DiCioccio, Richard A., PhD

Professor Emeritus

Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY 14263
Telephone : (716) 845-8059
Fax: (716) 845-1698
e-mail: Richard.DiCioccio@RoswellPark.org

General Research Interest

Genetic Basis of Ovarian Cancer

Current Program

Genetic Analysis of Familial Ovarian Cancer Using the Gilda Radner Familial Ovarian
Genetic Epidemiology of Ovarian Cancer Using a Population-based Ovarian Cancer Registry

Collaborators

Alice S. Whittemore, Ph.D., Stanford University
Bruce Ponder, M.D., University of Cambridge, England
M. Steven Piver, M.D., Sisters of Charity Hospital, Buffalo, NY

Description of Research

Ovarian cancer accounts for 3.3% of cancer cases and 5.7% of cancer deaths among USA women (American Cancer Society, 2007). An estimated 22,430 new cases of ovarian cancer and 15,280 deaths from this disease occurred in the USA for 2007. If diagnosed and treated at an early stage of disease, 93% of ovarian cancer patients survive 5 years or longer. However, if diagnosed at an advanced stage of disease, the survival rate diminishes to 45%. Unfortunately, 81% of cases are diagnosed at a late stage of disease. Thus, ovarian cancer is a major health problem and there is a need to improve the outlook for this dreaded disease. One approach is to increase our understanding of the fundamental causes of ovarian cancer. This information would provide a basis for developing new strategies for disease prevention, early detection, and treatment.

Cancer is a genetic disease resulting from gene alterations (ie. mutations) that disrupt normal cell growth and differentiation. The transformation of a normal cell, such as an ovarian epithelial cell, to a malignant tumor cell is considered a multistep process that proceeds through an accumulation of mutations in certain genes over the course of many years. Neither the exact number of gene alterations nor the identity of all genes involved in any form of cancer are known. Most mutations leading to cancer are acquired during the lifetime of an individual in somatic cells. Some mutations contributing to cancer are inherited in families. Inherited mutations leading to cancer account for 5% to 10% of cancer cases. Our laboratory is interested in characterizing both inherited and acquired genetic changes leading to ovarian cancer.

Project 1: Genetic Analysis Using The Gilda Radner Familial Ovarian Cancer Registry

The Registry has accessioned over 1800 families reporting 2 or more cases of ovarian cancer in close, blood relatives. We have verified over 300 families with two or more ovarian cancer cases by review of medical records and archival pathology material. Bloods from 780 individuals representing 253 families have been obtained. DNA has been isolated from blood of each individual. Mutation analysis of the BRCA1, BRCA2, MSH2 and MLH1 genes has been conducted with DNA from individuals from 139 families. BRCA1, BRCA2, and MSH2 mutations were found in 38, 13, and 2 families, respectively. Mutation analysis of these genes in additional Registry families is underway. We are planning to use families not segregating mutations in BRCA1, BRCA2, MSH2, or MLH1 to find new genes associated with familial ovarian cancer.

In epidemiologic studies, we found that oral contraceptive use for at least one year reduced the risk for developing ovarian cancer by 15% in carriers of BRCA1 and BRCA2 mutations. The risk decreased with increasing duration of use with a decreased risk of 38% for use of six years. This risk reduction for oral contraceptive use in BRCA1 and BRCA2 carriers is similar to the risk reduction previously reported for the general population. Thus carriers of BRCA1 and BRCA2 mutations receive the same benefit of oral contraceptive use as the general female public. In the near future, we hope to evaluate associations relating ovarian cancer in women with BRCA1 and BRCA2 mutations to other epidemiologic attributes known to affect risk for developing ovarian cancer such as parity, tubal ligation, and hormone replacement therapy.

Project 2: Genetic Epidemiology of Ovarian Cancer

This project has collected pedigree information, epidemiological data, and biologic specimens from a multiethnic, population-based series of 750 patients with ovarian cancer and 420 of their female relatives, and 600 demographically matched healthy controls. This resource is used for interdisciplinary etiologic and translational research.

Mutation analysis of BRCA1 has been conducted with DNA from cancer cases and female relatives. BRCA1 mutations have been found in 7% of this population. A unique BRCA1 mutation at a splice site junction was characterized. Moreover, we determined that a missense BRCA1 mutation, V1804D, reduced transcriptional activation function of BRCA1. We also used the data to calculate that 0.24% of non-Hispanic white women and 1.2% Ashkenasi Jewish women in the USA are carriers of a BRCA1 mutation. From demographic information we determined that 1) oral contraceptive use was associated with 45% decreased risk of ovarian cancer in both BRCA1 mutation carriers and non-carriers, 2) history of tubal ligation was associated with 35% decreased risk, and parity with a 20% decreased risk. Additionally, we screened the population for polymorphisms in STK15, a putative oncogene that codes for a serine/threonine kinase involved in accurate chromosome segregation in mitosis. We found that inheritance of the I31 allele of the polymorphism F31I increases risk for ovarian cancer by 1.2% and thus may be a common cancer susceptibility allele of low penetrance. Currently, polymorphisms in other potential cancer susceptibility genes are being screened to identify more cancer susceptibility alleles. Collectively, this information will be useful for planning ovarian cancer prevention and early detection strategies.

Key Publications

Lee JS, John EM, McGuire V, Felberg A, Ostrow KL, DiCioccio RA, Li FP, Miron A, West DW,Whittemore AS. Breast and ovarian cancer in relatives of cancer patients with and without BRCA mutations. Cancer Epidemiology, Biomarkers, and Prevention 15: 359-363, 2006.
McGuire V, Felberg A, Mills M, Ostrow KL, DiCioccio RA, John EM, West DW, Whittemore AS. Contraceptive and reproductive history in relation to ovarian cancer risk in carriers and noncarriers of BRCA1 mutations. Am J Epidemiology 160: 613-618, 2004.
Laskie Ostrow K, McGuire V, Whittemore AS, DiCioccio RA. The effects of BRCA1 missense variants V1804D and M1628T on transcriptional activity. Cancer Genetics and Cytogenetics 153:177-180, 2004.
DiCioccio RA, Song H, Waterfall C, Kimura MT, Nagase H, McGuire V, Hogdall E, Shah MN, Luben RN, Easton DF, Jacons IJ, Ponder BAJ, Whittemore AS, GaytherSA, Pharoah DPP, Kruger-Kjaer S. STK15 polymorphisms and association with risk of invasive ovarian cancer. Cancer, Epidemiology Biomarkers and Prevention 13: 1589-1594, 2004.
Whittemore AS, Balise RR, Pharaoah P, DiCioccio RA, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Oakley-Girvan I, Ramus SJ, Daly M, Usinowicz MB, Garlinghouse-Jones K, Ponder BAJ, Buys S, Senie R, Andrulis I, John E, Hopper JL, Piver MS. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 and BRCA2 mutations. Br J Cancer 91:1911-1915, 2004.
Whittemore AS, Gong G, John EM, McGuire V, Li F, Laskie Ostrow K, DiCioccio R, Felberg A, Satariano E, West DW. Prevalence of BRCA1 mutation carriers among US Non-Hispanic Whites. Cancer Epidemiology, Biomarkers, and Prevention 13: 2078-2083, 2004.
Laskie Ostrow K, McGuire V, Whittemore AS, DiCioccio RA. A BRCA1 variant, IVS23+1G→A, causes abnormal RNA splicing by deleting exon 23. Cancer Genetics and Cytogenetics 127:188-190, 2001.