title: Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors.
abstract: To identify clinically important molecular subtypes of prostate cancer (PCa), we characterized the somatic landscape of aggressive tumors via deep, whole-genome sequencing. In our discovery set of ten tumor/normal subject pairs with Gleason scores of 8-10 at diagnosis, coordinated analysis of germline and somatic variants, including single-nucleotide variants, indels, and structural variants, revealed biallelic BRCA2 disruptions in a subset of samples. Compared to the other samples, the PCa BRCA2-deficient tumors exhibited a complex and highly specific mutation signature, featuring a 2.88-fold increased somatic mutation rate, depletion of context-specific C>T substitutions, and an enrichment for deletions, especially those longer than 10 bp. We next performed a BRCA2 deficiency-targeted reanalysis of 150 metastatic PCa tumors, and each of the 18 BRCA2-mutated samples recapitulated the BRCA2 deficiency-associated mutation signature, underscoring the potent influence of these lesions on somatic mutagenesis and tumor evolution. Among all 21 individuals with BRCA2-deficient tumors, only about half carried deleterious germline alleles. Importantly, the somatic mutation signature in tumors with one germline and one somatic risk allele was indistinguishable from those with purely somatic mutations. Our observations clearly demonstrate that BRCA2-disrupted tumors represent a unique and clinically relevant molecular subtype of aggressive PCa, highlighting both the promise and utility of this mutation signature as a prognostic and treatment-selection biomarker. Further, any test designed to leverage BRCA2 status as a biomarker for PCa must consider both germline and somatic mutations and all types of deleterious mutations.
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
authors.forename: Brennan
authors.initials: B
authors.lastname: Decker
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Karyadi
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Davis
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Karlins
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Tillmans
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stanford
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: eostrand@mail.nih.gov.
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
mesh_terms: D000368:Aged; D000483:Alleles; D024682:BRCA2 Protein / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000556:secondary*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human