Molecular profiling reveals novel therapeutic targets and clonal evolution in ovarian clear cell carcinoma
Journal
BMC Cancer
Journal Volume
24
Journal Issue
1
ISSN
1471-2407
Date Issued
2024-11-14
Author(s)
Angel Chao
Chen-Yang Huang
Willie Yu
Chiao-Yun Lin
Hao Lin
An-Shine Chao
Hung-Hsueh Chou
Kuang-Gen Huang
Huei-Jean Huang
Ting-Chang Chang
Steven G. Rozen
Ren-Chin Wu
Chyong-Huey Lai
Abstract
BACKGROUND: Ovarian clear cell carcinoma (OCCC) has a disproportionately high incidence among women in East Asia. Patients diagnosed with OCCC tend to experience worse clinical outcomes than those with high-grade serous carcinoma (HGSC) at advanced stages. The unfavorable prognosis of OCCC can be partly attributed to its frequent resistance to conventional chemotherapy. Within a precision medicine framework, we sought to provide a comprehensive molecular characterization of OCCC using whole-exome sequencing to uncover potential molecular targets that may inform novel therapeutic strategies. METHODS: We performed whole-exome sequencing analysis on tumor-normal paired samples from 102 OCCC patients. This comprehensive genomic characterization of a substantial cohort of OCCC specimens was coupled with an analysis of clonal progression. RESULTS: (n = 1), and ATM (n = 4) mutations. Furthermore, 45% of OCCC samples displayed ARID1A biallelic loss. Interestingly, we identified previously unreported mutations in the 5' untranslated region of the TERT gene that harbored an adverse prognostic significance. Clock-like mutational processes and activated APOBECs were major drivers of somatic point mutations. Mutations arising from DNA mismatch repair deficiency were uncommon. Reconstruction of clonal evolution revealed that early genetic events likely driving tumorigenesis included mutations in the ARID1A, PIK3CA, TERT, KRAS, and TP53 genes. CONCLUSIONS: Our study provides a comprehensive characterization of the genomic landscape and clonal evolution in OCCC within a substantial cohort. These findings unveil potentially actionable molecular alterations that could be leveraged to develop targeted therapies.
SDGs
Publisher
Springer Science and Business Media LLC
Type
journal article