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

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

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, 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 SoukupováPaul 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

Obstetrics and Gynaecology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	100079
Number of pages	7
Journal	European Journal of Human Genetics
DOIs	https://doi.org/10.1038/s41431-025-01786-0
Publication status	E-pub ahead of print - 12 Feb 2025

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10.1038/s41431-025-01786-0Licence: CC BY

NHMRC Enabling Grant 310670 - Australian Biospecimen Network-Oncology
Lake, R. (Chief Investigator), Robinson, B. (Chief Investigator), Zeps, N. (Chief Investigator), Devereux, L. (Chief Investigator), Catchpoole, D. (Chief Investigator), De Fazio, A. (Chief Investigator), Holloway, A. (Chief Investigator), Schmidt, C. (Chief Investigator) & Thorne, H. (Chief Investigator)
Sundry Grants
1/01/04 → 31/12/08
Project: Research

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Dicks, E. M., Tyrer, J. P., Ezquina, S., Jones, M., Baierl, J., Peng, P.-C., Diaz, M., Goode, E., Winham, S. J., Dörk, T., Gorp, T. V., Fazio, A. D., Bowtell, D. D. L., Garsed, D. W., Odunsi, K., Moysich, K., Pavanello, M., Fostira, F., Webb, P. M., ... Pharoah, P. D. P. (2025). Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer. European Journal of Human Genetics, Article 100079. Advance online publication. https://doi.org/10.1038/s41431-025-01786-0

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

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.",

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doi = "10.1038/s41431-025-01786-0",

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Dicks, EM, Tyrer, JP, Ezquina, S, Jones, M, Baierl, J, Peng, P-C, Diaz, M, Goode, E, Winham, SJ, Dörk, T, Gorp, TV, Fazio, AD, Bowtell, DDL, Garsed, DW, Odunsi, K, Moysich, K, Pavanello, M, Fostira, F, Webb, PM, Soukupová, J, Cohen, PA, Sieh, W, Fortner, RT, Ricker, C, Karlan, B, Campbell, I, Brenton, JD, Ramus, SJ, Gayther, SA & Pharoah, PDP 2025, 'Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer', European Journal of Human Genetics. https://doi.org/10.1038/s41431-025-01786-0

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T1 - Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer

AU - Dicks, Ed M

AU - Tyrer, Jonthan P

AU - Ezquina, Suzana

AU - Jones, Michelle

AU - Baierl, John

AU - Peng, Pei-Chen

AU - Diaz, Michael

AU - Goode, Ellen

AU - Winham, Stacey J

AU - Dörk, Thilo

AU - Gorp, Toon Van

AU - Fazio, Anna De

AU - Bowtell, David D L

AU - Garsed, Dale W

AU - Odunsi, Kunle

AU - Moysich, Kirsten

AU - Pavanello, Marina

AU - Fostira, Florentia

AU - Webb, Penelope M

AU - Soukupová, Jana

AU - Cohen, Paul A

AU - Sieh, Weiva

AU - Fortner, Renée Turzanski

AU - Ricker, Charite

AU - Karlan, Beth

AU - Campbell, Ian

AU - Brenton, James D

AU - Ramus, Susan J

AU - Gayther, Simon A

AU - Pharoah, Paul D P

PY - 2025/2/12

Y1 - 2025/2/12

N2 - 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.

AB - 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.

U2 - 10.1038/s41431-025-01786-0

DO - 10.1038/s41431-025-01786-0

M3 - Article

C2 - 39939714

SN - 1018-4813

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

M1 - 100079

ER -

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

Abstract

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NHMRC Enabling Grant 310670 - Australian Biospecimen Network-Oncology

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