Gray BRCA
Pre-Cancer Atlas Gray Foundation

Projects

Determinants of immune activity and molecular features in BRCA1/2 mutation carriers

Project Lead: Katherine Nathanson, MD
Team: Domchek

Research Questions:

  • What are the immune functional status in BRCA carriers?
  • Are there associations between molecular and immune status with therapeutic response and survival?
This project aims at creating a biorepository that will allow a better understanding of the interplay between molecular features and immunogenicity in BRCA1/2-associated breast cancer, which represents critical information in the design of novel therapies. The BRCA1 or BRCA2 genes are host to a suite of different mutations that are associated with varying levels of risk. Dr. Katherine Nathanson's group at the University of Pennsylvania has demonstrated the frequency of different BRCA1 and BRCA2 mutations, their distribution around the world, and risk of cancers associated with these mutations. Her team has also characterized tumors associated with BRCA1/2 germline mutations and demonstrated that a significant proportion do not have allele-specific loss of heterozygosity, associated with differential genetic/genomic characteristics and survival after treatment.

Related Publications

Results Comparison Click to Enlarge

  • Shah JB, Pueschl D, Wubbenhorst B, et al. Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers. Nat Commun. 2022 Nov 7;13(1):6728. doi: 10.1038/s41467-022-34523-y. PMID: 36344544; PMCID: PMC9640723.

  • Hakkaart C, Pearson JF, Marquart L, et al. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers. Commun Biol. 2022 Oct 6;5(1):1061. doi: 10.1038/s42003-022-03978-6. PMID: 36203093; PMCID: PMC9537519.

  • Maxwell KN, Patel V, Nead KT, et al. Fanconi anemia caused by biallelic inactivation of BRCA2 can present with an atypical cancer phenotype in adulthood. Clin Genet. 2023 Jan;103(1):119-124. doi: 10.1111/cge.14231. Epub 2022 Sep 26. PMID: 36089892; PMCID: PMC9742260.

    Investigating the origins and early diagnosis of ovarian cancer

    Project Lead: Ronny Drapkin, MD, PhD and Charles Drescher, MD
    The goal of this project is to generate genomic, transcriptomic, and imaging data on early BRCA ovarian lesions to be incorporated into the Gray BRCA Precancer Atlas.

    Related Publications

    Ovarian STIC Project Click to Enlarge

    • Ferrari AJ, Rawat P, Rendulich HS, Annapragada AV, Kinose Y, Zhang X, Devins K, Budina A, Scharpf RB, Mitchell MA, Tanyi JL, Morgan MA, Schwartz LE, Soong TR, Velculescu VE, Drapkin R. H2Bub1 loss is an early contributor to clear cell ovarian cancer progression. JCI Insight 8 (12): e164995. doi: 10.1172/jci.insight.164995. PMID: 37345659. PMCID: PMC10371241.

    Dissecting early pathogenesis of BRCA1/2-associated cancer for risk prediction and prevention

    Project Lead: Leif Ellisen, MD, PhD

    Research Questions:

    • What are the early changes in cells of BRCA carrier breast tissue?
    • What are the BRCA cellular vulnerabilities?
    • What are tissue-based markers for prevention approaches?
    The overarching goal of this proposal is to gain better molecular knowledge of early lesions in order to improve prediction, early detection and cancer prevention for BRCA mutation carriers. While germline mutations in the DNA repair genes BRCA1 and BRCA2 confer dramatically elevated risk of cancers of the breast, ovary and pancreas, the precise pathogenesis of BRCA1/2-associated cancer remains to be elucidated. Dr. Leif Ellisen at MGH is carrying out systematic studies of early events that give rise to these cancers, in part through detailed molecular analysis of normal and pre-cancerous tissues from BRCA1/2 mutation carriers. Defining the altered signaling and early cooperating events in this context may reveal new markers of breast cancer predisposition and new targets for prevention. Dr. Ellisen’s recently published single-cell genome analysis has revealed extensive chromosomal damage in BRCA1/2-mutant breast tissues that precedes any histological abnormalities, implying the existence of early cellular defects and associated vulnerabilities that could be exploited for cancer prevention.

