Challenges and Opportunities in Studying the Epidemiology of Ovarian Cancer Subtypes
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Purpose of Review
Only recently has it become clear that epithelial ovarian cancer (EOC) is comprised of such distinct histotypes—with different cells of origin, morphology, molecular features, epidemiologic factors, clinical features, and survival patterns—that they can be thought of as different diseases sharing an anatomical location. Herein, we review opportunities and challenges in studying EOC heterogeneity,
The 2014 World Health Organization diagnostic guidelines incorporate accumulated evidence that high- and low-grade serous tumors have different underlying pathogenesis, and that, on the basis of shared molecular features, most high-grade tumors, including some previously classified as endometrioid, are now considered to be high-grade serous. At the same time, several studies have reported that high-grade serous EOC, which is the most common histotype, is itself made up of reproducible subtypes discernable by gene expression patterns.
These major advances in understanding set the stage for a new era of research on EOC risk and clinical outcomes with the potential to reduce morbidity and mortality. We highlight the need for multidisciplinary studies with pathology review using the current guidelines, further molecular characterization of the histotypes and subtypes, inclusion of women of diverse racial/ethnic and socioeconomic backgrounds, and updated epidemiologic and clinical data relevant to current generations of women at risk of EOC.
KeywordsEpithelial ovarian cancer Histotype Gene expression subtype Survival Pathology
We thank Dr. Mary Anne Rossing for her thoughtful insights on this manuscript.
Compliance with Ethical Standards
Conflict of Interest
Jennifer Anne Doherty reports grants from National Cancer Institute during the conduct of the study.
Lauren Cole Peres, Chen Wang, and Gregory P. Way each declare no potential conflicts of interest.
Casey S. Greene reports grants from Gordon and Betty Moore Foundation during the conduct of the study and personal fees from SomaLogic outside the submitted work.
Joellen M. Schildkraut reports grants from National Cancer Institute during the conduct of the study.
Human and Animal Rights and Informed Consent
This article contains no studies with human or animal subjects performed by any of the authors.
The research reported in this publication was supported by Huntsman Cancer Foundation and the National Cancer Institute of the National Institutes of Health under Award Number P30 CA042014, as well as R01 CA168758 (to JAD and MAR),R01 CA200854 to JAD and JMS, and R01 CA142081 (to JMS). It was also supported in part by a career enhancement award from the Mayo Clinic Ovarian Cancer SPORE to CW (P50 CA136393), and by a grant from the Gordon and Betty Moore Foundation (GBMF4552) to CSG. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 20.Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2013, National Cancer Institute. Bethesda, MD, based on November 2015 SEER data submission, posted to the SEER web site, April 2016. [Internet]. [cited 2016 Nov 2] Available from: http://seer.cancer.gov/csr/1975_2013/
- 23.• Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO Classification of Tumours of Female Reproductive Organs. 4th ed. Lyon: IARC; 2014. The new diagnostic guidelines for epithelial ovarian cancer encompass a large body of evidence that results in more reproducible diagnosis across pathologists, and potentially more biologically-relevant histotype classifications. Google Scholar
- 28.Jones S, Wang T-L, Shih I-M, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. 2010; 330(80- ):228–31.Google Scholar
- 30.Kommoss S, Gilks CB, du Bois A, Kommoss F. Ovarian carcinoma diagnosis: the clinical impact of 15 years of change. Br J Cancer Nat Publ Group. 2016;115:1–7.Google Scholar
- 34.Paracchini L, Mannarino L, Craparotta I, et al. Regional and temporal heterogeneity of epithelial ovarian cancer tumor biopsies: implications for therapeutic strategies. Oncotarget. 2016;5Google Scholar
- 36.Wong K-K, Tsang YTM, Deavers MT, et al. BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas. Am J Pathol Am Soc Investig Pathol. 2010;177:1611–7.Google Scholar
- 47.• Wentzensen N, Poole EM, Trabert B, et al. Ovarian cancer risk factors by histologic subtype: an analysis from the ovarian cancer cohort consortium. J Clin Oncol. 2016;34:2888–98. This large pooled analysis of cohort studies of invasive epithelial ovarian cancer reports differences in associations with several well-characterized epidemiologic factors by histotype. CrossRefPubMedPubMedCentralGoogle Scholar
- 49.Collaborative Group on Epidemiological Studies of Ovarian Cancer. Menopausal hormone use and ovarian cancer risk: Individual participant meta-analysis of 52 epidemiological studies. Lancet. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Open Access article distributed under the terms of CC BY; 2015;385:1835–42.Google Scholar
- 55.Phelan CM, Kuchenbaecker KB, Tyrer JP, et al. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. Nat Genet. 2017; doi: 10.1038/ng.3826.
