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<p>Rare, germline loss-of-function variants in a handful of DNA repair genes are associated with epithelial ovarian cancer. The aim of this study was to evaluate the role of rare, coding, loss-of-function variants across the genome in epithelial ovarian cancer. We carried out a gene-by-gene burden test with various histotypes using data from 2573 non-mucinous cases and 13,923 controls. Twelve genes were associated at a False Discovery Rate of less than 0.1 of which seven were the known ovarian cancer susceptibility genes <i>BRCA1</i>, <i>BRCA2</i>, <i>BRIP1</i>, <i>RAD51C</i>, <i>RAD51D, MSH6</i> and <i>PALB2</i>. The other five genes were <i>OR2T35, HELB, MYO1A</i> and <i>GABRP</i> which were associated with non-high-grade serous ovarian cancer and <i>MIGA1</i> which was associated with high-grade serous ovarian cancer. Further support for the association of <i>HELB</i> association comes from the observation that loss-of-function variants in <i>HELB</i> are associated with age at natural menopause and Mendelian randomisation analysis shows an association between genetically predicted age at natural menopause and endometrioid ovarian cancer, but not high-grade serous ovarian cancer.</p>

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Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月12日

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  • Ed M. Dicks,
  • Jonthan P. Tyrer,
  • Suzana Ezquina,
  • Michelle Jones,
  • John Baierl,
  • Pei-Chen Peng,
  • Michael Diaz,
  • Ellen Goode,
  • Stacey J. Winham,
  • Thilo Dörk,
  • Toon Van Gorp,
  • Anna De Fazio,
  • David D. L. Bowtell,
  • Dale W. Garsed,
  • Kunle Odunsi,
  • Kirsten Moysich,
  • Marina Pavanello,
  • Florentia Fostira,
  • Penelope M. Webb,
  • Jana Soukupová,
  • Paul A. Cohen,
  • Weiva Sieh,
  • Renée Turzanski Fortner,
  • Charite Ricker,
  • Beth Karlan,
  • Ian Campbell,
  • James D. Brenton,
  • Susan J. Ramus,
  • Simon A. Gayther,
  • Paul D. P. Pharoah

摘要

Rare, germline loss-of-function variants in a handful of DNA repair genes are associated with epithelial ovarian cancer. The aim of this study was to evaluate the role of rare, coding, loss-of-function variants across the genome in epithelial ovarian cancer. We carried out a gene-by-gene burden test with various histotypes using data from 2573 non-mucinous cases and 13,923 controls. Twelve genes were associated at a False Discovery Rate of less than 0.1 of which seven were the known ovarian cancer susceptibility genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6 and PALB2. The other five genes were OR2T35, HELB, MYO1A and GABRP which were associated with non-high-grade serous ovarian cancer and MIGA1 which was associated with high-grade serous ovarian cancer. Further support for the association of HELB association comes from the observation that loss-of-function variants in HELB are associated with age at natural menopause and Mendelian randomisation analysis shows an association between genetically predicted age at natural menopause and endometrioid ovarian cancer, but not high-grade serous ovarian cancer.