The contribution of rare germline variants to the immune landscape of breast cancer
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Many breast cancer predisposition genes are involved in DNA damage repair, leading to genome instability that can impact immunosurveillance, neoantigen formation, and the composition of the tumor immune microenvironment. METHODS: Here, we explored associations between germline protein truncating variants (PTVs) in 34 (putative) breast cancer predisposition genes, of which 26 involved in DNA damage repair, with the abundance of four immune cell markers, i.e., CD8 + , FOXP3 + , CD20 + and CD163 + , across 7,969 invasive breast tumors of women of European ancestry. RESULTS: The most apparent associations were those of CD163, a marker of M2-like tumor-associated macrophages, with genes involved in double- and single-strand break DNA repair, and with the 12 known breast cancer predisposition genes combined. Specifically, DNA damage repair genes, BRCA1, BRCA2, PALB2, RAD51D, and MSH6 were associated with a 1.3 to twofold abundance of CD163-positive cells. Estrogen receptor status was found to mediate associations to a limited extent. CONCLUSIONS: Our findings support a role of rare pathogenic germline variants involved in DNA damage repair, and particularly those predisposing to breast cancer, in the immune landscape of breast tumors. These insights may help guide the development of immunomodulatory strategies for breast cancer prevention and treatment.
Source: Genome Medicine
Authors: Felipe Rojas-Rodríguez, Sander Canisius, Renske Keeman, Aaron J. Bernstein, Amber N. Hurson, Thomas U. Ahearn, Irene L. Andrulis, Antonis C. Antoniou, Sabine Behrens, Katarzyna Białkowska, Fiona M. Blows, Manjeet K. Bolla, Nicola J. Camp, Melissa H. Cessna, Jenny Chang-Claude, Stephen J. Chanock, Joe Dennis, Peter Devilee, Alison M. Dunning, Jacek Gronwald, Ute Hamann, Antoinette Hollestelle, Maartje J. Hooning, Hugo M. Horlings, Agnes Jager, Anna Jakubowska, Brandt Jones, Rudolf Kaaks, Marleen Kok, Jolanta Lissowska, Jan Lubiński, Mehdi Manoochehri, Jodi L. Miller, Noor Muhammad, Anna Marie Mulligan, Nadia Obi, Muhammad U. Rashid, Hans-Peter Sinn, Carolien H. M. van Deurzen, Qin Wang, Justin A. Williams, Xiaohong R. Yang, Douglas F. Easton, H. Raza Ali, Montserrat García-Closas, Paul D. P. Pharoah, Mustapha Abubakar, Marjanka K. Schmidt
Institutions: The Netherlands Cancer Institute, National Institutes of Health, University of Cambridge, National Cancer Institute, National Center for Advancing Translational Sciences, Division of Cancer Epidemiology and Genetics, Mount Sinai Hospital, University of Toronto, Lunenfeld-Tanenbaum Research Institute, German Cancer Research Center, Pomeranian Medical University, University of Utah, Huntsman Cancer Institute, Intermountain Healthcare, Intermountain Medical Center, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, Leiden University Medical Center, Erasmus MC Cancer Institute, The Maria Sklodowska-Curie National Research Institute of Oncology, Cancer Research UK Cambridge Center, Shaukat Khanum Memorial Cancer Hospital and Research Center, University Health Network, Heidelberg University, University Hospital Heidelberg, Erasmus MC, Cancer Research UK, Institute of Cancer Research, Cedars-Sinai Medical Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,290
OpenAlex ID: W7160631430