The contribution of rare germline variants to the immune landscape of breast cancer

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.

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Publication Details

Journal
Genome Medicine
Published
2026-05-09
DOI
https://doi.org/10.1186/s13073-026-01662-6
Primary Topic
Genetic factors in colorectal cancer
Type
article
Field-Weighted Citation Impact
0.00

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article

The contribution of rare germline variants to the immune landscape of breast cancer

Jolanta Lissowska, Hans‐Peter Sinn, Melissa H. Cessna, Alison M. Dunning et al.
Genome Medicine
Genetic factors in colorectal cancer
article

The contribution of rare germline variants to the immune landscape of breast cancer

Jolanta Lissowska, Hans‐Peter Sinn, Melissa H. Cessna, Alison M. Dunning, Katarzyna Białkowska, Sabine Behrens, Anna Marie Mulligan, Nadia Obi, Fiona M. Blows, Brandt Jones, Renske Keeman, Montserrat García‐Closas, Felipe Rojas-Rodríguez, Justin A. Williams, Manjeet K. Bolla, Aaron J. Bernstein, Qin Wang, Rudolf Kaaks, Maartje J. Hooning, Amber N. Hurson, Hugo M. Horlings, Ute Hamann, Anna Jakubowska, Stephen J Chanock, Carolien H. M. van Deurzen, Xiaohong R. Yang, Irene L. Andrulis, Peter Devilee, Jan Lubiński, Nicola J. Camp, Agnes Jager, Noor Muhammad, Antoinette Hollestelle, Mustapha Abubakar, Douglas F. Easton, Marjanka K. Schmidt, Mehdi Manoochehri, Muhammad U. Rashid, Sander Canisius, Jenny Chang-Claude, Jacek Gronwald, Paul D. P. Pharoah, Marleen Kok, Thomas U. Ahearn, Antonis C. Antoniou, Joe Dennis, H. Raza Ali, Jodi L. Miller
article en

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.

Genome Medicine
Intermountain Healthcare (US), Cedars-Sinai Medical Center (US), National Institutes of Health (US), University Health Network (CA), Institute of Cancer Research (GB), Universität Hamburg (DE), German Cancer Research Center (DE), University of Toronto (CA), Lunenfeld-Tanenbaum Research Institute (CA), University of Utah (US), Heidelberg University (DE), University of Cambridge (GB), Leiden University Medical Center (NL), Huntsman Cancer Institute (US), Cancer Research UK (GB), Erasmus MC (NL), University Hospital Heidelberg (DE), Intermountain Medical Center (US), Cancer Research UK Cambridge Center (GB), University Medical Center Hamburg-Eppendorf (DE), National Institute of Oncology (HU), Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NL), University Cancer Center Hamburg (DE), Shaukat Khanum Memorial Cancer Hospital and Research Center (PK), National Cancer Institute (US), National Center for Advancing Translational Sciences (US), Sinai Health System (US), Erasmus MC Cancer Institute (NL), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Pomeranian Medical University (PL)
Horizon 2020 Framework Programme
Good health and well-being
Openalex Percentile: Top 7%
Genetic factors in colorectal cancer
DOIOpen Access PDFOpenAlex
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