Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing
Abstract High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-o...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-024-00447-3 |
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| author | Deepak N. Subramanian Maia Zethoven Kathleen I. Pishas Evanny R. Marinović Simone McInerny Simone M. Rowley Prue E. Allan Lisa Devereux Dane Cheasley Paul A. James Ian G. Campbell |
| author_facet | Deepak N. Subramanian Maia Zethoven Kathleen I. Pishas Evanny R. Marinović Simone McInerny Simone M. Rowley Prue E. Allan Lisa Devereux Dane Cheasley Paul A. James Ian G. Campbell |
| author_sort | Deepak N. Subramanian |
| collection | DOAJ |
| description | Abstract High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls. This confirms enrichment for nearly all previously identified genes. Additionally, one-hundred-and-eleven HGSOC tumours from variant carriers were sequenced alongside other complementary studies, seeking evidence of biallelic inactivation as supportive evidence. PALB2 and ATM validate as HGSOC predisposition genes, with 6/8 germline carrier tumours exhibiting biallelic inactivation accompanied by characteristic mutational signatures. Among candidate genes, only LLGL2 consistently shows biallelic inactivation and protein expression loss, supporting it as a novel HGSOC susceptibility gene. The remaining candidate genes fail to validate. Integrating case-control analyses with tumour sequencing is thus crucial for accurate gene discovery in familial cancer studies. |
| format | Article |
| id | doaj-art-18f591b9005448beb5d1a0ed8f98a2b6 |
| institution | Kabale University |
| issn | 2056-7944 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj-art-18f591b9005448beb5d1a0ed8f98a2b62025-01-12T12:33:49ZengNature Portfolionpj Genomic Medicine2056-79442025-01-0110111610.1038/s41525-024-00447-3Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencingDeepak N. Subramanian0Maia Zethoven1Kathleen I. Pishas2Evanny R. Marinović3Simone McInerny4Simone M. Rowley5Prue E. Allan6Lisa Devereux7Dane Cheasley8Paul A. James9Ian G. Campbell10Cancer Genetics Laboratory, Peter MacCallum Cancer CentreBioinformatics Core Facility, Peter MacCallum Cancer CentreCancer Genetics Laboratory, Peter MacCallum Cancer CentreCancer Genetics Laboratory, Peter MacCallum Cancer CentreParkville Familial Cancer Centre, Peter MacCallum Cancer Centre and The Royal Melbourne HospitalCancer Genetics Laboratory, Peter MacCallum Cancer CentreDepartment of Pathology, Peter MacCallum Cancer CentreSir Peter MacCallum Department of Oncology, The University of MelbourneCancer Genetics Laboratory, Peter MacCallum Cancer CentreSir Peter MacCallum Department of Oncology, The University of MelbourneCancer Genetics Laboratory, Peter MacCallum Cancer CentreAbstract High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls. This confirms enrichment for nearly all previously identified genes. Additionally, one-hundred-and-eleven HGSOC tumours from variant carriers were sequenced alongside other complementary studies, seeking evidence of biallelic inactivation as supportive evidence. PALB2 and ATM validate as HGSOC predisposition genes, with 6/8 germline carrier tumours exhibiting biallelic inactivation accompanied by characteristic mutational signatures. Among candidate genes, only LLGL2 consistently shows biallelic inactivation and protein expression loss, supporting it as a novel HGSOC susceptibility gene. The remaining candidate genes fail to validate. Integrating case-control analyses with tumour sequencing is thus crucial for accurate gene discovery in familial cancer studies.https://doi.org/10.1038/s41525-024-00447-3 |
| spellingShingle | Deepak N. Subramanian Maia Zethoven Kathleen I. Pishas Evanny R. Marinović Simone McInerny Simone M. Rowley Prue E. Allan Lisa Devereux Dane Cheasley Paul A. James Ian G. Campbell Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing npj Genomic Medicine |
| title | Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing |
| title_full | Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing |
| title_fullStr | Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing |
| title_full_unstemmed | Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing |
| title_short | Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing |
| title_sort | assessment of candidate high grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing |
| url | https://doi.org/10.1038/s41525-024-00447-3 |
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