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Background <p>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.</p> Methods <p>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.</p> Results <p>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, <i>BRCA1</i>, <i>BRCA2</i>, <i>PALB2</i>, <i>RAD51D</i>, and <i>MSH6</i> 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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • 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

摘要

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.