Genomic Characterization of High-Grade Serous Ovarian Cancer: Dissecting Its Molecular Heterogeneity as a Road Towards Effective Therapeutic Strategies

Current Oncology Reports

Volumn 18, Issue 7, 2016, Pages

  Mittempergher, Lorenza ^a  

^a NETHERLANDS CANCER INSTITUTE   (Netherlands)

Author keywords

CCNE1; CDK12; Genomics; High grade serous ovarian carcinoma (HGSOC); Homologous recombination (HR); miRNA; Molecular heterogeneity; Molecular subtypes; PARP inhibitors; TP53

Indexed keywords

BRCA1 PROTEIN; BRCA2 PROTEIN; CHEMOKINE RECEPTOR CXCR3; CXCL11 CHEMOKINE; CYCLIN DEPENDENT KINASE; GAMMA INTERFERON INDUCIBLE PROTEIN 10; MESSENGER RNA; MICRORNA; MINICHROMOSOME MAINTENANCE PROTEIN 2; MUCIN 1; MYC PROTEIN; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE INHIBITOR; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PLATINUM COMPLEX; POLO LIKE KINASE; PROTEIN P53; SMAD2 PROTEIN; SMAD7 PROTEIN; TRANSCRIPTION FACTOR PAX8; TRANSCRIPTION FACTOR SOX11; TRANSFORMING GROWTH FACTOR BETA; UVOMORULIN; VASCULOTROPIN RECEPTOR 2; ANTINEOPLASTIC AGENT; TUMOR PROTEIN;

APOPTOSIS; ATM GENE; ATR GENE; CANCER GRADING; CANCER SURVIVAL; CCNE1 GENE; CDK12 GENE; CELL VIABILITY; CHEK1 GENE; CHEK2 GENE; COPY NUMBER VARIATION; CSMD3 GENE; DDB1 GENE; DNA REPAIR; DOUBLE STRANDED DNA BREAK; EPITHELIAL MESENCHYMAL TRANSITION; ERCC2 GENE; ERCC3 GENE; ERCC4 GENE; ERCC5 GENE; ERCC6 GENE; EXCISION REPAIR; FANC1 GENE; FANCA GENE; FANCC GENE; FANCL GENE; FAT3 GENE; GABRA6 GENE; GENE AMPLIFICATION; GENE EXPRESSION PROFILING; GENE LOSS; GENE SEQUENCE; HIGH GRADE SEROUS OVARIAN CARCINOMA; HOMOLOGOUS RECOMBINATION; HUMAN; MISMATCH REPAIR; MNAT1 GENE; NF1 GENE; ONCOGENE MYC; OVARY CANCER; OVERALL SURVIVAL; PROGNOSIS; PROGRESSION FREE SURVIVAL; PTEN GENE; RAD23B GENE; RAD50 GENE; RAD51 GENE; RAD51C GENE; RAD54L GENE; RB1 GENE; REVIEW; RFC1 GENE; SIGNAL TRANSDUCTION; SOMATIC MUTATION; TUMOR GENE; XPC GENE; ANTAGONISTS AND INHIBITORS; CYSTADENOCARCINOMA, SEROUS; FEMALE; GENETICS; MOLECULARLY TARGETED THERAPY; OVARIAN NEOPLASMS; PATHOLOGY;

ANTINEOPLASTIC AGENTS; CYSTADENOCARCINOMA, SEROUS; FEMALE; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASM GRADING; NEOPLASM PROTEINS; OVARIAN NEOPLASMS; PROGNOSIS;

EID: 84973535675     PISSN: 15233790     EISSN: 15346269     Source Type: Journal    
DOI: 10.1007/s11912-016-0526-9     Document Type: Review

References (53)

