Molecular Mechanisms of Carcinogenesis of Epithelial Ovarian Cancers

Czech version

Authors: Z. Müllerová ¹; T. Müller ¹; K. Křivánková ²; B. Vojtěšek ²; P. Müller ²
Authors‘ workplace: Gynekologicko-porodnické oddělení, Nemocnice Nové Město na Moravě ¹; Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno ²
Published in: Klin Onkol 2016; 29(Supplementum 4): 46-53
Category: Review
doi: https://doi.org/10.14735/amko20164S46

Overview

Background:
Epithelial ovarian carcinomas are one of the most common causes of death among gynecologic malignancies in the Czech population. This group of tumors is characterized by considerable heterogeneity in terms of its pathogenesis and response to therapy. It is questionable whether advances in the elucidation of molecular pathogenesis of various types of epithelial ovarian carcinomas can contribute to application of personalized targeted therapy.

Aims:
This work aims to summarize current knowledge on carcinogenesis and molecular basis of epithelial ovarian cancers and point out their potential applications in clinical practice. The characterization of the epithelial ovarian carcinomas is based on a dualistic model, which divides these tumors into two groups based on their different origins and mechanisms of carcinogenesis. Type I includes low-grade serous carcinomas, endometrioid carcinomas, mucinous carcinomas and Brenner tumor. Type II then comprises high-grade serous carcinomas.

Conclusion:
The new findings acquired by next generation sequencing revealed major differences in the genetic alterations in both groups of tumors. Differences in genetic instability between the two groups of tumors determine the mechanisms of their carcinogenesis and show new ways for application of targeted therapy. Deficient homologous recombination and high genetic instability in type II tumors is a prerequisite for efficient application of platinum cytostatics and PARP (poly-ADP ribose polymerase) inhibitors. On the other hand, carcinogenesis of the less aggressive, but often resistant type I tumous is dependent on the activation of signaling pathways PI3K/AKT and RAS/BRAF/MEK/ERK pathway. Targeted inhibition of these pathways could efficiently improve therapy of type I tumors and decrease serious adverse side effects.

Key words:
ovarian cancer – high-grade serous ovarian carcinoma – low-grade ovarian carcinoma – endometrioid carcinoma – mucinous carcinoma – malignant transformation – genetic instability

We would like to thank M.Sc. Eva Michalova for critical reading of the manuscript.

This work was supported by the project MEYS – NPS I – LO1413.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
7. 8. 2016

Accepted:
29. 8. 2016

Sources

1. Uzis.cz [internetová stránka]. Novotvary 2011 ČR. Ústav zdravotnických informací a statistiky ČR, Česká republika; cÚZIS ČR 2010–2016 [aktualizováno 2016; citováno 7. srpna 2016]. Dostupné z: www.uzis.cz.

2. Miller DS, Blessing JA, Krasner CN et al. Phase II evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecologic Oncology Group. J Clin Oncol 2009; 27 (16): 2686–2691. doi: 10.1200/JCO.2008.19.2963.

3. Bast RC Jr, Hennessy B, Mills GB. The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 2009; 9 (6): 415–428. doi: 10.1038/nrc2644.

4. Boyd J. Specific keynote: hereditary ovarian cancer: what we know. Gynecol Oncol 2003; 88 (1 Pt 2): S8–S10.

5. Cobb LP, Gaillard S, Wang Y et al. Adenocarcinoma of Mullerian origin: review of pathogenesis, molecular biology, and emerging treatment paradigms. Gynecol Oncol Res Pract 2015; 2: 1. doi: 10.1186/s40661-015-0008-z.

6. Gershenson DM, Bodurka DC, Lu KH et al. Impact of age and primary disease site on outcome in women with low-grade serous carcinoma of the ovary or peritoneum: results of a large single-institution registry of a rare tumor. J Clin Oncol 2015; 33 (24): 2675–2682. doi: 10.1200/JCO.2015.61.0873.

