Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease.
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Date
2018-07-03Author
Mijuskovic, M
Saunders, EJ
Leongamornlert, DA
Wakerell, S
Whitmore, I
Dadaev, T
Cieza-Borrella, C
Govindasami, K
Brook, MN
Haiman, CA
Conti, DV
Eeles, RA
Kote-Jarai, Z
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. METHODS: We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. RESULTS: Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. CONCLUSIONS: Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application.
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Subject
Humans
Prostatic Neoplasms
Neoplasm Metastasis
Genetic Predisposition to Disease
Neovascularization, Pathologic
Cell Cycle Proteins
BRCA2 Protein
Nuclear Proteins
DNA Repair
Polymorphism, Single Nucleotide
Aged
Middle Aged
Male
Genetic Association Studies
Ataxia Telangiectasia Mutated Proteins
Whole Exome Sequencing
Research team
Oncogenetics
Language
eng
Date accepted
2018-05-17
License start date
2018-07
Citation
British journal of cancer, 2018, 119 (1), pp. 96 - 104
Publisher
SPRINGERNATURE