1. Ross JS, Ali SM, Wang K, Palmer G, Yelensky R, Lipson D, et al. Comprehensive genomic profiling of epithelial ovarian cancer by next generation sequencing-based diagnostic assay reveals new routes to targeted therapies. Gynecol Oncol. 2013;130(3):554–9.
2. Bowtell DD, Bohm S, Ahmed AA, Aspuria PJ, Bast Jr RC, Beral V, et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer. 2015;15(11):668–79. In this Opinion article the authors outline seven research priorities which should improve outcome and possibly reduce incidence of such a deadly disease as high grade serous ovarian carcinoma.
3. Itamochi H, Kigawa J. Clinical trials and future potential of targeted therapy for ovarian cancer. Int J Clin Oncol. 2012;17(5):430–40.
4. Verhaak RG, Tamayo P, Yang JY, Hubbard D, Zhang H, Creighton CJ, et al. Prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J Clin Invest. 2013;123(1):517–25.
5. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15. This is the first comprehensive molecular characterization of high grade serous ovarian carcinoma that integrates mutation, copy number, expression and methylation data.
6. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59(4):225–49.
7. Liu Z, Beach JA, Agadjanian H, Jia D, Aspuria PJ, Karlan BY, et al. Suboptimal cytoreduction in ovarian carcinoma is associated with molecular pathways characteristic of increased stromal activation. Gynecol Oncol. 2015.
8. Yap TA, Carden CP, Kaye SB. Beyond chemotherapy: targeted therapies in ovarian cancer. Nat Rev Cancer. 2009;9(3):167–81.
9. Coward JI, Middleton K, Murphy F. New perspectives on targeted therapy in ovarian cancer. Int J Women’s Health. 2015;7:189–203.
10. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137–54. In this interesting review several aspects of the homologous recombination (HR) deficiency of epithelial ovarian carcinoma are described with the intent of highlighting potential biomarkers of HR in addition to the well characterized BRCA1/2 mutation status. In addition they emphasized the importance of the de novo and acquired resistance observed in tumors followed by PARP inhibition.
11. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.
12. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):l1.
13. Cheung HW, Cowley GS, Weir BA, Boehm JS, Rusin S, Scott JA, et al. Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer. Proc Natl Acad Sci U S A. 2011;108(30):12372–7. The authors performed systematic loss-of-function studies to identify essential genes in different cancer cell types. Suppression of PAX8, a gene found amplified in 16% of high grade serous ovarian carcinoma, selectively induced apoptotic cell death of ovarian cancer cells. High-throughput in vitro functional studies should be considered for identification of tumor vulnerabilities, which are potentially targetable.
14. Bowtell DD. The genesis and evolution of high-grade serous ovarian cancer. Nat Rev Cancer. 2010;10(11):803–8.
15. Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol. 2010;221(1):49–56.
16. Joshi PM, Sutor SL, Huntoon CJ, Karnitz LM. Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors. J Biol Chem. 2014;289(13):9247–53.
17. Bajrami I, Frankum JR, Konde A, Miller RE, Rehman FL, Brough R, et al. Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity. Cancer Res. 2014;74(1):287–97. The authors provide evidences that CDK12 deficiency is a clinically relevant biomarker of PARP1/2 inhibitor sensitivity. This study investigated further the role of CDK12 as novel biomarker for high grade serous ovarian carcinoma targeted therapy.
18. Popova T, Manie E, Boeva V, Battistella A, Goundiam O, Smith NK, et al. Ovarian cancers harboring inactivating mutations in CDK12 display a distinct genomic instability pattern characterized by large tandem duplications. Cancer Res. 2016.
19. Ekumi KM, Paculova H, Lenasi T, Pospichalova V, Bosken CA, Rybarikova J, et al. Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex. Nucleic Acids Res. 2015;43(5):2575–89.
20. Walsh T, Lee MK, Casadei S, Thornton AM, Stray SM, Pennil C, et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A. 2010;107(28):12629–33.
21. Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(21):2654–63.
22. Pal T, Permuth-Wey J, Betts JA, Krischer JP, Fiorica J, Arango H, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807–16.
23. Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1(6–7):315–22.
24. Hughes-Davies L, Huntsman D, Ruas M, Fuks F, Bye J, Chin SF, et al. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell. 2003;115(5):523–35.