7. Howitt BE, Hanamornroongruang S, Lin DI et al. Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation status, histology, and tubal intraepithelial carcinoma. Am J Surg Pathol 2015; 39 (3): 287–293. doi: 10.1097/PAS.0000000000000369.

8. Espinosa I, Catasus L, Canet B et al. Gene expression analysis identifies two groups of ovarian high-grade serous carcinomas with different prognosis. Mod Pathol 2011; 24 (6): 846–854. doi: 10.1038/modpathol. 2011.12.

9. Soslow RA, Han G, Park KJ et al. Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma. Mod Pathol 2012; 25 (4): 625–636. doi: 10.1038/modpathol.2011.183.

10. Tothill RW, Tinker AV, George J et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res 2008; 14 (16): 5198–5208. doi: 10.1158/1078-0432.CCR-08-0196.

11. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474 (7353): 609–615. doi: 10.1038/nature10166.

12. Helland A, Anglesio MS, George J et al. Deregulation of MYCN, LIN28B and LET7 in a molecular subtype of aggressive high-grade serous ovarian cancers. PLoS One 2011; 6 (4): e18064. doi: 10.1371/journal.pone.0018064.

13. Konecny GE, Wang C, Hamidi H et al. Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer. J Natl Cancer Inst 2014; 106 (10): pii: dju249. doi: 10.1093/jnci/dju249.

14. Kurman RJ, Vang R, Junge J et al. Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis. Am J Surg Pathol 2011; 35 (11): 1605–1614. doi: 10.1097/PAS.0b013e318229449f.

15. Nakayama K, Nakayama N, Kurman RJ et al. Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer Biol Ther 2006; 5 (7): 779–785.

16. Singer G, Oldt R 3rd, Cohen Y et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 2003; 95 (6): 484–486.

17. Campbell IG, Russell SE, Choong DY et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 2004; 64 (21): 7678–7681.

18. Kuo KT, Mao TL, Jones S et al. Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. Am J Pathol 2009; 174 (5): 1597–1601. doi: 10.2353/ajpath.2009.081000.

19. Auersperg N. The origin of ovarian carcinomas: a unifying hypothesis. Int J Gynecol Pathol 2011; 30 (1): 12–21. doi: 10.1097/PGP.0b013e3181f45f3e.

20. Seidman JD, Khedmati F. Exploring the histogenesis of ovarian mucinous and transitional cell (Brenner) neoplasms and their relationship with Walthard cell nests: a study of 120 tumors. Arch Pathol Lab Med 2008; 132 (11): 1753–1760. doi: 10.1043/1543-2165-132.11.1753.

21. Wang Y, Wu RC, Shwartz LE et al. Clonality analysis of combined Brenner and mucinous tumours of the ovary reveals their monoclonal origin. J Pathol 2015; 237 (2): 146–151. doi: 10.1002/path.4572.

22. Piek JM, van Diest PJ, Zweemer RP et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 2001; 195 (4): 451–456.

23. Medeiros F, Muto MG, Lee Y et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 2006; 30 (2): 230–236.

24. Kindelberger DW, Lee Y, Miron A et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am J Surg Pathol 2007; 31 (2): 161–169.

25. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature 2009; 458 (7239): 719–724. doi: 10.1038/nature07943.

26. Patch AM, Christie EL, Etemadmoghadam D et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 2015; 521 (7553): 489–494. doi: 10.1038/nature14410.

27. Hartman AR, Ford JM. BRCA1 and p53: compensatory roles in DNA repair. J Mol Med (Berl) 2003; 81 (11): 700–707.

28. Zheng L, Li S, Boyer TG et al. Lessons learned from BRCA1 and BRCA2. Oncogene 2000; 19 (53): 6159–6175.

29. Lee V, Le DT. Efficacy of PD-1 blockade in tumors with MMR deficiency. Immunotherapy 2016; 8 (1): 1–3. doi: 10.2217/imt.15.97.

30. Blocking PD-1 in tumors with faulty DNA repair. Cancer Discov 2016; 6 (8): OF6. doi: 10.1158/2159-8290.CD-NB2016-082.

