Journal Article

POT1 loss-of-function variants predispose to familial melanoma

Gartside, Michael G, Johansson, Peter, Petljak, Mia, Quesada, Víctor, Keane, Thomas M, Choi, Jiyeon, Makowski, Matthew, Harland, Mark, Tiffen, Jessamy C, Brown, Kevin M, Adams, David J, Snowden, Helen, López-Otín, Carlos, Liu, Jimmy Z, Symmons, Judith, Pritchard, Antonia L, Montgomery, Grant W, Aoude, Lauren G, Martin, Nicholas G, Stark, Mitchell S, Dunning, Alison M, Ding, Zhihao, Pooley, Karen A, Ramsay, Andrew J, Palmer, Jane M, Newton-Bishop, Julia A, Gruis, Nelleke A, Bishop, D Timothy, Robles-Espinoza, Carla Daniela, Hayward, Nicholas K

2014

Overview

David Adams, Julia Newton-Bishop, Timothy Bishop, Nicholas Hayward and colleagues identify loss-of-function variants in POT1 in several families with early onset multiple primary melanoma. They further show that these variants disrupt telomere binding by POT1 and are associated with increased telomere length. Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases 1 , and rare variants in CDK4 , BRCA2 , BAP1 and the promoter of TERT have also been linked to the disease 2 , 3 , 4 , 5 . Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene ( POT1 ), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/23 / 631/208 / 692/699/67/1813/1634 / Agriculture / Amino Acid Sequence / Animal Genetics and Genomics / Australia / Base Sequence / Biomedicine / Breast cancer / Cancer Research / Gene Function / Gene mutations / Genetic aspects / Genetic Predisposition to Disease - genetics / Genetic research / Genetic susceptibility / Genomes / Health aspects / Health risk assessment / Human Genetics / Humans / letter / Medical research / Melanoma / Melanoma - genetics / Melanoma, Cutaneous Malignant / Models, Molecular / Molecular Sequence Data / Netherlands / Pedigree / Protein Binding / Proteins / Reverse Transcriptase Polymerase Chain Reaction / Risk factors / Sequence Alignment / Sequence Analysis, DNA / Shelterin Complex / Skin cancer / Skin Neoplasms / Telomere - chemistry / Telomere - genetics / Telomere - metabolism / Telomere-Binding Proteins - chemistry / Telomere-Binding Proteins - genetics / Telomere-Binding Proteins - metabolism / Telomeres / United Kingdom