Purpose: Breast cancers with BRCA1/2 alterations have a relatively high mutational load, suggesting that immune checkpoint blockade may be a potential treatment option. However, the degree of immune cell infiltration varies widely, and molecular features contributing to this variability remain unknown.Experimental Design: We hypothesized that genomic signatures might predict immunogenicity in BRCA1/2 breast cancers. Using The Cancer Genome Atlas (TCGA) genomic data, we compared breast cancers with (89) and without (770) either germline or somatic BRCA1/2 alterations. We also studied 35 breast cancers with germline BRCA1/2 mutations from Penn using WES and IHC.Results: We found that homologous recombination deficiency (HRD) scores were negatively associated with expressionbased immune indices [cytolytic index (P ¼ 0.04), immune ESTIMATE (P ¼ 0.002), type II IFN signaling (P ¼ 0.002)] despite being associated with a higher mutational/neoantigen burden, in BRCA1/2 mutant breast cancers. Further, absence of allele-specific loss of heterozygosity (LOH negative; P ¼ 0.01) or subclonality (P ¼ 0.003) of germline and somatic BRCA1/2 mutations, respectively, predicted for heightened cytolytic activity. Gene set analysis found that multiple innate and adaptive immune pathways that converge on NF-kB may contribute to this heightened immunogenicity. IHC of Penn breast cancers demonstrated increased CD45 þ (P ¼ 0.039) and CD8 þ infiltrates (P ¼ 0.037) and increased PDL1 expression (P ¼ 0.012) in HRD-low or LOH-negative cancers. Triple-negative cancers with low HRD had far greater CD8 þ T cells (P ¼ 0.0011) and Perforin 1 expression (P ¼ 0.014) compared with hormone receptor-positive HRD-high cancers.Conclusions: HRD scores and hormone receptor subtype are predictive of immunogenicity in BRCA1/2 breast cancers and may inform the design of optimal immune therapeutic strategies.
Germline mutations in the tumor suppressors BRCA1 and BRCA2 lead to increased risks of breast and ovarian cancers at least in part due to their roles in homologous recombination based double stranded DNA repair. Genetic alterations including loss of the wild-type BRCA1/2 allele, PTEN loss and TP53 mutations are thought to contribute to genomic instability in susceptible tissues and therefore tumor formation. In order to further investigate the mechanisms of tumorigenesis in BRCA1/2 carriers, we performed whole exome sequencing of 39 breast and ovarian tumors and matched blood germline DNA. Sequencing data were analyzed using GATK and MuTECT for variant calls and ngCGH and Sequenza for copy number analysis. Using cellularity corrected tumor versus germline allele frequency calculations, we found no evidence of loss of heterozygosity (LOH) in 17% of BRCA1 tumors (n = 4 of 24) and 40% of BRCA2 tumors (n = 6 of 15). Genomic instability as measured by percentage of genome in the diploid state showed that BRCA1/2 tumors with no evidence of LOH had decreased genomic instability (average% genome diploid 76+27% vs 57+16%, p = 0.01) with no difference in the overall somatic mutation rate (average 50+71 vs 83+156 single nucleotide variants per megabase, p = NS). While there were also no significant differences in the average number of predicted deleterious somatic mutations in BRCA1/2 tumors with no LOH versus tumors with LOH (n = 13+15 vs 13+6, p = NS), tumors without LOH were significantly less likely to have mutations or loss in TP53 or loss of PTEN (50% versus 93%, p = 0.007). Of the ten tumors with no LOH, five were from patients who had received prior cytotoxic chemotherapy. Other tumors with no LOH were from patients with atypical presentations including a mixed histology epithelial ovarian tumor in a BRCA1 carrier, and a triple negative breast cancer in a 70 year old BRCA2 carrier. Of the 29 tumors with evidence of LOH, no patient had received cytotoxic chemotherapy for a prior malignancy or in the neoadjuvant setting. No recurrent driver mutations other than TP53 mutations were identified in the BRCA1/2 tumors with or without LOH. Twenty-six pathogenic likely driver mutations were identified in 25 cancer genes outside of TP53, including NRAS, PIK3CA, and ABL2. Our results indicate that approximately 75% of tumors in BRCA1/2 germline mutation carriers arise via a classic pathway involving LOH of the wildtype allele, loss of function of TP53 and/or PTEN and significant genomic instability. However, approximately 25% of tumors may arise via an alternative pathway, possibly related to prior chemotherapy in some cases. Further studies are needed to determine the molecular and clinical factors associated with this proposed classic versus atypical pathway of tumorigenesis in BRCA1/2 carriers and whether these characteristics are associated with outcomes such as survival and platinum and/or PARP inhibitor sensitivity. Citation Format: Kara N. Maxwell, Daniel De Sloover, Bradley Wubbenhorst, Brandon Wenz, Nicole Lunceford, Lyndsey Emery, Kurt D'Andrea, Robert D. Daber, Michael D. Feldman, Susan M. Domchek, Katherine L. Nathanson. Evidence for diverse mechanisms of tumorigenesis in breast and ovarian tumors of BRCA1/2 carriers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2990. doi:10.1158/1538-7445.AM2015-2990
<p>Differentially regulated canonical pathways by HRD level in BRCA1/2 Mutated Breast Cancers</p>
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