Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors

Brennan Decker, Danielle M. Karyadi, Brian W. Davis, Eric Karlins, Lori S. Tillmans, Janet L. Stanford, Stephen N Thibodeau, Elaine A. Ostrander

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Human Genetics
DOIs
StateAccepted/In press - Nov 5 2015

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Prostate
Mutation
Prostatic Neoplasms
Neoplasms
Biomarkers
Alleles
Germ-Line Mutation
Neoplasm Grading
Mutation Rate
Mutagenesis
Nucleotides
Genome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Decker, B., Karyadi, D. M., Davis, B. W., Karlins, E., Tillmans, L. S., Stanford, J. L., ... Ostrander, E. A. (Accepted/In press). Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors. American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2016.03.003

Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors. / Decker, Brennan; Karyadi, Danielle M.; Davis, Brian W.; Karlins, Eric; Tillmans, Lori S.; Stanford, Janet L.; Thibodeau, Stephen N; Ostrander, Elaine A.

In: American Journal of Human Genetics, 05.11.2015.

Research output: Contribution to journalArticle

Decker, Brennan ; Karyadi, Danielle M. ; Davis, Brian W. ; Karlins, Eric ; Tillmans, Lori S. ; Stanford, Janet L. ; Thibodeau, Stephen N ; Ostrander, Elaine A. / Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors. In: American Journal of Human Genetics. 2015.
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