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

Cancer Res. 2021 Apr 15;81(8):1954-1964. doi: 10.1158/0008-5472.CAN-20-3065. Epub 2021 Feb 18.


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 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. SIGNIFICANCE: This study identifies the tumor-suppressor gene PTPN14 as a high-impact BCC predisposition gene and indicates that inactivation of PTPN14 by germline sequence variants may also lead to increased risk of cervical cancer.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Carcinoma, Basal Cell / epidemiology
  • Carcinoma, Basal Cell / genetics*
  • Case-Control Studies
  • Exome Sequencing / statistics & numerical data
  • Female
  • Gene Frequency
  • Genes, Tumor Suppressor
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Genome-Wide Association Study
  • Genotype
  • Germ-Line Mutation
  • Humans
  • Iceland / epidemiology
  • Loss of Function Mutation*
  • Male
  • Odds Ratio
  • Penetrance*
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics*
  • Skin Neoplasms / epidemiology
  • Skin Neoplasms / genetics*
  • Tissue Banks / statistics & numerical data
  • United Kingdom / epidemiology
  • Uterine Cervical Neoplasms / epidemiology
  • Uterine Cervical Neoplasms / genetics*
  • Whole Genome Sequencing / statistics & numerical data


  • PTPN14 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor