title: A 3'-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  US National Institutes of Health.
authors: Department of Therapeutic Radiology, Yale University, New Haven, CT 06880, USA.
authors: Trupti
authors: T
authors: Paranjape
authors: Helen
authors: H
authors: Heneghan
authors: Robert
authors: R
authors: Lindner
authors: Florence K
authors: FK
authors: Keane
authors: Aaron
authors: A
authors: Hoffman
authors: Antoinette
authors: A
authors: Hollestelle
authors: Jemima
authors: J
authors: Dorairaj
authors: Kimberly
authors: K
authors: Geyda
authors: Cory
authors: C
authors: Pelletier
authors: Sunitha
authors: S
authors: Nallur
authors: John Wm
authors: JW
authors: Martens
authors: Maartje J
authors: MJ
authors: Hooning
authors: Michael
authors: M
authors: Kerin
authors: Daniel
authors: D
authors: Zelterman
authors: Yong
authors: Y
authors: Zhu
authors: David
authors: D
authors: Tuck
authors: Lyndsay
authors: L
authors: Harris
authors: Nicola
authors: N
authors: Miller
authors: Frank
authors: F
authors: Slack
authors: Joanne
authors: J
authors: Weidhaas
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D018631:ras Proteins / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D018631:ras Proteins; C117307:KRAS protein, human; C508053:ERBB2 protein, human