Molecular profiling reveals novel therapeutic targets and clonal evolution in ovarian clear cell carcinoma.

Autor: Chao A; Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan.; Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan City, 333, Taiwan., Huang CY; Division of Hematology-Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan City, 333, Taiwan.; Center for Computational Biology, Duke-NUS Medical School, Singapore, 169857, Singapore.; Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore., Yu W; Center for Computational Biology, Duke-NUS Medical School, Singapore, 169857, Singapore.; Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore., Lin CY; Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan.; Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan City, 333, Taiwan., Lin H; Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 833, Taiwan., Chao AS; Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan.; Department of Obstetrics and Gynecology, New Taipei City Municipal Tucheng Hospital, New Taipei City, 236, Taiwan., Lin CT; Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan.; Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan City, 333, Taiwan., Chou HH; Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan.; Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan City, 333, Taiwan., Huang KG; Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan.; Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan City, 333, Taiwan., Huang HJ; Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan.; Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan City, 333, Taiwan., Chang TC; Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan.; Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan City, 333, Taiwan., Rozen SG; Center for Computational Biology, Duke-NUS Medical School, Singapore, 169857, Singapore.; Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore.; Cancer Therapeutics Research Laboratory, Division of Medical Sciences, National Cancer Center Singapore, Singapore, 169610, Singapore., Wu RC; Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan City, 333, Taiwan. qby@cgmh.org.tw.; Department of Pathology, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan. qby@cgmh.org.tw., Lai CH; Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan. laich46@cgmh.org.tw.; Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan City, 333, Taiwan. laich46@cgmh.org.tw.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2024 Nov 14; Vol. 24 (1), pp. 1403. Date of Electronic Publication: 2024 Nov 14.
DOI: 10.1186/s12885-024-13125-5
Abstrakt: 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: On analyzing 102 OCCC samples, ARID1A (67%) and PIK3CA (49%) emerged as the most frequently mutated driver genes. We identified tier 1 or 2 clinically actionable molecular targets in 40% of cases. This included DNA mismatch repair deficiency (n = 1), as well as BRCA2 (n = 1), PIK3CA (n = 36), KRAS G12C (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.
Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board of the Chang Gung Memorial Hospital (reference number: 202000143B0). Given the retrospective nature of the analysis, the requirement for informed consent was waived. Consent for publication All authors have provided their consent for the publication of this manuscript. Competing interests The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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