Loss-of-Function Variants in the Tumor Suppressor Gene PTPN14 confer increased Cancer Risk.

The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next generation sequence data with associated phenotype information are needed. Here we used genotype data on 166,281 Icelanders, of which 49,708 were whole-genome sequenced, and 408,595 individuals from the UK Biobank, of which 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in PTPN14 conferred substantial risks of BCC (OR=8.0, P=1.9×10-12), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the PTPN14 locus were associated with BCC, suggesting PTPN14 as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants are associated with high risk of cervical cancer (OR=12.7, P=1.6×10-4) and low age at diagnosis. Our findings, using power-increasing methods with high quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis.