A let-7 microRNA SNP in the KRAS 3'UTR is prognostic in early-stage colorectal cancer

Abstract

Purpose: Colorectal cancer (CRC) is a common cause of death worldwide. Tumor-node-metastasis-system stage is currently used to guide therapy decisions but lacks precision. Prognostic biomarkers are needed to refine stratification of patients for chemotherapy but validated biomarkers are not yet available. Recently, a SNP in a lethal-7 (let-7) miRNA complementary site (LCS6) in the KRAS 3'untranslated region was suggested to affect survival in metastatic CRC. Effects in early-stage CRC are however unknown. We studied KRAS-LCS6 genotype, hypothesizing that it might identify early-stage cases with a poor prognosis, and could potentially be used in therapy decision-making.

Experimental design: We studied 409 early stage, 182 stage III, and 69 stage IV cases, and 1,886 subcohort members from the Netherlands Cohort Study. KRAS-LCS6 genotype was assessed with TaqMan PCR. Kaplan-Meier analyses or Cox regression were used to assess associations between genotype and CRC risk or cause-specific survival.

Results: Early-stage cases with the KRAS-LCS6 variant had a lower CRC risk (incidence-rate ratio 0.68; 95% CI: 0.49-0.94) and a better survival (log-rank P = 0.038; HR 0.46; 95% CI: 0.18-1.14). In patients with KRAS-mutated CRC carrying the KRAS-LCS6 variant, the better outcome was enhanced as no patients died of CRC (log-rank P = 0.017). In advanced patients, no clear association between genotype and CRC risk or survival was observed.

Conclusions: Our results indicate that early-stage CRC cases with the KRAS-LCS6 variant have a better outcome. In advanced disease, the better outcome no longer exists. For early-stage patients, KRAS-LCS6 genotype combined with KRAS mutations merits validation as a prognostic biomarker and consideration in therapy decision-making.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

J.B. Weidhaas has a consultant and advisory role in MiraDX, her husband is a board member of MiraDX (uncompensated), and she has stock ownership of MiraDX. The other authors disclosed no potential conflicts of interest.

©2011 AACR.

Figures

Figure 1

A, Kaplan–Meier curve for the KRAS-LCS6 variant and cause-specific survival in early-stage (stage I and II) CRC. B, Kaplan–Meier curve for the KRAS-LCS6 variant and cause-specific survival in stage III CRC. C, Kaplan–Meier curve for the KRAS-LCS6 variant and cause-specific survival in stage IV CRC.

Figure 2

A, Kaplan–Meier curve for the KRAS-LCS6 variant, KRAS mutations and cause-specific survival in early-stage (stage I and II) CRC, P = 0.875. B, Kaplan–Meier curve for the KRAS-LCS6 variant, KRAS mutations and cause-specific survival in stage III CRC. C, Kaplan–Meier curve for the KRAS-LCS6 variant, KRAS mutations and cause-specific survival in stage IV CRC.

Figure 3

Kaplan–Meier curve for the KRAS-LCS6 variant, MSI status and cause-specific survival in early-stage (stage I and II) CRC.