A 3′-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis

Abstract

Summary Background We previously identified a functional variant in a let-7 microRNA (miRNA) complementary site in the 3′-untranslated region of the KRAS oncogene (rs61764370) which is associated with cancer. We aimed to investigate the association of this KRAS variant with breast cancer and tumour biology. Methods We assessed frequency distributions of the KRAS variant in 415 patients with histologically confirmed breast cancer and 457 controls from Connecticut, USA (study group 1) and association of this variant with breast-cancer subtypes in 690 Irish women with known oestrogen receptor (ER), progesterone receptor (PR), and HER2 statuses, and 360 controls (study group 2). We pooled data for study groups 1 and 2 with a cohort of 140 women with triple-negative breast cancer and 113 controls to assess the association of the KRAS variant with triple-negative breast cancer risk, and genome-wide mRNA and specific miRNA expression in patients with triple-negative breast cancer. Findings Although frequency distributions of the KRAS variant in study group 1 did not differ between all genotyped individuals, eight (33%) of 24 premenopausal women with ER/PR-negative cancer had the KRAS variant, compared with 27 (13%) of 201 premenopausal controls (p=0·015). In study group 2, the KRAS variant was significantly enriched in women with triple-negative breast cancer (19 [21%] of 90 cases) compared with 64 (13%) of 478 for luminal A, 13 (15%) of 87 for luminal B, and two (6%) of 35 for HER2-positive subgroups (p=0·044). Multivariate analysis in the pooled study groups showed that the KRAS variant was associated with triple-negative breast cancer in premenopausal women (odds ratio 2·307, 95% CI 1·261–4·219, p=0·0067). Gene-expression analysis of triple-negative breast-cancer tumours suggested that KRAS-variant positive tumours have significantly altered gene expression, and are enriched for the luminal progenitor and BRCA1 deficiency signatures. miRNA analysis suggested reduced levels of let-7 miRNA species in KRAS-variant tumours. Interpretation The KRAS variant might be a genetic marker for development of triple-negative breast cancer in premenopausal women, and altered gene and miRNA expression signatures should enable molecular and biological stratification of patients with this subgroup of breast cancer. Funding US National Institutes of Health.

Comparison of the prevalence of KRAS-LCS6 polymorphism (rs61764370) within different tumour types (colorectal, breast, non-small cell lung cancer and brain tumours). A study of the Czech population

“…Furthermore, there is no significant difference in the frequency of the G-allele (TG/GG genotype) KRAS-LCS6 polymorphisms either across cancer groups or between cancer and general population reported in study by Chin LJ 1. Similarly, Paranjape 6 found no difference in the overall frequency distributions of the KRAS-variant genotype in cases of breast cancer and controls. In this study, a significant association of the KRAS-LCS6 was only found in a group with breast cancer in premenopausal patients with oestrogen/ progesterone-negative tumours.…”

“…Germline SNP (rs61764370) has been recently extensively studied in relation to several types of cancer, especially in connection with associated risk, prognosis, and/or treatment response/resistance to therapy [1][2][3][4][5][6][7][8][9][10][11] . The let-7 family of miRNAs has been found to play an important role in tumorigenesis by regulating the expression of multiple oncogenes, including KRAS.…”

Estrogen withdrawal, increased breast cancer risk and the KRAS-variant

“…1 One of the first mutations discovered in this class is the KRAS-variant, a let-7 binding site mutation in the 3 0 UTR of the KRAS oncogene. 2 This mutation predicts an increased risk of several cancers, including non-small cell lung cancer, 2 triple negative breast cancer (TNBC) in premenopausal women 3 and ovarian cancer. [4][5][6] The KRAS-variant also predicts unique tumor biology, with tumors in KRAS-variant patients exhibiting a KRAS-addicted signature, as well as an estrogen negative, basal-like gene expression pattern.…”

“…[4][5][6] The KRAS-variant also predicts unique tumor biology, with tumors in KRAS-variant patients exhibiting a KRAS-addicted signature, as well as an estrogen negative, basal-like gene expression pattern. 3,5 Perhaps most powerful is the extensive evidence that the KRAS-variant is biologically functional, as exemplified by its role as a strong biomarker of response to cancer therapy. KRAS-variant patients with ovarian cancer or head and neck cancer are cisplatin resistant, 5,7 those with colon cancer or head and neck cancer exhibit cetuximab sensitivity, 7,8 and those with non-small cell lung cancer (NSCLC) are resistant to erlotinib but sensitive to sorafenib.…”

MicroRNA signatures differentiate melanoma subtypes

“…5,6 In addition, miRNA disruptions through inherited variants in their binding sites or coding sequences are strong genetic markers of cancer risk. [7][8][9][10][11][12] One of the first such variants, located in the 3' untranslated region (3'UTR) of the KRAS oncogene and referred to as the KRAS-variant, has been associated with altered miRNA signatures in tumors 7 as well as poor outcome and response to treatment in several cancers (Ratner et al submitted), 13,14 while a variant in the KIT 3'UTR is associated with acral melanoma. 9 These findings suggest that miRNA 3'UTR-binding variants may be associated with melanoma and can also lead to miRNA expression alterations and altered biology in the tumors that they are associated with.…”