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

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 an 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 the expression of genes that play a role in NAD biosynthesis. This is the 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.