Dataset Information

Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy.

ABSTRACT: Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced cancer, but the determinants of response remain poorly understood. Here we report differential effects of mutations in the homologous recombination genes BRCA1 and BRCA2 on response to ICB in mouse and human tumors, and further show that truncating mutations in BRCA2 are associated with superior response compared to those in BRCA1. Mutations in BRCA1 and BRCA2 result in distinct mutational landscapes and differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immunity enriched in BRCA2-deficient tumors. Single-cell RNA sequencing further revealed distinct T cell, natural killer, macrophage, and dendritic cell populations enriched in BRCA2-deficient tumors. Taken together, our findings reveal the divergent effects of BRCA1 and BRCA2-deficiency on ICB outcome, and have significant implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy.

SUBMITTER: Samstein RM

PROVIDER: S-EPMC8023400 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Mutations in <i>BRCA1</i> and <i>BRCA2</i> differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy.

Samstein Robert M RM Krishna Chirag C Ma Xiaoxiao X Pei Xin X Lee Ken-Wing KW Makarov Vladimir V Kuo Fengshen F Chung Jonathan J Srivastava Raghvendra M RM Purohit Tanaya A TA Hoen Douglas R DR Mandal Rajarsi R Setton Jeremy J Wu Wei W Shah Rachna R Qeriqi Besnik B Chang Qing Q Kendall Sviatoslav S Braunstein Lior L Weigelt Britta B Blecua Carrillo Albornoz Pedro P Morris Luc G T LGT Mandelker Diana L DL Reis-Filho Jorge S JS de Stanchina Elisa E Powell Simon N SN Chan Timothy A TA Riaz Nadeem N

Nature cancer 20201116 12

Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced cancer, but the determinants of response remain poorly understood. Here we report differential effects of mutations in the homologous recombination genes BRCA1 and BRCA2 on response to ICB in mouse and human tumors, and further show that truncating mutations in BRCA2 are associated with superior response compared to those in BRCA1. Mutations in BRCA1 and BRCA2 result in distinct mutational landscapes and differenti ...[more]

PMID: 33834176

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Project description:BACKGROUND: Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA repair and is associated with treatment outcome in ovarian cancer. METHODS AND RESULTS: The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated with shorter progression-free survival (PFS) and overall survival (OS), independent of other prognostic factors in multivariate analysis. Patients with mBRCA-associated cancers and a high Nmut had remarkably favorable PFS and OS. The association with survival was similar in cancers with either BRCA1 or BRCA2 mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery. CONCLUSIONS: Tumor Nmut was associated with treatment response and with both PFS and OS in patients with high-grade serous ovarian cancer carrying BRCA1 or BRCA2 mutations. In the TCGA cohort, low Nmut predicted resistance to chemotherapy, and for shorter PFS and OS, while high Nmut forecasts a remarkably favorable outcome in mBRCA-associated ovarian cancer. Our observations suggest that the total mutation burden coupled with BRCA1 or BRCA2 mutations in ovarian cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative mechanisms.

Dataset Information

Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy.

Publications

Mutations in <i>BRCA1</i> and <i>BRCA2</i> differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy.

Similar Datasets

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