| Title: | Loss-of-Function Variants in the Tumor-Suppressor Gene PTPN14 Confer Increased Cancer Risk |
| Journal: | Cancer Research |
| Published: | 18 Feb 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/33602785/ |
| DOI: | https://doi.org/10.1158/0008-5472.can-20-3065 |
| URL: | https://aacrjournals.org/cancerres/article-pdf/81/8/1954/3090481/1954.pdf |
Publication 9556
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Abstract
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.</p>
39 Authors
- Thorhildur Olafsdottir
- Simon N Stacey
- Gardar Sveinbjornsson
- Gudmar Thorleifsson
- Kristjan Norland
- Bardur Sigurgeirsson
- Kristin Thorisdottir
- Arni Kjalar Kristjansson
- Laufey Tryggvadottir
- Kavita Y Sarin
- Rafn Benediktsson
- Jon G Jonasson
- Asgeir Sigurdsson
- Aslaug Jonasdottir
- Snaedis Kristmundsdottir
- Hakon Jonsson
- Arnaldur Gylfason
- Asmundur Oddsson
- Run Fridriksdottir
- Sigurjon A Gudjonsson
- Florian Zink
- Sigrun H Lund
- Solvi Rognvaldsson
- Pall Melsted
- Valgerdur Steinthorsdottir
- Julius Gudmundsson
- Evgenia Mikaelsdottir
- Pall I Olason
- Lilja Stefansdottir
- Hannes P Eggertsson
- Bjarni V Halldorsson
- Unnur Thorsteinsdottir
- Tomas T Agustsson
- Karl Olafsson
- Jon H Olafsson
- Patrick Sulem
- Thorunn Rafnar
- Daniel F Gudbjartsson
- Kari Stefansson
1 Application
| Application ID | Title |
|---|---|
| 56270 | Evaluating and comparing sequence variant associations between the deCODE and UK Biobank datasets across a range of human traits |
Enabling scientific discoveries that improve human health