Whole-genome Characterization of Chemoresistant Ovarian Cancer

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

Citing Articles

Learning directed acyclic graphs for ligands and receptors based on spatially resolved transcriptomic data of ovarian cancer.

Chowdhury S, Ferri-Borgogno S, Yang P, Wang W, Peng J, C Mok S Brief Bioinform. 2025; 26(2).

PMID: 40062614 PMC: 11891659. DOI: 10.1093/bib/bbaf085.

Global research trends in liquid biopsy for ovarian cancer from 1999 to 2023: A 25-year bibliometric analysis.

Wan J, Rao Z, Liu H, Wan J J Liq Biopsy. 2025; 5:100158.

PMID: 40027939 PMC: 11863938. DOI: 10.1016/j.jlb.2024.100158.

Immunogenic cryptic peptides dominate the antigenic landscape of ovarian cancer.

Raja R, Mangalaparthi K, Madugundu A, Jessen E, Pathangey L, Magtibay P Sci Adv. 2025; 11(8):eads7405.

PMID: 39970218 PMC: 11837991. DOI: 10.1126/sciadv.ads7405.

Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer.

Dicks E, Tyrer J, Ezquina S, Jones M, Baierl J, Peng P Eur J Hum Genet. 2025; 33(3):297-303.

PMID: 39939714 PMC: 11894177. DOI: 10.1038/s41431-025-01786-0.

Molecular Subgroups of HRD Positive Ovarian Cancer and Their Prognostic Significance.

Kekeeva T, Dudina I, Andreeva Y, Tanas A, Kalinkin A, Musatova V Int J Mol Sci. 2025; 25(24.

PMID: 39769312 PMC: 11677867. DOI: 10.3390/ijms252413549.

References

George J, Alsop K, Etemadmoghadam D, Hondow H, Mikeska T, Dobrovic A . Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. Clin Cancer Res. 2013; 19(13):3474-84. DOI: 10.1158/1078-0432.CCR-13-0066. View

Geisler J, Hatterman-Zogg M, Rathe J, Buller R . Frequency of BRCA1 dysfunction in ovarian cancer. J Natl Cancer Inst. 2002; 94(1):61-7. DOI: 10.1093/jnci/94.1.61. View

Mukhopadhyay A, Elattar A, Cerbinskaite A, Wilkinson S, Drew Y, Kyle S . Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Clin Cancer Res. 2010; 16(8):2344-51. DOI: 10.1158/1078-0432.CCR-09-2758. View

Popova T, Manie E, Rieunier G, Caux-Moncoutier V, Tirapo C, Dubois T . Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 2012; 72(21):5454-62. DOI: 10.1158/0008-5472.CAN-12-1470. View

Norquist B, Wurz K, Pennil C, Garcia R, Gross J, Sakai W . Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011; 29(22):3008-15. PMC: 3157963. DOI: 10.1200/JCO.2010.34.2980. View

Soslow R, Han G, Park K, Garg K, Olvera N, Spriggs D . Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma. Mod Pathol. 2011; 25(4):625-36. DOI: 10.1038/modpathol.2011.183. View

Castellarin M, Milne K, Zeng T, Tse K, Mayo M, Zhao Y . Clonal evolution of high-grade serous ovarian carcinoma from primary to recurrent disease. J Pathol. 2012; 229(4):515-24. DOI: 10.1002/path.4105. View

Li B, Dewey C . RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011; 12:323. PMC: 3163565. DOI: 10.1186/1471-2105-12-323. View

Etemadmoghadam D, DeFazio A, Beroukhim R, Mermel C, George J, Getz G . Integrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas. Clin Cancer Res. 2009; 15(4):1417-27. PMC: 2670486. DOI: 10.1158/1078-0432.CCR-08-1564. View

10.

Lengyel E . Ovarian cancer development and metastasis. Am J Pathol. 2010; 177(3):1053-64. PMC: 2928939. DOI: 10.2353/ajpath.2010.100105. View

11.

Korbel J, Campbell P . Criteria for inference of chromothripsis in cancer genomes. Cell. 2013; 152(6):1226-36. DOI: 10.1016/j.cell.2013.02.023. View

12.

Verhaak R, Tamayo P, Yang J, Hubbard D, Zhang H, Creighton C . Prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J Clin Invest. 2012; 123(1):517-25. PMC: 3533304. DOI: 10.1172/JCI65833. View

13.

Swisher E, Sakai W, Karlan B, Wurz K, Urban N, Taniguchi T . Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 2008; 68(8):2581-6. PMC: 2674369. DOI: 10.1158/0008-5472.CAN-08-0088. View

14.

Stephens P, Greenman C, Fu B, Yang F, Bignell G, Mudie L . Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011; 144(1):27-40. PMC: 3065307. DOI: 10.1016/j.cell.2010.11.055. View

15.

Cowin P, George J, Fereday S, Loehrer E, Van Loo P, Cullinane C . LRP1B deletion in high-grade serous ovarian cancers is associated with acquired chemotherapy resistance to liposomal doxorubicin. Cancer Res. 2012; 72(16):4060-73. DOI: 10.1158/0008-5472.CAN-12-0203. View

16.

Ojesina A, Lichtenstein L, Freeman S, Pedamallu C, Imaz-Rosshandler I, Pugh T . Landscape of genomic alterations in cervical carcinomas. Nature. 2014; 506(7488):371-5. PMC: 4161954. DOI: 10.1038/nature12881. View

17.

Rausch T, Jones D, Zapatka M, Stutz A, Zichner T, Weischenfeldt J . Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell. 2012; 148(1-2):59-71. PMC: 3332216. DOI: 10.1016/j.cell.2011.12.013. View

18.

Koboldt D, Zhang Q, Larson D, Shen D, McLellan M, Lin L . VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012; 22(3):568-76. PMC: 3290792. DOI: 10.1101/gr.129684.111. View

19.

Gorringe K, Jacobs S, Thompson E, Sridhar A, Qiu W, Choong D . High-resolution single nucleotide polymorphism array analysis of epithelial ovarian cancer reveals numerous microdeletions and amplifications. Clin Cancer Res. 2007; 13(16):4731-9. DOI: 10.1158/1078-0432.CCR-07-0502. View

20.

Friedlander M, Stockler M, Butow P, King M, McAlpine J, Tinker A . Clinical trials of palliative chemotherapy in platinum-resistant or -refractory ovarian cancer: time to think differently?. J Clin Oncol. 2013; 31(18):2362. DOI: 10.1200/JCO.2012.47.7927. View