KRAS rs61764370 is associated with HER2-overexpressed and poorly-differentiated breast cancer in hormone replacement therapy users: a case control study

Jasmina-Ziva Cerne,Vida Stegel,Srdjan Novakovic,Ksenija Gersak

doi:10.1186/1471-2407-12-105

Abstract

BackgroundA single nucleotide polymorphism located in the 3'-untranslated region of the KRAS oncogene (KRAS variant; rs61764370) disrupts a let-7 miRNA binding and was recently reported to act as a genetic marker for increased risk of developing human cancers. We aimed to investigate an association of the KRAS variant with sporadic and familial breast cancer and breast tumor characteristics.MethodsGenotyping was accomplished in 530 sporadic postmenopausal breast cancer cases, 165 familial breast cancer cases (including N = 29, who test positive for BRCA1/2 mutations) and 270 postmenopausal control women using the flurogenic 5' nuclease assay. Information on hormone replacement therapy (HRT) use and tumor characteristics in sporadic breast cancer cases was ascertained from a postal questionnaire and pathology reports, respectively. Associations between the KRAS genotype and breast cancer or breast tumor characteristics were assessed using chi-square test and logistic regression models.ResultsNo evidence of association was observed between the KRAS variant and risk of sporadic and familial breast cancer - either among BRCA carriers or non-BRCA carriers. The KRAS variant was statistically significantly more often associated with human epidermal growth factor receptor 2 (HER2) - positive tumors and tumors of higher histopathologic grade. However, both associations were detected only in HRT users.ConclusionOur data do not support the hypothesis that the KRAS variant rs61764370 is implicated in the aetiology of sporadic or of familial breast cancer. In postmenopausal women using HRT, the KRAS variant might lead to HER2 overexpressed and poorly-differentiated breast tumors, both indicators of a worse prognosis.

Highlights

A single nucleotide polymorphism located in the 3’-untranslated region of the KRAS oncogene (KRAS variant; rs61764370) disrupts a let-7 miRNA binding and was recently reported to act as a genetic marker for increased risk of developing human cancers
We aimed to investigate the association of the KRAS variant with breast tumor characteristics among Slovenian postmenopausal sporadic breast cancer cases stratified by hormone replacement therapy (HRT) use
The study population consisted of 530 postmenopausal sporadic breast cancer cases, 165 familial breast cancer cases and 270 postmenopausal control women with no history of breast and/or ovarian cancer

Summary

Introduction

A single nucleotide polymorphism located in the 3’-untranslated region of the KRAS oncogene (KRAS variant; rs61764370) disrupts a let-7 miRNA binding and was recently reported to act as a genetic marker for increased risk of developing human cancers. The KRAS variant was demonstrated to be functional by disrupting a let-7 miRNA-binding site, and leading to increased KRAS levels in vitro [5]. The same group identified the KRAS variant to be associated with 2.3-fold increased risk for non-small-cell lung cancer (NSCLC) among moderate smokers [5]. The variant allele was identified in 25% of non-selected EOC cases and in 61% of EOC patients from hereditary breast and ovarian cancer (HBOC) families previously considered uninformative for gene mutations [8]. Data from a subsequent meta-analysis excluded the possibility of an association between the KRAS variant and a clinically significant risk of unselected, serous, familial EOC, or EOC among women carrying deleterious mutations in BRCA1 [9]

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