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Grant Details

Grant Number: 5R01CA111914-05 Interpret this number
Primary Investigator: Pal, Tuya
Organization: H. Lee Moffitt Cancer Ctr & Res Inst
Project Title: Ovarian Cancer and Mismatch Repair Deficiency
Fiscal Year: 2009
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Abstract

DESCRIPTION (provided by applicant): 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.

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Publications

Association between IHC and MSI testing to identify mismatch repair-deficient patients with ovarian cancer.
Authors: Lee JH, Cragun D, Thompson Z, Coppola D, Nicosia SV, Akbari M, Zhang S, McLaughlin J, Narod S, Schildkraut J, Sellers TA, Pal T
Source: Genet Test Mol Biomarkers, 2014 Apr;18(4), p. 229-35.
EPub date: 2014 Mar 4.
PMID: 24592941
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Risk factors for ovarian cancers with and without microsatellite instability.
Authors: Segev Y, Pal T, Rosen B, McLaughlin JR, Sellers TA, Risch HA, Zhang S, Ping S, Narod SA, Schildkraut J
Source: Int J Gynecol Cancer, 2013 Jul;23(6), p. 1010-5.
PMID: 23748177
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Long-term ovarian cancer survival associated with mutation in BRCA1 or BRCA2.
Authors: McLaughlin JR, Rosen B, Moody J, Pal T, Fan I, Shaw PA, Risch HA, Sellers TA, Sun P, Narod SA
Source: J Natl Cancer Inst, 2013 Jan 16;105(2), p. 141-8.
EPub date: 2012 Dec 20.
PMID: 23257159
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Uncertainty in the utility of immunohistochemistry in mismatch repair protein expression in epithelial ovarian cancer.
Authors: Coppola D, Nicosia SV, Doty A, Sellers TA, Lee JH, Fulp J, Thompson Z, Galeb S, McLaughlin J, Narod SA, Schildkraut J, Pal T
Source: Anticancer Res, 2012 Nov;32(11), p. 4963-9.
PMID: 23155266
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Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.
Authors: Pal T, Akbari MR, Sun P, Lee JH, Fulp J, Thompson Z, Coppola D, Nicosia S, Sellers TA, McLaughlin J, Risch HA, Rosen B, Shaw P, Schildkraut J, Narod SA
Source: Br J Cancer, 2012 Nov 6;107(10), p. 1783-90.
EPub date: 2012 Oct 9.
PMID: 23047549
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Sampling strategies for tissue microarrays to evaluate biomarkers in ovarian cancer.
Authors: Permuth-Wey J, Boulware D, Valkov N, Livingston S, Nicosia S, Lee JH, Sutphen R, Schildkraut J, Narod S, Parker A, Coppola D, Sellers T, Pal T
Source: Cancer Epidemiol Biomarkers Prev, 2009 Jan;18(1), p. 28-34.
PMID: 19124477
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Systematic review and meta-analysis of ovarian cancers: estimation of microsatellite-high frequency and characterization of mismatch repair deficient tumor histology.
Authors: Pal T, Permuth-Wey J, Kumar A, Sellers TA
Source: Clin Cancer Res, 2008 Nov 1;14(21), p. 6847-54.
PMID: 18980979
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A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer.
Authors: Pal T, Permuth-Wey J, Sellers TA
Source: Cancer, 2008 Aug 15;113(4), p. 733-42.
PMID: 18543306
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Improved survival in BRCA2 carriers with ovarian cancer.
Authors: Pal T, Permuth-Wey J, Kapoor R, Cantor A, Sutphen R
Source: Fam Cancer, 2007;6(1), p. 113-9.
PMID: 17160431
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