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<p>More than 80% of patients who meet clinical criteria for hereditary breast and ovarian cancer (HBOC) do not show pathogenic variants in <i>BRCA1, BRCA2</i>, and other diagnostically consented core genes. We hypothesized that variants in further DNA repair genes, cryptic genomic alterations, or polygenic factors may explain HBOC risk. We studied 134 patients with breast cancer and/or ovarian cancer by the use of whole genome sequencing (WGS), whole transcriptome sequencing (WTS), optical genome mapping (OGM), and mobile element analysis. We identified (likely) pathogenic variants in DNA repair genes in 18 patients, including several RECQ helicase and other DNA repair genes, an intragenic <i>FANCM</i> deletion, and six rare mobile element insertions (MEIs) in DNA repair genes. Incorporating PRS306 shifted estimated lifetime breast cancer risk by ≥5 percentage points in a subset of women (<i>n</i> = 75), including carriers of rare variants in DNA repair genes, resulting in both upward and downward risk estimation.</p>

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Multi-omics analysis in suspected hereditary breast and ovarian cancer cases reveals novel candidate susceptibility factors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • B. Aldrige Allister,
  • Winfried Hofmann,
  • Jonathan L. Lühmann,
  • Björn Sander,
  • Lena Wendeburg,
  • Gunnar Schmidt,
  • Bernd Auber,
  • Susanne Morlot,
  • Hannah Wallaschek,
  • Nataliya di Donato,
  • Brigitte Schlegelberger,
  • Monika M. Golas,
  • Doris Steinemann

摘要

More than 80% of patients who meet clinical criteria for hereditary breast and ovarian cancer (HBOC) do not show pathogenic variants in BRCA1, BRCA2, and other diagnostically consented core genes. We hypothesized that variants in further DNA repair genes, cryptic genomic alterations, or polygenic factors may explain HBOC risk. We studied 134 patients with breast cancer and/or ovarian cancer by the use of whole genome sequencing (WGS), whole transcriptome sequencing (WTS), optical genome mapping (OGM), and mobile element analysis. We identified (likely) pathogenic variants in DNA repair genes in 18 patients, including several RECQ helicase and other DNA repair genes, an intragenic FANCM deletion, and six rare mobile element insertions (MEIs) in DNA repair genes. Incorporating PRS306 shifted estimated lifetime breast cancer risk by ≥5 percentage points in a subset of women (n = 75), including carriers of rare variants in DNA repair genes, resulting in both upward and downward risk estimation.