examined loci identified by GWAS for CRC susceptibility in relation to prognosis.8–11 These studies also have yielded inconsistent results, but each were limited by small sample sizes. We therefore evaluated associations between 16 CRC susceptibility SNPs identified from prior GWAS and survival after CRC diagnosis, using genotype and survival information from 2611 men and women diagnosed with incident invasive CRC after enrolling in one of the following prospective cohort studies: the Health Professionals Follow-Up Study, the Nurses' Health Study, the Physicians' Health Study, the VITamins And Lifestyle study, and 2 subsets of the Women's Health Initiative (WHI1 and WHI2).
Characteristics of incident CRC cases enrolled in each of the included study populations are provided in Table 1. In total, 979 of 2611 (37%) CRC cases died during study follow-up, with the proportion of cases who died ranging from 32% in WHI2 to 49% in the Health Professionals Follow-Up Study, and with the proportion of deaths attributable to CRC ranging from 52% in the Physicians' Health Study to 78% in WHI2.
In meta-analyses of overall survival (OS) adjusted for age at diagnosis and sex, we observed a Bonferroni-adjusted statistically significant association with rs4939827 (18q21, SMAD7) (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.06-1.27; P = .002) consistent with a 16% increased risk of all-cause mortality per copy of the minor allele (G) (Table 2). After additional adjustment for stage at diagnosis, this association with rs4939827 was modestly attenuated (HR, 1.13; 95% CI, 1.01–1.25; P = .03). Rs4939827 also was associated with poorer disease-specific survival (DSS), with borderline significance after Bon-ferroni-adjustment for multiple comparisons (HR, 1.17; 95% CI, 1.05–1.30; P = .005). Associations with rs4939827 were similar across individual studies (P heterogeneity = .80 and .96 for OS and DSS, respectively) (Supplementary Figure 1). Prior studies of rs4939827 have indicated no association with overall survival,9–11 although one study did find an association between rs4939827 and survival confined to women who were regular users of nonsteroidal anti-inflammatory drugs.11 We found no significant difference in our observed associations with rs4939827 in analyses stratified by reported use of nonsteroidal anti-inflammatory drugs (Pinteraction = .97 and .54 for OS and DSS, respectively). In our study, the association between rs4939827 and survival also did not appear to differ according to smoking history or body mass index, but there was a suggestive, albeit not statistically significant, difference according to family history of CRC: the HRs for OS were 1.18 (95% CI, 1.05–1.32; P = .004) for cases without family history compared with 1.01 (95% CI, 0.69–1.46; P = .97) for cases with a family history (Pinteraction = .78).
In analyses adjusted for age, sex, and stage, we observed modest associations with OS for the minor alleles of rs10795668 (10p14) (HR, 1.14; 95% CI, 1.02–1.28; P = .03) and rs4925386/rs2151512 (20q13) (HR, 1.14; 95% CI, 1.02–1.29; P = .03). However, these associations were not statistically significant after Bonferroni adjustment. Other evaluated SNPs were not associated significantly with OS or DSS, consistent with previous studies.9–11
We assessed differences in our results according to tumor site (colon, rectum), sex, stage at diagnosis (I–II, III–IV), first-degree family history of CRC (absent, present), smoking history (never, ever), body mass index (<30, ≥30 kg/m2), and use of nonsteroidal anti-inflammatory drugs (no, yes). Although the number of individuals within each analysis was limited, results did not differ appreciably across these strata (not shown).
We calculated a risk score across all 16 SNPs by summing risk alleles as defined by the results from previous GWAS for CRC incidence; however, no association was evident per risk allele for OS (HR, 0.96; 95% CI, 0.91–1.01; P = .13) or DSS (HR, 0.98; 95% CI, 0.93–1.03; P = .43). When we instead calculated a risk score by summing risk alleles as defined by our findings in relation to survival, we did note significantly poorer OS (HR, 1.06; 95% CI, 1.02– 1.10; P = .001) and DSS (HR, 1.09; 95% CI, 1.04–1.13; P < .001) per risk allele. By using a risk score limited to the SNPs most strongly associated with survival in our analysis (rs4939827, rs10795668, and rs4925386/rs2151512), we also observed significantly poorer survival per risk allele (HROS, 1.13; 95% CI, 1.06 –1.20; P < .001; and HRDSS, 1.14; 95% CI, 1.05–1.23; P = .001).
Recent genome-wide association studies have shown the importance of common genetic variation in mediating the risk of CRC.1,2 Our findings provide support for a role of genetic variation in survival after CRC diagnosis. Specifically, the G allele in rs4939827, previously associated with lower risk of incident CRC,1 was associated with poorer survival after CRC diagnosis. Rs4939827 is located in an intronic region of SMAD7, a downstream inhibitor of transforming growth factor-β1 (TGF-β1). The seemingly contrary associations of rs4939827 with decreased risk of incident CRC but poorer survival after CRC diagnosis may be owing to the pleiotropic functions of the TGF-β pathway. In normal epithelium, TGF-β1 appears to function as a tumor suppressor through induction of cell arrest and inhibition of cell proliferation12; however, once cells are resistant to TGF-β1-mediated proliferative inhibition (ie, in established tumors), TGF-β1 promotes metastasis by enhancing angiogenesis and extracellular matrix disruption and inhibiting infiltrating tumor immune cells.12 Thus, although the functionality of rs4939827 is currently unknown, it is plausible that a variant in SMAD7 that contributes to up-regulation of TGF-β1 could result in decreased cancer risk but poorer survival. The consistency of the association between this SNP and survival across each of our included cohorts and our prospective design add strength to this finding. Nonetheless, it is notable that most GWAS-identified susceptibility loci for CRC we evaluated were not associated with CRC survival. Thus, these findings also suggest that common genetic variants most associated with CRC survival may be distinct from those that underlie initial tumor development.
The authors wish to acknowledge Patrice Soule and Hardeep Ranu for genotyping at the Dana-Farber Harvard Cancer Center High Throughput Polymorphism Core, under the supervision of Immaculata Devivo, as well as Carolyn Guo and Haiyan Zhang for programming assistance. The authors also wish to acknowledge Dave Duggan at TGen and Andrew Crenshaw at the Broad Institute for genotyping. The authors also thank the Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, VITamins And Lifestyle study, and Women's Health Initiative investigators and staff for their dedication, and the study participants for making these programs possible. A full listing of Women's Health Initiative investigators can be found at: https://cleo.whi.org/researchers/SitePages/Write%20a%20Paper.aspx.
Conflicts of interest: The authors disclose the following: Dr Chan has received funding as an ad hoc consultant for Bayer Healthcare, Pfizer, and Millenium Pharmaceuticals.
Supplementary Material: Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at http://dx.doi.org/10.1053/j.gastro.2012.04.052