Ovarian cancer ranks fifth in both cancer incidence and cancer mortality in U.S. women and has the highest mortality rate among gynecologic cancers, with most patients presenting with late stage metastatic disease. Traditionally, most carcinomas have been treated as though they represent a single disease, and treatments have been based on stage and grade. Data is emerging that the response to treatments may differ, depending on the genetic etiology of the cancer. A better understanding of the molecular events that lead to the evolution of cancer and underlie tumor heterogeneity should lead to more specific treatment regimens. One of the best defined molecular pathways involved in both inherited and sporadic cancer pathogenesis involves the mismatch repair (MMR) pathway, which leads to microsatellite instability (MSI). MSI may result from both genetic (i.e.: germline mutations in the MMR genes, including MLH1, MSH2, and MSH6) and epigenetic (i.e.: MLH1 promoter hypermethylation) mechanisms. It is the purpose of the present proposal to quantify the proportion of ovarian tumors due to the mismatch repair genes and to characterize the tumors in this group. Our ability to classify ovarian cancers by their genetic basis offers promise for improvements in cancer prevention and screening of high risk women, in basing diagnosis and prognosis on molecular markers, and in development of individualized treatments. To date, only a few small studies of MMR in ovarian cancer have been performed and none have been population-based. This is in part due to the difficulty in recruiting large numbers of patients with ovarian cancer who are representative of the population. The proposed study is feasible to conduct only because of the extensive resources already available through the use of data and samples from three existing North American population-based studies, representing the majority of population-based cases in North America to date. This study will include 2200 incident epithelial ovarian cancers based at the Moffitt Cancer Center, Duke Comprehensive Cancer Center, and the University of Toronto and will be the largest collection of its type in the world. Paraffin-embedded tumor samples will be analyzed from all subjects with incident ovarian cancers to perform MSI testing and investigate MMR gene protein expression. In those samples with MSI-H status or with loss of expression of MMR gene proteins, epigenetic (MLH1 promoter hypermethylation) and genetic (germline MMR mutations) will be investigated. The clarification of factors that determine the etiology of MSI-H ovarian tumors are relevant to up to one-fifth of patients who have this deadly disease, hence these data may serve to advance clinical practice in several areas, including risk stratification, behavioral modification, and eventually have therapeutic relevance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA111914-01
Application #
6858918
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Kasten-Sportes, Carol H
Project Start
2005-04-20
Project End
2010-03-31
Budget Start
2005-04-20
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$522,611
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Segev, Y; Zhang, S; Akbari, M R et al. (2015) Survival in women with ovarian cancer with and without microsatellite instability. Eur J Gynaecol Oncol 36:681-4
Lee, Ji-Hyun; Cragun, Deborah; Thompson, Zachary et al. (2014) Association between IHC and MSI testing to identify mismatch repair-deficient patients with ovarian cancer. Genet Test Mol Biomarkers 18:229-35
Segev, Yakir; Pal, Tuya; Rosen, Barry et al. (2013) Risk factors for ovarian cancers with and without microsatellite instability. Int J Gynecol Cancer 23:1010-5
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Coppola, Domenico; Nicosia, Santo V; Doty, Andrea et al. (2012) Uncertainty in the utility of immunohistochemistry in mismatch repair protein expression in epithelial ovarian cancer. Anticancer Res 32:4963-9
Pal, T; Akbari, M R; Sun, P et al. (2012) Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer 107:1783-90
Permuth-Wey, Jenny; Boulware, David; Valkov, Nikola et al. (2009) Sampling strategies for tissue microarrays to evaluate biomarkers in ovarian cancer. Cancer Epidemiol Biomarkers Prev 18:28-34
Pal, Tuya; Permuth-Wey, Jenny; Kumar, Ambuj et al. (2008) Systematic review and meta-analysis of ovarian cancers: estimation of microsatellite-high frequency and characterization of mismatch repair deficient tumor histology. Clin Cancer Res 14:6847-54
Pal, Tuya; Permuth-Wey, Jenny; Sellers, Thomas A (2008) A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer. Cancer 113:733-42

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