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KRAS mutation may be linked to varying colorectal cancer prognoses
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A variant in the KRAS single nucleotide polymorphism was associated with improved outcomes in early-stage colorectal cancer and poorer outcomes in late-stage colorectal cancer, according to findings presented at a press conference.
Kim M. Smits, PhD, a molecular biologist and epidemiologist in the GROW-School for Oncology and Developmental Biology at Maastricht University Medical Center in the Netherlands, said microRNAs may be important prognostic biomarkers for predicting colorectal cancer outcomes.
Smits said a variant in the lethal-7 (let-7) complementary site (LCS6) in the KRAS 3’ untranslated region has been linked to response to targeted therapy and survival in late-stage colorectal cancer. The aim of the current study was to determine whether the KRAS-LCS6 variant may aid in identifying early-stage colorectal cancer with a different prognosis and affect treatment regimens.
“It is important to note that this large prospective cohort study performed in the Netherlands involved an unselected population,” Smits said. “All participants were healthy at the outset, and we wanted to see who developed colorectal cancer.”
The initial population involved more than 700 people. The final analysis was composed of 409 early-stage (Dukes A and B), 182 Dukes C and 69 Dukes D colorectal cancer cases identified from 1989 to 1994 in the Netherlands Cohort Study on diet and cancer.
The researchers analyzed portions of tumor tissue — particularly the KRAS-LCS6 variant — with a TaqMan polymerase chain reaction assay that was designed to identify the T or G allele of the KRAS-LCS6 SNP.
Patients self-reported baseline data and follow-up data — including tumor localization, tumor staging, differentiation grade and incidence date, and mortality information — were gathered through 2005.
The median OS rate was 7.6 years. Multivariate analysis results indicated that early-stage patients with the variant had better cause-specific survival than patients with the wild type (HR=0.46; 95% CI, 0.18-1.14). Carriers of the KRAS-LCS6 wild type with a KRAS mutation also experienced a survival benefit compared with KRAS-LCS6 variant carriers without a KRAS mutation (P=.017).
“This was a surprising result,” Smits said. “We did not expect that in early-stage cases, patients with the KRAS SNP would have a better prognosis when they had the variant allele, and that the survival benefit would be enhanced when you took into account the KRAS mutation.”
Smits also noted that no patients with a KRAS mutation and the variant died because of colorectal cancer.
Among late-stage patients, there was no link between the variant and cause-specific survival. “Metastatic patients have worse survival if they have this genetic variation in the target site,” Smits said. “In fact, the survival benefit of KRAS was completely lost.”
These findings suggest that it may be important to catch people that harbor the KRAS-variant early in the course of colorectal cancer to allow the best outcomes. “The KRAS-LCS6 variant, especially in combination with KRAS mutational status, merits to be validated as a prognostic biomarker in early-stage [colorectal cancer],” the researchers wrote.
Smits said further investigation of the phenomenon is under way. “Our current hypothesis is that there is some sort of compensatory mechanism going on in early-stage patients, but that has yet to be validated.”