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.

Candidate genes for hereditary colorectal cancer: Mutational screening and systematic review

“…Overall, Type‐A variants in HNRNPA0 and WIF1 are extremely rare and are not found enriched in cases (Wei et al, 2015; CanVar; current study) compared with controls. Despite the absence of association with HNRNPA0 , WIF1 Type‐B variants are found more frequently among cases that controls (3/2,960 [0.1%] vs. 39/118,190 [0.03%]; p = .083).…”

“…Wei et al reported the presence HNRNPA0 c.−110G>C (cpMAF: 0.14%) and WIF1 c.977G>T (p.Cys326Phe, cpMAF: 0.001%, REVEL: 0.89) in multiple members of a large family with increased susceptibility to various types of cancers, including early‐onset CRC, breast and prostate cancers (Wei et al, 2015). The HNRNPA0 variant was predicted to affect the binding site of transcriptional factors, thus affecting gene regulation and expression.…”

“…It is possible though, that both HNRNPA0 c.‐110G>C and WIF1 c.977G>T (p.Cys326Phe) are low/moderate cancer risk variants that in combination confer an increased risk to various tumor types. In fact, in the family described by Wei et al, 9/9 (100%) relatives carrying both variants had developed cancer (age range at diagnosis: 26–77), three of whom had been diagnosed with two primary tumors (Wei et al, 2015).…”

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…The CRC risk of FCCTX patients is double that of the general population (a third of that for Lynch syndrome patients), and FCCTX families lack extracolonic cancers (Lindor et al, 2005). The genetic basis of FCCTX remains unknown, however, recent investigations suggest that it may, like LLS, be a heterogeneous condition with mutations in several genes responsible (Nieminen et al, 2014;Schulz et al, 2014;Spier et al, 2015;Wei et al, 2015).…”

Wnts grasp the WIF domain of Wnt Inhibitory Factor 1 at two distinct binding sites

“…The therapeutic importance of Wnt Inhibitory Factor 1 may be illustrated by the fact that epigenetic silencing of WIF‐1 is associated with aberrant activation of the Wnt pathways in a variety of cancers, whereas restoration of its expression inhibits tumor progression[32–34]. The significance of WIF‐1 as a tumor suppressor is also supported by the recent observation that a Cys294Phe mutation of the WIF1 gene predisposes members of a large family to multiple early onset cancers including prostate, breast, colon, and several other uncommon cancers[40]. Since the Cys294Phe mutation disrupts a conserved disulfide bond of the fourth EGF domain of the WIF‐1 protein it seems plausible to assume that the misfolded protein is unable to fulfill its function as a negative regulator of various Wnts, leading to aberrant activation of the various Wnt‐Fzd‐LRP5/LRP6 signaling pathways.…”