Germline variation in ADAMTSL1 is associated with prognosis following breast cancer treatment in young women

Nat Commun. 2017 Nov 21;8(1):1632. doi: 10.1038/s41467-017-01775-y.

Abstract

To identify genetic variants associated with breast cancer prognosis we conduct a meta-analysis of overall survival (OS) and disease-free survival (DFS) in 6042 patients from four cohorts. In young women, breast cancer is characterized by a higher incidence of adverse pathological features, unique gene expression profiles and worse survival, which may relate to germline variation. To explore this hypothesis, we also perform survival analysis in 2315 patients aged ≤ 40 years at diagnosis. Here, we identify two SNPs associated with early-onset DFS, rs715212 (P meta = 3.54 × 10-5) and rs10963755 (P meta = 3.91 × 10-4) in ADAMTSL1. The effect of these SNPs is independent of classical prognostic factors and there is no heterogeneity between cohorts. Most importantly, the association with rs715212 is noteworthy (FPRP <0.2) and approaches genome-wide significance in multivariable analysis (P multivariable = 5.37 × 10-8). Expression quantitative trait analysis provides tentative evidence that rs715212 may influence AREG expression (P eQTL = 0.035), although further functional studies are needed to confirm this association and determine a mechanism.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS Proteins / genetics*
  • ADAMTS Proteins / metabolism
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amphiregulin / genetics
  • Antineoplastic Agents / administration & dosage
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Disease-Free Survival
  • Extracellular Matrix Proteins / genetics*
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Genome-Wide Association Study
  • Germ-Line Mutation*
  • Humans
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Treatment Outcome
  • Young Adult

Substances

  • ADAMTSL1 protein, human
  • AREG protein, human
  • Amphiregulin
  • Antineoplastic Agents
  • Extracellular Matrix Proteins
  • ADAMTS Proteins