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• W2197441794 abstract "Much effort is ongoing in cataloguing driving somatic mutations in cancer and designing intervention strategies1. But do we have an understanding as to whether heritable variation might affect patient survival by modulating the pathophysiology of the stromal, vascular, and immune systems, all interacting with the cancer cells? The answer is no.The paper of Dai et al.2 is one of the first trying to answer this question in colorectal cancer by testing the hypothesis that cancer susceptibility variants might also have an effect on prognosis. These pleiotropic features of the human genome are still poorly understood. The paper of Dai et al.1 describes a prospective analysis of SNPs previously associated with risk of colorectal cancer for their association with survival and recurrence in stage II and III patients.There is large collection of heritable risk markers from the numerous GWAS for sporadic cancer3, but their value as prognosticators has been explored only in a few tumor types. The experience so far in prostate cancer has led to inconclusive results4. Dai et al.2 leverage the genome-wide association studies (GWAS) for risk of colorectal cancer and, out of the 26 tested single-nucleotide polymorphisms (SNPs), an intriguing finding is for rs6983267 in 8q24. Dai et al.2 demostrate that this variant increases risk of both cancer and death in stage III patients. I pose particular attention to rs6983267 (instead of the others suggested as significantly associated with survival or recurrence) simply because it has been demonstrated to be functional at molecular level5 and the underlying biological mechanism is consistent with the observed clinical effect. It will be intriguing to replicate prospectively the association with worse survival in stage III patients, and also to address whether rs6983267 interacts with adjuvant treatment.The chance of finding false positives when multiple SNPs (n=26) are looked at under three genetic models for association with clinical phenotypes could be high if the p values are not corrected for multiple comparisons, and the present paper is not immune from this problem. This issue could be, in part, overcome by 1) enrichment of the statistical association with molecular, mechanistic data, 2) external replication of findings, 3) or (ideally) both.There as not been enough capitalization on the investment made so far in oncology GWAS, and more analyses like those of Dai et al.2 should be conducted, so that SNPs for testing could be prioritized for external replication by other groups. Eventually, the prognostic value of the concordant markers across different studies could be collectively meta-analyzed to identify the amount of predicted risk and to establish their clinical utility. The Dai et al.2 study leads the way forward into this new direction." @default.
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• W2197441794 date "2012-07-01" @default.
• W2197441794 modified "2023-09-23" @default.
• W2197441794 title "One SNP for both cancer risk and survival in colorectal cancer: two for the price of one?" @default.
• W2197441794 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4128334" @default.
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