- 57.National Cancer Institute. Cancer Stat Facts: Ovarian Cancer. Bethesda, MD;Google Scholar
- 62.Bandera EV, Lee VS, Rodriguez-Rodriguez L, Powell CB, Kushi LH. Racial/ethnic disparities in ovarian cancer treatment and survival. Clin Cancer Res [Internet]. 2016;22:5909–14. Available from: http://clincancerres.aacrjournals.org/cgi/doi/10.1158/1078-0432.CCR-16-1119 CrossRefGoogle Scholar
- 63.National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: ovarian cancer including fallopian tube cancer and primary peritoneal cancer [Internet]. 2016. Available from: https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
- 64.Brown J, Frumovitz M. Mucinous tumors of the ovary: current thoughts on diagnosis and management. Curr Oncol Rep. 2014;16Google Scholar
- 69.Wang C, Winterhoff BJ, Kalli KR, et al. Expression signature distinguishing two tumour transcriptome classes associated with progression-free survival among rare histological types of epithelial ovarian cancer. Br J Cancer. Nature Publishing Group; 2016;114:1412–20.Google Scholar
- 76.Buckley AR, Standish KA, Bhutani K, et al. Pan-cancer analysis reveals technical artifacts in TCGA germline variant cells. bioRxiv. 2016;91263.Google Scholar
- 79.• Wang C, Armasu SM, Kalli KR, et al. Pooled clustering of high-grade serous ovarian cancer gene expression leads to novel consensus subtypes associated with survival and surgical outcomes. Clin Cancer Res. 2017; doi: 10.1158/1078-0432.CCR-17-0246. This paper reports that the mesenchymal high grade serous gene expression subtype that is associated with poor survival is also associated with a higher rate of residual disease after surgical debulking compared to the other subtypes.
- 80.Way GP, Rudd J, Wang C, et al. Comprehensive cross-population analysis of high-grade serous ovarian cancer supports no more than three subtypes. G3 Genes, Genomes, Genet. 2016;g3.116.033514.Google Scholar
- 84.Gentles AJ, Bratman SV, Lee LJ, et al. Integrating tumor and stromal gene expression signatures with clinical indices for survival stratification of early-stage non–small cell lung cancer. JNCI J Natl Cancer Inst. 2015;107.Google Scholar
- 85.Zhang S, Jing Y, Zhang M, et al. Stroma-associated master regulators of molecular subtypes predict patient prognosis in ovarian cancer. Sci Rep. Nature Publishing Group. 2015;5:16066.Google Scholar
- 86.Murakami R, Matsumura N, Mandai M, et al. Establishment of a novel histopathological classification of high-grade serous ovarian carcinoma correlated with prognostically distinct gene expression subtypes. Am J Pathol. American Society for Investigative Pathology. 2016;186:1103–13.Google Scholar
- 88.Patel AP, Tirosh I, Trombetta JJ, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science (80- ). 2014;344:1396–401.Google Scholar
- 89.Wang Q, Hu X, Hu B, et al. Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment. bioRxiv. 2016;52076.Google Scholar
- 90.Jaitin DA, Kenigsberg E, Keren-Shaul H, et al. Massively parallel single-cell RNA-Seq for marker-free decomposition of tissues into cell types. Science. 2014;343(80- ):776–9.Google Scholar
- 93.• Kommoss S, Winterhoff B, Oberg AL, et al. Bevacizumab may differentially improve ovarian cancer outcome in patients with proliferative and mesenchymal molecular subtypes. Clin Cancer Res. 2017; This paper provides supportive evidence for differences in response to treatment by high-grade serous gene expression subtypes, which is evidence against a “one size fits all” approach to treatment of ovarian cancer. Google Scholar
- 100.Riester M, Wei W, Waldron L, et al. Risk prediction for late-stage ovarian cancer by meta-analysis of 1525 patient samples. J Natl Cancer Inst. 2014;106Google Scholar
- 104.Schildkraut JM, Abbott SE, Alberg AJ, et al. Association between body powder use and ovarian cancer: the African American cancer epidemiology study (AACES). Cancer Epidemiol Biomarkers Prev [Internet]. 2016;25:1411–8. Available from: http://cebp.aacrjournals.org/content/early/2016/05/12/1055-9965.EPI-15-1281.abstract CrossRefGoogle Scholar
- 105.Cannioto RA, Trabert B, Poole EM, Schildkraut JM. Ovarian cancer epidemiology in the era of collaborative team science. Cancer Causes Control. Springer International Publishing; 2017;0:0.Google Scholar