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Open Access Highly Accessed Research article

Let-7 miRNA-binding site polymorphism in the KRAS 3UTR; colorectal cancer screening population prevalence and influence on clinical outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin +/− cetuximab

Janne B Kjersem1, Tone Ikdahl2, Tormod Guren2, Eva Skovlund3, Halfdan Sorbye4, Julian Hamfjord1, Per Pfeiffer5, Bengt Glimelius67, Christian Kersten8, Hiroko Solvang1, Kjell M Tveit2 and Elin H Kure1*

Author Affiliations

1 Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

2 Department of Oncology, Oslo University Hospital, Oslo, Norway

3 School of Pharmacy, University of Oslo and the Norwegian Institute of Public Health, Oslo, Norway

4 Department of Oncology, Haukeland University Hospital, Bergen, Norway

5 Department of Oncology, Odense University Hospital, Odense, Denmark

6 Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden

7 Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden

8 Center for Cancer Treatment, Southern Hospital Trust, Kristiansand, Norway

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BMC Cancer 2012, 12:534  doi:10.1186/1471-2407-12-534

Published: 20 November 2012

Abstract

Background

Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6) within the 3untranslated region (3UTR) of KRAS (rs61764370) and clinical outcome in metastatic colorectal cancer (mCRC) patients receiving cetuximab. The variant allele has also been associated with increased cancer risk. We aimed to reveal the incidence of the variant allele in a colorectal cancer screening population and to investigate the clinical relevance of the variant allele in mCRC patients treated with 1st line Nordic FLOX (bolus 5-fluorouracil/folinic acid and oxaliplatin) +/− cetuximab.

Methods

The feasibility of the variant allele as a risk factor for CRC was investigated by comparing the LCS6 gene frequencies in 197 CRC patients, 1060 individuals with colorectal polyps, and 358 healthy controls. The relationship between clinical outcome and LCS6 genotype was analyzed in 180 mCRC patients receiving Nordic FLOX and 355 patients receiving Nordic FLOX + cetuximab in the NORDIC-VII trial (NCT00145314).

Results

LCS6 frequencies did not vary between CRC patients (23%), individuals with polyps (20%), and healthy controls (20%) (P = 0.50). No statistically significant differences were demonstrated in the NORDIC-VII cohort even if numerically increased progression-free survival (PFS) and overall survival (OS) were found in patients with the LCS6 variant allele (8.5 (95% CI: 7.3-9.7 months) versus 7.8 months (95% CI: 7.4-8.3 months), P = 0.16 and 23.5 (95% CI: 21.6-25.4 months) versus 19.5 months (95% CI: 17.8-21.2 months), P = 0.31, respectively). Addition of cetuximab seemed to improve response rate more in variant carriers than in wild-type carriers (from 35% to 57% versus 44% to 47%), however the difference was not statistically significant (interaction P = 0.16).

Conclusions

The LCS6 variant allele does not seem to be a risk factor for development of colorectal polyps or CRC. No statistically significant effect of the LCS6 variant allele on response rate, PFS or OS was found in mCRC patients treated with 1st line Nordic FLOX +/− cetuximab.

Keywords:
Colorectal cancer; LCS6; MiRNA polymorphism; Cetuximab; Oxaliplatin; 5-fluorouracil