Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers

Chongjuan Wei, Bo Peng, Younghun Han, Wei V. Chen, Joshua Rother, Gail E. Tomlinson, C. Richard Boland, Marc Chaussabel, Marsha L. Frazier, Christopher I. Amos

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

We studied a large family that presented a strong familial susceptibility to multiple early onset cancers including prostate, breast, colon, and several other uncommon cancers. Through targeted gene, linkage, and whole genome sequencing analyses, we show that the presence of a variant in the regulatory region of HNRNPA0 associated with elevated cancer incidence in this family (Hazard ratio = 7.20, p = 0.0004). Whole genome sequencing identified a second rare protein changing mutation of WIF1 that interacted with the HNRNPA0 variant resulting in extremely high risk for cancer in carriers of mutations in both genes (p = 1.98 × 10−13). Analysis of downstream targets of the mutations in these two genes showed that the HNRNPA0 mutation affected expression patterns in the PI3 kinase and ERK/MAPK signaling pathways, while the WIF1 variant influenced expression of genes that play a role in NAD biosynthesis. This is a first report of variation in HNRNPA0 influencing common cancers or of a striking interaction between rare variants coexisting in an extended pedigree and jointly affecting cancer risk.

Original languageEnglish (US)
Pages (from-to)297-306
Number of pages10
JournalFamilial Cancer
Volume14
Issue number2
DOIs
StatePublished - Jun 15 2015

Keywords

  • Colon cancer
  • Complex disease
  • Expression analysis
  • Linkage analysis
  • Prostate cancer
  • Whole genome sequencing

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Genetics(clinical)
  • Cancer Research

Fingerprint Dive into the research topics of 'Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers'. Together they form a unique fingerprint.

Cite this