Rethinking ovarian cancer: recommendations for improving outcomes

Vaughan, Sebastian; Coward, Jermaine; Bast, Robert C.; Berchuck, A.; Berek, Jonathan S.; Brenton, James D.; Coukos, George; Crum, Christopher; Drapkin, Ronny; Etemadmoghadam, Dariush; Friedlander, Michael; Gabra, Hani; Kaye, Stan B.; Lord, Christopher J.; Lengyel, Ernst; Levine, Douglas A.; McNeish, Iain A.; Menon, Usha; Mills, Gordon B.; Nephew, Kenneth P.; Oza, Amit M.; Sood, Anil K.; Stronach, Euan A.; Walczak, Henning; Bowtell, David D.L.; Balkwill, Frances R.

doi:10.1038/nrc3144

Cited by 1,134 publications

(1,066 citation statements)

References 83 publications

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“…A recent paradigm shift points toward distinct tissues of origin in ovarian cancer that are responsible for its various histologic subtypes. 33 Because our study was designed to be exploratory, we deliberately included different histologic subtypes of ovarian cancer, because we were acutely aware of the recent controversy regarding their differing origin and pathogenesis. 34,35 Nevertheless, the vast majority of our patients, particularly in the validation cohort, were diagnosed with advanced stage, high-grade, serous ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Pils

Horak

Vaňhara

et al. 2012

Cancer

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BACKGROUND. Current prognostic information in ovarian cancer is based on tumor stage, tumor grade, and postoperative tumor size. Reliable molecular prognostic markers are scarce. In this article, the authors describe epigenetic events in a frequently deleted region on chromosome 8p22 that influence the expression of tumor suppressor candidate 3 (TUSC3), a putative tumor suppressor gene in ovarian cancer. METHODS. Messenger RNA expression and promoter hypermethylation of TUSC3 were studied in ovarian cancer cell lines and in tumor samples from 2 large, independent ovarian cancer cohorts using polymerase chain reaction-based methods. RESULTS. The results indicated that TUSC3 expression is decreased significantly because of promoter methylation in malignant ovarian tumors compared with benign controls. Almost 33% of ovarian cancer samples had detectable TUSC3 promoter methylation. Furthermore, methylation status of the TUSC3 promoter had a significant and independent influence on progression-free and overall survival. CONCLUSIONS. TUSC3 hypermethylation predicted progression-free and overall survival in ovarian cancer. The current observations suggested a role for N-glycosylating events in ovarian cancer pathogenesis in general and identified the epigenetic silencing of TUSC3 as a prognostic factor in this disease. Cancer 2013;119:946-54. V C 2012 American Cancer Society.KEYWORDS: TUSC3, methylation, ovarian cancer, glycosylation, progression-free survival, overall survival, biomarker.. INTRODUCTIONEpithelial ovarian cancer is the most lethal gynecologic malignancy and the fourth most frequent cause of cancer-related death among women in industrialized countries. 1 Because >75% of women are diagnosed with advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stages III and IV), an early diagnosis presents 1 of the challenges of this disease. Patients with advanced ovarian cancer undergo intensive multimodal therapy consisting of cytoreductive surgery and (neo)adjuvant platinum-based and taxane-based chemotherapy. Regardless of the progress made in surgical and medical therapies over recent decades, the outcome for women with advanced ovarian cancer remains grim. Innovative, hypothesis-driven approaches to biomarker development remain essential even in the era of high-throughput sequencing and various omics. Studies of promoter methylation patterns in tumor suppressor genes have yielded several promising methylated biomarker candidates. [2][3][4] In contrast to a gene or protein expression analysis, methylation can easily be detected using polymerase chain reaction (PCR)-based methods in both tumor material and body fluids. [5][6][7] TUSC3 (tumor suppressor candidate 3), originally named N33, was identified as a potential tumor suppressor gene in prostate cancer 8,9 and is located on chromosome band 8p22. Known homozygous deletions of this region in pancreatic cell lines 10,11 and prostate cancer cell lines 12,13 contain no other cancer-related genes except TUSC3, although mutations of the T...

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Section: Discussionmentioning

confidence: 99%

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Pils

Horak

Vaňhara

et al. 2012

Cancer

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“…1,2 Accumulating evidence suggests that OCCC has distinct clinical and molecular characteristics compared with other histologic subtypes of epithelial ovarian cancer. 3,4 Clinically, patients with advanced-stage OCCC have poorer survival outcomes than those with advanced-stage serous ovarian carcinoma (SOC), whereas patients with early-stage OCCC and SOC have similar survival outcomes. 5,6 However, the reasons for this discrepancy and the mechanisms leading to poor survival outcomes in patients with advanced-stage OCCC have yet to be completely elucidated.…”

Section: Introductionmentioning

confidence: 99%

Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma

Matsuo¹,

Hasegawa²,

Yoshino³

et al. 2015

European Journal of Cancer

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“…In 2014, there were estimated 21,980 new cases of and 14,270 deaths caused by ovarian cancer in the United States (2). Unfortunately, more than 70% of the ovarian cancer patients present with advanced stage disease (stage III/IV) at the initial diagnosis, and are thus given a poor prognosis (3,4). Despite many advances in surgical techniques and chemotherapy during the past decades, the 5-year survival rates remain as low as 35% and 20% for stages III and IV, respectively (5-7).…”

Section: Introductionmentioning

confidence: 99%

Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway

Dong

et al. 2015

Molecular Cancer Therapeutics

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NISCH encodes the imidazoline receptor Nischarin and is a known tumor suppressor in many human malignancies; however, its roles in ovarian cancer are still largely unknown. Here, we aim to investigate the biologic functions of NISCH in ovarian cancer. We found that NISCH was significantly downregulated, which correlated considerably with advanced tumor stage, poor differentiation, lymph node metastasis, and the serous/mucinous subtypes in a panel of ovarian cancer tissues. Moreover, NISCH gene silencing was mainly the product of promoter hypermethylation, which could be reversed by treatment with 5-aza-dC. In vitro, NISCH overexpression suppressed cell proliferation and colony formation by hindering cell-cycle progression, whereas the opposite was observed in NISCH knockdown counterparts. In vivo, abundant NISCH expression hindered the growth of HO8910 xenografts, whereas NISCH knockdown accelerated the growth of SKOV3 xenografts. In addition, NISCH significantly attenuated cell invasion by inhibiting the phosphorylation of FAK and ERK, which could be neutralized by PF-562271 (a FAK/Pyk2 inhibitor). Accordingly, NISCH knockdown xenografts exhibited increased peritoneal/pelvic metastases that were not present in counterparts treated with PF-562271. Furthermore, NISCH expression in primary ovarian cancer cells predicted a cellular resistance to PF-562271. In conclusion, we showed that NISCH was frequently silenced by promoter hypermethylation in human ovarian cancer. NISCH manipulated cellular proliferation and invasion by arresting cell cycle and inhibiting the FAK signal. Our findings revealed the biologic functions of NISCH in ovarian cancer, and might be useful for treating patients with aberrant expression of NISCH.

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Rethinking ovarian cancer: recommendations for improving outcomes

Cited by 1,134 publications

References 83 publications

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma

Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway

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