A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall-cell lung cancer

Abstract

A unique approach with rare resources was used to identify candidate variants predisposing to familial nonsquamous nonsmall-cell lung cancers (NSNSCLC). We analyzed sequence data from NSNSCLC-affected cousin pairs belonging to high-risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank. Evidence for linkage with lung cancer was also reviewed in families from the Genetic Epidemiology of Lung Cancer Consortium. Protein prediction modeling compared the mutation with reference. We sequenced NSNSCLC-affected cousin pairs from eight high-risk lung cancer pedigrees and identified 66 rare candidate variants shared in the cousin pairs. One variant in the FGF5 gene also showed significant association with lung cancer in UKBiobank. This variant was observed in 3/163 additional sampled Utah lung cancer cases, 2 of whom were related in another independent pedigree. Modeling of the predicted protein predicted a second binding site for SO₄ that may indicate binding differences. This unique study identified multiple candidate predisposition variants for NSNSCLC, including a rare variant in FGF5 that was significantly associated with lung cancer risk and that segregated with lung cancer in the two pedigrees in which it was observed. FGF5 is an oncogenic factor in several human cancers, and the mutation found here (W81C) changes the binding ability of heparan sulfate to FGF5, which might lead to its deregulation. These results support FGF5 as a potential NSNSCLC predisposition gene and present additional candidate predisposition variants.

Keywords: FGF5; UPDB; nonsquamous non small cell lung cancer; pedigree; predisposition.

Figure 1.

The sequenced high risk NSNSCLC pedigree including a lung-cancer-affected cousin pair sharing the rare FGF5 variant.

Figure 2.

Two related FGF5 variant-carrying lung cancer cases identified by assay. The founding male had 2 marriages, shown with an arrow on the top marriage line.

Figure 3.

Superposition of the top models predicted by RaptorX for the WT (in gold) and MUT (in light blue) structures of FGF5. The mutation site W81C is marked in dark blue for both structures, showing very little structural change. The binding sites with SO₄ predicted by RaptorX are depicted in green (V95, N193, K194, K199, H210, I211, S212) for both the WT and MUT structure; the new binding site found for the MUT structure (N193, K199 and R205) is shown in RED. The structure in the vicinity of the binding sites is not substantially changed by the mutation.