Whole-exome Sequencing of Epithelial Ovarian Carcinomas Differing in Resistance to Platinum Therapy

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2022 Oct 13

PMID 36229065

Authors

Viktor Hlavac

Petr Holy

Radka Vaclavikova

Lukas Rob

Martin Hruda

Marcela Mrhalova

Petr cernaj

Jiri Bouda

Pavel Soucek

Affiliations

Soon will be listed here.

Abstract

Epithelial ovarian carcinoma (EOC) is highly fatal because of the risk of resistance to therapy and recurrence. We performed whole-exome sequencing of blood and tumor tissue pairs of 50 patients with surgically resected EOC. Compared with sensitive patients, platinum-resistant patients had a significantly higher somatic mutational rate in TP53 and lower in several genes from the Hippo pathway. We confirmed the pivotal role of somatic mutations in homologous recombination repair genes in platinum sensitivity and favorable prognosis of EOC patients. Implementing the germline homologous recombination repair profile significantly improved the prediction. In addition, distinct mutational signatures, for example, SBS6, and overall mutational load, somatic mutations in PABPC1, PABPC3, and TFAM co-segregated with the resistance status, high-grade serous carcinoma subtype, or overall survival of patients. We generated germline and somatic genetic landscapes of prognostically different subgroups of EOC patients for further follow-up studies focused on utilizing the observed associations in precision oncology.

Citing Articles

Prognostic potential of whole exome sequencing in the clinical management of metachronous colorectal cancer liver metastases.

Heczko L, Hlavac V, Holy P, Dvorak P, Liska V, Vycital O Cancer Cell Int. 2023; 23(1):295.

PMID: 38008721 PMC: 10676609. DOI: 10.1186/s12935-023-03135-x.

References

Kruger S, Piro R . decompTumor2Sig: identification of mutational signatures active in individual tumors. BMC Bioinformatics. 2019; 20(Suppl 4):152. PMC: 6472187. DOI: 10.1186/s12859-019-2688-6. View

Ellrott K, Bailey M, Saksena G, Covington K, Kandoth C, Stewart C . Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines. Cell Syst. 2018; 6(3):271-281.e7. PMC: 6075717. DOI: 10.1016/j.cels.2018.03.002. View

Rojas V, Hirshfield K, Ganesan S, Rodriguez-Rodriguez L . Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment. Int J Mol Sci. 2016; 17(12). PMC: 5187913. DOI: 10.3390/ijms17122113. View

McMullen M, Karakasis K, Madariaga A, Oza A . Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer. Cancers (Basel). 2020; 12(6). PMC: 7352566. DOI: 10.3390/cancers12061607. View

Talevich E, Shain A, Botton T, Bastian B . CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing. PLoS Comput Biol. 2016; 12(4):e1004873. PMC: 4839673. DOI: 10.1371/journal.pcbi.1004873. View

Shyr C, Tarailo-Graovac M, Gottlieb M, Lee J, Van Karnebeek C, Wasserman W . FLAGS, frequently mutated genes in public exomes. BMC Med Genomics. 2014; 7:64. PMC: 4267152. DOI: 10.1186/s12920-014-0064-y. View

Gabrielson M, Bjorklund M, Carlson J, Shoshan M . Expression of mitochondrial regulators PGC1α and TFAM as putative markers of subtype and chemoresistance in epithelial ovarian carcinoma. PLoS One. 2014; 9(9):e107109. PMC: 4170973. DOI: 10.1371/journal.pone.0107109. View

Matz M, Coleman M, Carreira H, Salmeron D, Chirlaque M, Allemani C . Worldwide comparison of ovarian cancer survival: Histological group and stage at diagnosis (CONCORD-2). Gynecol Oncol. 2016; 144(2):396-404. PMC: 6195190. DOI: 10.1016/j.ygyno.2016.11.019. View

Rheinbay E, Nielsen M, Abascal F, Wala J, Shapira O, Tiao G . Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Nature. 2020; 578(7793):102-111. PMC: 7054214. DOI: 10.1038/s41586-020-1965-x. View

10.

Zheng H, Shu T, Zhu S, Zhang C, Gao M, Zhang N . Construction and Validation of a Platinum Sensitivity Predictive Model With Multiple Genomic Variations for Epithelial Ovarian Cancer. Front Oncol. 2021; 11:725264. PMC: 8481766. DOI: 10.3389/fonc.2021.725264. View

11.

Xiang K, Bartel D . The molecular basis of coupling between poly(A)-tail length and translational efficiency. Elife. 2021; 10. PMC: 8253595. DOI: 10.7554/eLife.66493. View

12.

Seborova K, Vaclavikova R, Rob L, Soucek P, Vodicka P . Non-Coding RNAs as Biomarkers of Tumor Progression and Metastatic Spread in Epithelial Ovarian Cancer. Cancers (Basel). 2021; 13(8). PMC: 8069230. DOI: 10.3390/cancers13081839. View

13.

Sztupinszki Z, Diossy M, Borcsok J, Prosz A, Cornelius N, Kjeldsen M . Comparative Assessment of Diagnostic Homologous Recombination Deficiency-Associated Mutational Signatures in Ovarian Cancer. Clin Cancer Res. 2021; 27(20):5681-5687. DOI: 10.1158/1078-0432.CCR-21-0981. View

14.

Pilie P, Gay C, Byers L, OConnor M, Yap T . PARP Inhibitors: Extending Benefit Beyond -Mutant Cancers. Clin Cancer Res. 2019; 25(13):3759-3771. DOI: 10.1158/1078-0432.CCR-18-0968. View

15.

Lawrence M, Stojanov P, Polak P, Kryukov G, Cibulskis K, Sivachenko A . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. PMC: 3919509. DOI: 10.1038/nature12213. View

16.

Plagnol V, Curtis J, Epstein M, Mok K, Stebbings E, Grigoriadou S . A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinformatics. 2012; 28(21):2747-54. PMC: 3476336. DOI: 10.1093/bioinformatics/bts526. View

17.

Thomas A, Kelly G, Strasser A . Of the many cellular responses activated by TP53, which ones are critical for tumour suppression?. Cell Death Differ. 2022; 29(5):961-971. PMC: 9090748. DOI: 10.1038/s41418-022-00996-z. View

18.

Cunningham R, Hansen C . The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer. Clin Sci (Lond). 2022; 136(3):197-222. PMC: 8819670. DOI: 10.1042/CS20201474. View

19.

Li H . Toward better understanding of artifacts in variant calling from high-coverage samples. Bioinformatics. 2014; 30(20):2843-51. PMC: 4271055. DOI: 10.1093/bioinformatics/btu356. View

20.

Yang S, Lheureux S, Karakasis K, Burnier J, Bruce J, Clouthier D . Landscape of genomic alterations in high-grade serous ovarian cancer from exceptional long- and short-term survivors. Genome Med. 2018; 10(1):81. PMC: 6208125. DOI: 10.1186/s13073-018-0590-x. View