31. Le DT, Uram JN, Wang H et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372 (26): 2509–2520. doi: 10.1056/NEJMoa1500596.

32. Budczies J, Bockmayr M, Denkert C et al. Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) – associations with gene expression, mutational load, and survival. Genes Chromosomes Cancer 2016; 55 (8): 626–639. doi: 10.1002/gcc. 22365.

33. Hamanishi J, Mandai M, Konishi I. Immune checkpoint inhibition in ovarian cancer. Int Immunol 2016; 28 (7): 339–348. doi: 10.1093/intimm/dxw020.

34. Jones S, Wang TL, Shih Ie M et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 2010; 330 (6001): 228–231. doi: 10.1126/science.1196333.

35. Wiegand KC, Shah SP, Al-Agha OM et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 2010; 363 (16): 1532–1543. doi: 10.1056/NEJMoa1008433.

36. Guan B, Rahmanto YS, Wu RC et al. Roles of deletion of Arid1a, a tumor suppressor, in mouse ovarian tumorigenesis. J Natl Cancer Inst 2014; 106 (7): pii: dju146. doi: 10.1093/jnci/dju146.

37. Chandler RL, Damrauer JS, Raab JR et al. Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling. Nat Commun 2015; 6: 6118. doi: 10.1038/ncomms7118.

38. Jones S, Wang TL, Kurman RJ et al. Low-grade serous carcinomas of the ovary contain very few point mutations. J Pathol 2012; 226 (3): 413–420. doi: 10.1002/path.3967.

39. Forbes SA, Beare D, Gunasekaran P et al. COSMIC: exploring the world‘s knowledge of somatic mutations in human cancer. Nucleic Acids Res 2015; 43 (Database issue): D805–D811. doi: 10.1093/nar/gku1075.

40. Teplinsky E, Muggia F. Targeting HER2 in ovarian and uterine cancers: challenges and future directions. Gynecol Oncol 2014; 135 (2): 364–370. doi: 10.1016/j.ygyno.2014.09.003.

41. Makhija S, Amler LC, Glenn D et al. Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol 2010; 28 (7): 1215–1223. doi: 10.1200/JCO.2009.22.3354.

42. Teplinsky E, Muggia F. EGFR and HER2: is there a role in ovarian cancer? Translational Cancer Research 2015; 4 (1): 107–117.

43. Davies S, Holmes A, Lomo L et al. High incidence of ErbB3, ErbB4, and MET expression in ovarian cancer. Int J Gynecol Pathol 2014; 33 (4): 402–410. doi: 10.1097/PGP.0000000000000081.

44. Stany MP, Vathipadiekal V, Ozbun L et al. Identification of novel therapeutic targets in microdissected clear cell ovarian cancers. PLoS One 2011; 6 (7): e21121. doi: 10.1371/journal.pone.0021121.

45. Anglesio MS, George J, Kulbe H et al. IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clin Cancer Res 2011; 17 (8): 2538–2548. doi: 10.1158/1078-0432.CCR-10-3314.

46. Farley J, Brady WE, Vathipadiekal V et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol 2013; 14 (2): 134–140. doi: 10.1016/S1470-2045 (12) 70572-7.

47. Jones RM, Mortusewicz O, Afzal I et al. Increased replication initiation and conflicts with transcription underlie cyclin E-induced replication stress. Oncogene 2013; 32 (32): 3744–3753. doi: 10.1038/onc.2012.387.

48. Teixeira LK, Wang X, Li Y et al. Cyclin E deregulation promotes loss of specific genomic regions. Curr Biol 2015; 25 (10): 1327–1333. doi: 10.1016/j.cub.2015.03.022.

49. Asghar U, Witkiewicz AK, Turner NC et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015; 14 (2): 130–146. doi: 10.1038/nrd4504.

50. Konecny GE. Cyclin-dependent kinase pathways as targets for women‘s cancer treatment. Curr Opin Obstet Gynecol 2016; 28 (1): 42–48. doi: 10.1097/GCO.0000000000000243.