. 2025 Mar;33(3):297-303.

doi: 10.1038/s41431-025-01786-0. Epub 2025 Feb 12.

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

Ed M Dicks¹, Jonthan P Tyrer¹, Suzana Ezquina¹, Michelle Jones², John Baierl³, Pei-Chen Peng³, Michael Diaz², Ellen Goode⁴, Stacey J Winham⁴, Thilo Dörk⁵, Toon Van Gorp⁶, Anna De Fazio^{7

8

9}, David D L Bowtell^{10

11}, Dale W Garsed^{10

11}, Kunle Odunsi¹², Kirsten Moysich¹³, Marina Pavanello¹⁴, Florentia Fostira¹⁵, Penelope M Webb¹⁶, Jana Soukupová¹⁷, Paul A Cohen¹⁸, Weiva Sieh¹⁹, Renée Turzanski Fortner^{20

21}, Charite Ricker²², Beth Karlan²³, Ian Campbell^{10

11}, James D Brenton²⁴, Susan J Ramus^{14

25}, Simon A Gayther²⁶, Paul D P Pharoah²⁷

Affiliations

¹ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
² Department of Biomedical Sciences, Cedars-Sinai Medical Centre, Los Angeles, CA, USA.
³ Department of Computational Biomedicine, Cedars-Sinai Medical Centre, Los Angeles, CA, USA.
⁴ Mayo Clinic, Rochester, MN, USA.
⁵ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
⁶ Division of Gynaecological Oncology, Leuven Cancer Institute, University Hospital Leuven and KU Leuven, Leuven, Belgium.
⁷ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia.
⁸ The Daffodil Centre, The University of Sydney, A JOINT Venture with Cancer Council NSW, Sydney, NSW, Australia.
⁹ Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.
¹⁰ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹¹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
¹² University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA.
¹³ Division of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
¹⁴ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW, Australia.
¹⁵ Human Molecular Genetics Laboratory, National Centre for Scientific Research, Athens, Greece.
¹⁶ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹⁷ Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia.
¹⁸ Division of Obstetrics and Gynaecology, Medical School, University of Western Australia, Crawley, WA, Australia.
¹⁹ MD Anderson Cancer Center, Houston, TX, USA.
²⁰ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
²¹ Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway.
²² Keck School of Medicine, Division of Medical Oncology, University of Southern California, Los Angeles, CA, USA.
²³ University of California Los Angeles, Los Angeles, CA, USA.
²⁴ Department of Oncology, University of Cambridge, Cambridge, UK.
²⁵ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW, Sydney, NSW, Australia.
²⁶ Center for Inherited Oncogenesis, Department of Medicine, UT Health San Antonio, San Antonio, Texas, USA.
²⁷ Department of Computational Biomedicine, Cedars-Sinai Medical Centre, Los Angeles, CA, USA. paul.pharoah@cshs.org.

PMID: 39939714
PMCID: PMC11894177
DOI: 10.1038/s41431-025-01786-0

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

Ed M Dicks et al. Eur J Hum Genet. 2025 Mar.

. 2025 Mar;33(3):297-303.

doi: 10.1038/s41431-025-01786-0. Epub 2025 Feb 12.

Authors

Affiliations

¹ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
² Department of Biomedical Sciences, Cedars-Sinai Medical Centre, Los Angeles, CA, USA.
³ Department of Computational Biomedicine, Cedars-Sinai Medical Centre, Los Angeles, CA, USA.
⁴ Mayo Clinic, Rochester, MN, USA.
⁵ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
⁶ Division of Gynaecological Oncology, Leuven Cancer Institute, University Hospital Leuven and KU Leuven, Leuven, Belgium.
⁷ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia.
⁸ The Daffodil Centre, The University of Sydney, A JOINT Venture with Cancer Council NSW, Sydney, NSW, Australia.
⁹ Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.
¹⁰ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹¹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
¹² University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA.
¹³ Division of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
¹⁴ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW, Australia.
¹⁵ Human Molecular Genetics Laboratory, National Centre for Scientific Research, Athens, Greece.
¹⁶ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹⁷ Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia.
¹⁸ Division of Obstetrics and Gynaecology, Medical School, University of Western Australia, Crawley, WA, Australia.
¹⁹ MD Anderson Cancer Center, Houston, TX, USA.
²⁰ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
²¹ Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway.
²² Keck School of Medicine, Division of Medical Oncology, University of Southern California, Los Angeles, CA, USA.
²³ University of California Los Angeles, Los Angeles, CA, USA.
²⁴ Department of Oncology, University of Cambridge, Cambridge, UK.
²⁵ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW, Sydney, NSW, Australia.
²⁶ Center for Inherited Oncogenesis, Department of Medicine, UT Health San Antonio, San Antonio, Texas, USA.
²⁷ Department of Computational Biomedicine, Cedars-Sinai Medical Centre, Los Angeles, CA, USA. paul.pharoah@cshs.org.

PMID: 39939714
PMCID: PMC11894177
DOI: 10.1038/s41431-025-01786-0

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethicals approval: The exome sequencing for this study was approved by the Institutional Review Board of the University of Southern California Health Sciences Campus (HS-11-0061) and the Human Research Ethics Advisory Panels A and D of the University of New South Wales (HC16225 and HC210636). Details of the ethics approvals for the constituent studies are provided in Supplementary Table 4.

Figures

**Fig. 1**
QQ plot for association analysis of genes with at least one case or control loss-of-function variant carrier in the non-UK Biobank data set (three genes with smallest P-values excluded).

**Fig. 2. Power to detect risk alleles by carrier frequency and effect size (odds ratio) at a type 1 error probability of 5 × 10⁻⁴.**
A 2630 cases and 15,000 controls—the carrier frequency and effect size corresponding to BRCA1, BRIP1 and RAD51C are shown for reference. B 20,000 cases and 20,000 controls.

See this image and copyright information in PMC

Update of

Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer.
Dicks EM, Tyrer JP, Ezquina S, Jones M, Baierl J, Peng PC, Diaz M, Goode E, Winham SJ, Dörk T, Van Gorp T, De Fazio A, Bowtell D, Odunsi K, Moysich K, Pavanello M, Campbell I, Brenton JD, Ramus SJ, Gayther SA, Pharoah PDP. Dicks EM, et al. medRxiv [Preprint]. 2024 Apr 3:2024.04.02.24304968. doi: 10.1101/2024.04.02.24304968. medRxiv. 2024. Update in: Eur J Hum Genet. 2025 Mar;33(3):297-303. doi: 10.1038/s41431-025-01786-0. PMID: 38633804 Free PMC article. Updated. Preprint.

References

1. Ramus SJ, Song H, Dicks E, Tyrer JP, Rosenthal AN, Intermaggio MP, et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst 2015; 107. - PMC - PubMed
1. Song H, Dicks E, Ramus SJ, Tyrer JP, Intermaggio MP, Hayward J, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol. 2015;33:2901–7. - PMC - PubMed
1. Song H, Dicks EM, Tyrer J, Intermaggio M, Chenevix-Trench G, Bowtell DD, et al. Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer. J Med Genet. 2021;58:305–13. - PMC - PubMed
1. Phelan CM, Kuchenbaecker KB, Tyrer JP, Kar SP, Lawrenson K, Winham SJ, et al. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. Nat Genet. 2017;49:680–91. - PMC - PubMed
1. Dareng EO, Coetzee SG, Tyrer JP, Peng PC, Rosenow W, Chen S, et al. Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions. Am J Hum Genet. 2024; 111: 1061–83. - PMC - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous