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

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• 作者：Trupti Paranjape PhD^a ; ^† ; ; Helen Heneghan MD^g ; ^† ; ; Robert Lindner BSc^b ; ^h ; Florence K Keane BA^c ; Aaron Hoffman PhD^d ; ⁱ ; Antoinette Hollestelle PhD^j ; Jemima Dorairaj BA^g ; Kimberly Geyda PhD^e ; Cory Pelletier PhD^a ; Sunitha Nallur BS^a ; John WM Martens PhD^j ; Maartje J Hooning MD^j ; Michael Kerin MD^g ; Prof Daniel Zelterman PhD^d ; Yong Zhu PhD^d ; David Tuck MD^b ; Lyndsay Harris MD^e ; Nicola Miller PhD^g ; Prof Frank Slack PhD^f ; Dr Joanne Weidhaas PhD^a ; ^{joanne.weidhaas@yale.edu}
• 刊名：Lancet Oncology
• 出版年：2011
• 出版时间：April 2011
• 年：2011
• 卷：12
• 期：4
• 页码：377-386
• 全文大小：410 K

文摘

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.