    Related Publications

    Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers Click to Enlarge

    • Karaayvaz-Yildirim M, Silberman RE, Langenbucher A, Saladi SV, Ross KN, Zarcaro E, Desmond A, Yildirim M, Vivekanandan V, Ravichandran H, Mylavagnanam R, Specht MC, Ramaswamy S, Lawrence M, Amon A, Ellisen LW. Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers. Sci Adv. 2020 Jan 29;6(5):eaay2611. doi: 10.1126/sciadv.aay2611. PMID: 32064343; PMCID: PMC6989139.

      Interplay and perturbations of the local microbiome and host immune system in breast cancer

      Project Lead: Charis Eng, MD, PhD

      Research Questions:

      • What are the differences in microbes found with normal versus BRCA breast cancers?
      • How do microbes contribute to immune changes and cancer?
      • Could microbiome engineering prevent cancer?
      The overall goal of this project is to better understand how microbes and the immune system interact and how this affects the development of BRCA breast cancers. Over half of breast cancer cases are unrelated to known risk factors, highlighting the importance of as yet undiscovered determinants of breast cancer risk. Dr. Charis Eng hypothesized that interactions between the breast microbiome and local immune responses to influence breast cancer pathogenesis. Eng’s group is comparing the microbiomes of healthy and diseased breast tissue to identify microbial profiles associated with the disease and reveal how different interactions between the immune system and the breast microbiome relate to disease progression.

      Related Publications

      • Tzeng A, Sangwan N, Jia M, Liu CC, Keslar KS, Downs-Kelly E, Fairchild RL, Al-Hilli Z, Grobmyer SR, Eng C. Human breast microbiome correlates with prognostic features and immunological signatures in breast cancer. Genome Med. 2021 Apr 16;13(1):60. doi: 10.1186/s13073-021-00874-2. PMID: 33863341; PMCID: PMC8052771.

        Devising new strategies to track and prevent breast cancer development in BRCA mutation carriers

        Project Lead: Joan Brugge, PhD
        Team: Brugge, Nathanson, Ellisen, Aparicio, Long, Dillon, Garber

        Research Questions:

        • How do basal and luminal breast cells contribute to BRCA-related cancers?
        • How do BRCA tumor cells evolve?
        • What are the molecular defects during tumor evolution?
        • How do we detection cancer evolution in carriers?
        • How do we intercept and eradicate tumor development?
        The overall goal of this project is to better understand the earliest stages of BRCA cancer development, in order to design strategies to prevent its progression to frank cancer. Dr. Joan Brugge’s laboratory studies the mechanisms of cancer initiation, progression, and drug resistance in breast, ovarian and other BRCA-related cancers. Specifically, Brugge’s team investigates tumor heterogeneity, cell-cell interactions, tumor microenvironment, cancer metabolism, drug resistance, and cell signaling using wide collection of tools, including 3D/organoid cell cultures, genetically-engineered and transplantation-based animal models, single-cell analysis, metabolomics, high-throughput microscopy, and other advanced technologies.

        Related Publications

        A Human Breast Atlas Integrating Single Cell Proteomics and Transcriptomics Click to Enlarge

        • A human breast atlas integrating single-cell proteomics and transcriptomics. Gray GK, Li CM-C, Rosenbluth JM, Selfors LM, Girnius N, Lin J-R, Schackmann RCJ, Goh WL, Moore K, Shapiro HK, Mei S, D’Andrea K, Nathanson KL, Sorger PK, Santagata S, Regev A, Garber JE, Dillon DA, Brugge JS. Dev Cell, 57(11):1400-1420.e7. doi: 10.1016/j.devcel.2022.05.003. PMID: 35617956. PMCID: PMC9202341

        Early detection of cancer in high-risk BRCA mutation carriers using liquid biopsies

        Project Lead: Victor Velculescu, MD, PhD

        Research Questions:

        • What are the molecular characteristics of circulation free DNA in BRCA carriers with and without cancer?
        • What is the strategy for screening?
        The goal of this project is to develop a sensitive blood test that will allow the detection of early BRCA cancers.