Subramanian Deepak N, Zethoven Maia, Pishas Kathleen I, Marinović Evanny R, McInerny Simone, Rowley Simone M, Allan Prue E, Devereux Lisa, Cheasley Dane, James Paul A, Campbell Ian G
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
NPJ Genom Med. 2025 Jan 10;10(1):1. doi: 10.1038/s41525-024-00447-3.
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.
高级别浆液性卵巢癌（HGSOC）具有显著的遗传成分，其中只有一半得到了解释。此前，我们对BRCA1和BRCA2阴性的HGSOC患者进行了种系外显子组测序，发现了3个提出的和43个新的候选基因，这些基因富含罕见的功能丧失变异。为了进行验证，我们使用来自无病对照的基因组数据进行了病例对照分析。这证实了几乎所有先前确定的基因都存在富集。此外，对来自变异携带者的111个HGSOC肿瘤进行了测序，并开展了其他补充研究，寻找双等位基因失活的证据作为支持证据。PALB2和ATM被确认为HGSOC易感基因，8个种系携带者肿瘤中有6个表现出双等位基因失活，并伴有特征性的突变特征。在候选基因中，只有LLGL2始终显示双等位基因失活和蛋白质表达缺失，支持其作为一种新的HGSOC易感基因。其余候选基因未能得到验证。因此，将病例对照分析与肿瘤测序相结合对于家族性癌症研究中准确的基因发现至关重要。
