title: Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers.
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.
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Chongjuan
authors.initials: C
authors.lastname: Wei
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.forename: Younghun
authors.initials: Y
authors.lastname: Han
authors.forename: Wei V
authors.initials: WV
authors.lastname: Chen
authors.forename: Joshua
authors.initials: J
authors.lastname: Rother
authors.forename: Gail E
authors.initials: GE
authors.lastname: Tomlinson
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Marc
authors.initials: M
authors.lastname: Chaussabel
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Frazier
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000596429:HNRNPA0 protein, human; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D012097:Repressor Proteins; C485569:WIF1 protein, human