title: Assessment of PALB2 as a candidate melanoma susceptibility gene.
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.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; University of Queensland, Brisbane, QLD, Australia.
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Aoude
authors.affiliation: National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Mai
authors.initials: M
authors.lastname: Xu
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Zhen Zhen
authors.initials: ZZ
authors.lastname: Zhao
authors.affiliation: National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Kovacs
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Palmer
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Johansson
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Judith
authors.initials: J
authors.lastname: Symmons
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Trent
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: National Cancer Institute, Bethesda, Maryland, United States of America; Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
mesh_terms: D024682:BRCA2 Protein / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004252:DNA Mutational Analysis; D004260:DNA Repair; D000076164:Fanconi Anemia Complementation Group N Protein; D020022:Genetic Predisposition to Disease; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D012878:Skin Neoplasms; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000096142:Cutaneous Malignant Melanoma
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins