Assessment of PALB2 as a candidate melanoma susceptibility gene

Lauren G Aoude; Mai Xu; Zhen Zhen Zhao; Michael Kovacs; Jane M Palmer; Peter Johansson; Judith Symmons; Jeffrey M Trent; Nicholas G Martin; Grant W Montgomery; Kevin M Brown; Nicholas K Hayward

doi:10.1371/journal.pone.0100683

Assessment of PALB2 as a candidate melanoma susceptibility gene

PLoS One. 2014 Jun 20;9(6):e100683. doi: 10.1371/journal.pone.0100683. eCollection 2014.

Affiliations

¹ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; University of Queensland, Brisbane, QLD, Australia.
² National Cancer Institute, Bethesda, Maryland, United States of America.
³ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁴ Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
⁵ National Cancer Institute, Bethesda, Maryland, United States of America; Translational Genomics Research Institute, Phoenix, Arizona, United States of America.

Abstract

Partner and localizer of BRCA2 (PALB2) interacts with BRCA2 to enable double strand break repair through homologous recombination. Similar to BRCA2, germline mutations in PALB2 have been shown to predispose to Fanconi anaemia as well as pancreatic and breast cancer. The PALB2/BRCA2 protein interaction, as well as the increased melanoma risk observed in families harbouring BRCA2 mutations, makes PALB2 a candidate for melanoma susceptibility. In order to assess PALB2 as a melanoma predisposition gene, we sequenced the entire protein-coding sequence of PALB2 in probands from 182 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, and BAP1. In addition, we interrogated whole-genome and exome data from another 19 kindreds with a strong family history of melanoma for deleterious mutations in PALB2. Here we report a rare known deleterious PALB2 mutation (rs118203998) causing a premature truncation of the protein (p.Y1183X) in an individual who had developed four different cancer types, including melanoma. Three other family members affected with melanoma did not carry the variant. Overall our data do not support a case for PALB2 being associated with melanoma predisposition.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

BRCA2 Protein / metabolism
DNA Breaks, Double-Stranded
DNA Mutational Analysis*
DNA Repair
Fanconi Anemia Complementation Group N Protein
Genetic Predisposition to Disease*
Humans
Melanoma / genetics*
Melanoma / pathology
Melanoma, Cutaneous Malignant
Mutation
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Pedigree
Skin Neoplasms
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism

Substances

BRCA2 Protein
BRCA2 protein, human
Fanconi Anemia Complementation Group N Protein
Nuclear Proteins
PALB2 protein, human
Tumor Suppressor Proteins

Grants and funding

This work was supported by the Melanoma Research Alliance and the National Health and Medical Research Council (NHMRC) of Australia. NKH and GWM receive salary support through a NHMRC Senior Principal Research Fellowship. LGA receives salary support by the Australia and New Zealand Banking Group Limited Trustees PhD scholarship. KMB is supported by the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.