Breakthroughs in Ovarian and Uterine Cancer Translational Research


The Gynecology Research Laboratory at Memorial Sloan Kettering Cancer Center is a disease-focused laboratory in which we apply genomics and biology to elucidate disease processes and improve treatments for women with ovarian and uterine malignancies. We have active programs in four key areas prevention, early detection, precision medicine, and rare tumors with unmet needs — with an overarching goal of accelerating the translation of laboratory findings into clinical care.

Important Breakthroughs

The most effective approach to reducing mortality from ovarian cancer is to develop efficient, stratified prevention. A major breakthrough in this area over the past decade has been the discovery that most high-grade serous ovarian cancers (HGSOCs) originate from the end of the fallopian tube and not the surface of the ovary. This revolutionizes our approach to cancer prevention and allows us to consider a number of new strategies. We also discovered that 50 percent of advanced-stage HGSOCs have an associated precursor lesion within the fallopian tube, termed serous tubal intra-epithelial carcinoma (STIC). Capitalizing on this new knowledge, we are performing integrative genomic analyses to determine the relationship between the precursor lesions and established cancers.

Early detection methods for ovarian cancer have largely failed in multiple prospective screening trials, mandating novel approaches. To identify ovarian cancer biomarkers in other body tissues, we recently completed a pilot study in which we measured four established biomarkers in fluid from the uterine cavity from women with and without ovarian cancer. We were able to demonstrate that all of the biomarkers were detectable and elevated in women with HGSOC compared to controls.

We are also developing a new program to study tumor-derived serum exosomes. These are small protein fragments that circulate in the blood and may reflect the status of the tumor deep within the pelvis. In addition, we have identified and validated a number of genes that are elevated in women with cancer, compared with controls. We will continue to refine our methods for and approaches to early detection.

Back to top

National Trials

MSK is also translating research findings into discovery on national clinical trials. On several trials, we are interrogating tumors and then correlating the results with the outcomes to determine what molecular features of the tumors are associated with response to therapy. Our work on these clinical trials shares the common goal of identifying the basis for response to targeted agents in molecularly defined subsets of gynecologic oncology patients. We are also identifying additional genes, other than BRCA1 and BRCA2, that may be associated with outstanding responses to chemotherapy in ovarian cancer patients.

Back to top

Rare Tumors

Rare tumors with unmet needs are characterized by a high mortality rate, limited research funding, and low population prevalence. Given our large volume, international reputation, and laboratory resources, MSK is uniquely suited to study these diseases. We have developed multiple programs to study rare ovarian and uterine tumors, including small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), uterine leiomyosarcoma (ULMS), uterine carcinosarcoma, and mucinous ovarian carcinoma. Recently, we discovered universal mutations in SMARCA4 that drive SCCOHT (Figure 1), (1) and that ULMS has a high recurrence rate even when initially confined to the uterus. We also developed a genomic signature to stratify newly diagnosed patients into low- and high-risk subtypes that is now being validated through samples from a prospective cooperative group.

Figure 1

Figure 1 — SMARCA4 mutations in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and TCGA samples. (a) Domain structure of the SMARCA4 protein (UniProt, SMCA4_HUMAN) overlaid with the alterations identified in 11 of the 12 SCCOHT cases in this study (case numbers in parentheses; case 103 with exon deletion is not shown). (b) Percentages of samples with nonsynonymous SMARCA4 mutations in SCCOHT and TCGA non-hypermutated samples (numbers of samples per study in parentheses). Blue bars represent samples with missense-only mutations, and orange bars represent samples with non-missense (including nonsense, frameshift, splice-site and indel) mutations. Jelinic P, et al. Nat Genet 2014;46:424-6. Abbreviations: SNF2_N = SNF2 family N-terminal domain; Helicase = helicase-conserved C-terminal domain; SnAC = Snf2-ATP coupling, chromatin-remodeling complex; Bromo = bromodomain; GBM = glioblastoma multiforme; AML = acute myeloid leukemia.

Back to top

Funding Support

Our research is supported by funding from government agencies, private foundations, and philanthropic sources, and for that, we are truly grateful. We look forward to making new discoveries that will continue to improve treatments for women with ovarian and uterine malignancies.

Back to top
  1. Jelinic P, Mueller JJ, Olvera N, et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet 2014;46:424-6.