25. Ceccaldi R, O’Connor KW, Mouw KW, Li AY, Matulonis UA, D’Andrea AD, et al. A unique subset of epithelial ovarian cancers with platinum sensitivity and PARP inhibitor resistance. Cancer Res. 2015;75(4):628–34.
26. Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20(3):764–75.
27. Konstantinopoulos PA, Spentzos D, Karlan BY, Taniguchi T, Fountzilas E, Francoeur N, et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(22):3555–61.
28. Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood AK, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011;306(14):1557–65.
29. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.
30. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7.
31. McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109–15.
32. Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, et al. Homologous-recombination-deficient tumours are dependent on poltheta-mediated repair. Nature. 2015;518(7538):258–62.
33. Li M, Yu X. Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell. 2013;23(5):693–704.
34. Langelier MF, Pascal JM. PARP-1 mechanism for coupling DNA damage detection to poly(ADP-ribose) synthesis. Curr Opin Struct Biol. 2013;23(1):134–43.
35. Wang ZC, Birkbak NJ, Culhane AC, Drapkin R, Fatima A, Tian R, et al. Profiles of genomic instability in high-grade serous ovarian cancer predict treatment outcome. Clin Cancer Res Off J Am Assoc Cancer Res. 2012;18(20):5806–15.
36. Sohn I, Jung WY, Sung CO. Somatic hypermutation and outcomes of platinum based chemotherapy in patients with high grade serous ovarian cancer. Gynecol Oncol. 2012;126(1):103–8.
37. Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. Emerging landscape of oncogenic signatures across human cancers. Nat Genet. 2013;45(10):1127–33.
38. Patch AM, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015;521(7553):489–94. This is one of the first studies that have analyzed in depth using transcriptome, methylome and microRNA expression analysis paired primary and relapse high-grade serous ovarian carcinoma samples to highlight new mechanisms of platinum-based chemotherapy resistance.
39. Martins FC, Santiago I, Trinh A, Xian J, Guo A, Sayal K, et al. Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier. Genome Biol. 2014;15(12):526.
40. Etemadmoghadam D, Au-Yeung G, Wall M, Mitchell C, Kansara M, Loehrer E, et al. Resistance to CDK2 inhibitors is associated with selection of polyploid cells in CCNE1-amplified ovarian cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2013;19(21):5960–71.
41. Etemadmoghadam D, George J, Cowin PA, Cullinane C, Kansara M, Australian Ovarian Cancer Study G, et al. Amplicon-dependent CCNE1 expression is critical for clonogenic survival after cisplatin treatment and is correlated with 20q11 gain in ovarian cancer. PLoS One. 2010;5(11):e15498.
42. Etemadmoghadam D, Weir BA, Au-Yeung G, Alsop K, Mitchell G, George J, et al. Synthetic lethality between CCNE1 amplification and loss of BRCA1. Proc Natl Acad Sci U S A. 2013;110(48):19489–94.
43. Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(16):5198–208.
44. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3):203–13.
45. Konecny GE, Wang C, Hamidi H, Winterhoff B, Kalli KR, Dering J, et al. Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer. J Natl Cancer Inst. 2014;106(10). The authors robustly validated the four molecular subtypes of high grade serous ovarian carcinoma previously described using three independent patient cohorts in order to add a significant prognostic value to the subtypes.
46. Parikh A, Lee C, Joseph P, Marchini S, Baccarini A, Kolev V, et al. microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial-mesenchymal transition. Nat Commun. 2014;5:2977.
47. Yang D, Sun Y, Hu L, Zheng H, Ji P, Pecot CV, et al. Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. Cancer Cell. 2013;23(2):186–99.
48. Vecchione A, Belletti B, Lovat F, Volinia S, Chiappetta G, Giglio S, et al. A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis. Proc Natl Acad Sci U S A. 2013;110(24):9845–50.
49. Kurrey NK, Amit K, Bapat SA. Snail and slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecol Oncol. 2005;97(1):155–65.
50. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484–96.
51. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473–83.
52. Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(13):1302–8.
53. Gourley G. Molecular subgroup of high-grade serous ovarian cancer (HGSOC) as a predictor of outcome following bevacizumab. J Clin Oncol. 2014;32.