Loss-of-Function Variants in the Tumor-Suppressor Gene PTPN14 Confer Increased Cancer Risk

• Published in: Cancer research (Chicago, Ill.) Vol. 81; no. 8; pp. 1954 - 1964
• Main Authors: Olafsdottir, Thorhildur, Stacey, Simon N, Sveinbjornsson, Gardar, Thorleifsson, Gudmar, Norland, Kristjan, Sigurgeirsson, Bardur, Thorisdottir, Kristin, Kristjansson, Arni Kjalar, Tryggvadottir, Laufey, Sarin, Kavita Y, Benediktsson, Rafn, Jonasson, Jon G, Sigurdsson, Asgeir, Jonasdottir, Aslaug, Kristmundsdottir, Snaedis, Jonsson, Hakon, Gylfason, Arnaldur, Oddsson, Asmundur, Fridriksdottir, Run, Gudjonsson, Sigurjon A, Zink, Florian, Lund, Sigrun H, Rognvaldsson, Solvi, Melsted, Pall, Steinthorsdottir, Valgerdur, Gudmundsson, Julius, Mikaelsdottir, Evgenia, Olason, Pall I, Stefansdottir, Lilja, Eggertsson, Hannes P, Halldorsson, Bjarni V, Thorsteinsdottir, Unnur, Agustsson, Tomas T, Olafsson, Karl, Olafsson, Jon H, Sulem, Patrick, Rafnar, Thorunn, Gudbjartsson, Daniel F, Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: United States 15.04.2021
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-20-3065

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. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in conferred substantial risks of BCC (OR, 8.0; = 1.9 × 10 ), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the locus were associated with BCC, suggesting as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, = 1.6 × 10 ) 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. SIGNIFICANCE: This study identifies the tumor-suppressor gene as a high-impact BCC predisposition gene and indicates that inactivation of by germline sequence variants may also lead to increased risk of cervical cancer.