GENETIC EPIDEMIOLOGY OF PROSTATE CANCER
AND BREAST CANCER

Prostate and breast cancers are the most commonly occurring cancers in males and females, respectively. The estimated number of new breast cancer cases among women in the US in 1998 was 178,300 with 43,500 deaths. In the US alone, nearly 200,000 new cases of prostate cancer are diagnosed each year, resulting in 40,000 deaths. Despite the medical significance of both breast cancer and prostate cancer in terms of morbidity, mortality and health costs, our understanding of the molecular determinants of prostate cancer susceptibility remains rudimentary. Epidemiological studies supporting the existence of hereditary forms of these cancers have led to the initiation of genome-wide searches for loci contributing to hereditary breast and prostate cancer. Linkage analysis of families burdened with prostate cancer remains the best method for determining the various possible genetic loci contributing to the hereditary forms of the disease. It is also suggested that mutations in hereditary cancer genes often predispose individuals to more than one histologic type of cancer. Studies of familial co-aggregation of prostate cancer with breast cancer may sharpen the clinical diagnosis of a cancer predisposition syndrome.

In a previous study reported by Smith, et al (Science 274:1371, 1996), a genome-wide scan for hereditary prostate cancer (HPC) genes was performed and a prostate cancer susceptibility locus was identified on chromosome 1 at 1q24-25. In addition, this scan identified other possible susceptibility loci, including 1q, 4q, 5p, 7p, 13q and Xq. On the basis of prostate cancer risk in relatives of affected men, it has been suggested that an HPC susceptibility locus may reside on the X chromosome. Several population studies have reported a statistically significant excess risk of prostate cancer in men with affected brothers, as compared with those with affected fathers, consistent with the hypothesis of an X-linked, or recessive, model of inheritance. These indications prompted a more detailed analysis of potential X-linkage in HPC families. A set of prostate cancer family data from Finland was analyzed for linkage to the X chromosome. To investigate if additional loci would be more important than the HPC locus in Finland, we performed, as part of a large consortium (1), targeted linkage analyses of regions on the X chromosome showing positivity in the original genome scan by Smith et al. Significant evidence for linkage was seen in the Finnish data to marker DXS1205 on chromosome X among the `no-male-to-male-transmission' (no father-to-son transmission) families. Both the two-point and multipoint analyses demonstrate maximum lod-scores of >2.0 in the region near DXS1205 (Figure 1). Homogeneity testing, however, indicates that the Finnish data are compatible with heterogeneity. Half of the families appear linked to the Xq27-28 region, while the rest are linked to chromosome 1 or to another unidentified locus.

With a combination of families from the original Smith et al. study plus new US families, genome-wide significance was obtained with a maximum two-point lod-score of 4.60 (1). The work is being followed with fine-mapping and association studies in an attempt to narrow the region of the gene localization for future positional cloning.

GENETIC EPIDEMIOLOGY OF PROSTATE CANCER AND BREAST CANCER. BAFFOE-BONNIE, in collaboration with BAILEY-WILSON,^a ROSS,^§ BALSHEM,^§ DALY,^§ HANKS^§

Previous investigation has suggested a potential genetic association between breast cancer and prostate cancer, mainly through familial aggregation of these two common cancers. One aim of the Prostate Cancer Family Risk Assessment Program (PRAP) for men at high risk of developing prostate cancer is to study the genetics of prostate cancer through the collection of multiplex families suitable for linkage studies, as well as modeling the breast-prostate cancer phenotype. PRAP has data on the families of 235 men either previously diagnosed with prostate cancer or at high risk for prostate cancer. To date, 134 men were previously diagnosed with prostate cancer; 98% are Caucasian (2). Of the 101 men at high risk for prostate cancer, 51% are African-American. Of the nearly 3000 individuals comprising the families of these 235 men, pedigree sizes range from 4 to 44 individuals, with a mean of 15 persons. There are equal numbers of males and females among the individuals in all the pedigrees. Among these individuals, 500 have been diagnosed with cancer; 43% have prostate cancer, 15% have breast cancer and 8% have lung cancer. In our previous work, a genetic epidemiologic approach was adopted to test the hypothesis of coaggregation of breast cancer and prostate cancer in family data (Baffoe-Bonnie, Ph.D. Dissertation, Johns Hopkins University, 1997). Analysis of two family data sets comprising prostate cancer and breast cancer probands, respectively, was the basis of the breast-prostate cancer phenotype modeling in each data set separately. The prostate cancer data had 690 nuclear families ascertained through young (35-76 years old) prostatectomy patients seen between 1982 and 1989 at the Johns Hopkins Hospital, Baltimore, Maryland. The Icelandic Cancer Registry provided a sample comprising 389 breast cancer probands born in or after 1920 (3). In segregation analyses with the computer program S.A.G.E. (Statistical Analysis for Genetic Epidemiology), the age of onset of cancer was best modeled as a truncated trait that followed a logistic distribution after log-transformation (with familial effects). The age of onset of prostate cancer and breast cancer was tested separately for Mendelian autosomal control, before modeling the combined cancer phenotype (defined as breast cancer in females or prostate cancer in males). The combined breast/prostate cancer phenotype in the population-based Icelandic Cancer Registry data was under Mendelian control with sex-specific ages of onset. In addition to the above methodology, multivariate survival models will be applied for the analysis of the data being accrued at the Fox Chase Cancer Center through collaboration with the Departments of Radiation Oncology and Surgical Oncology. Data for the combined breast/prostate cancer phenotype is also being collected from the Family Risk Assessment Program (FRAP) for women with a family history of breast and/or ovarian cancer.

1.   XU, J., MEYERS, D., FREIJE, D., ISAACS, S., WILEY, K., NUSSKERN, D., EWING, C., WILKENS, E., BUJNOVSZKY, P., BOVA, G.S., WALSH, P., ISAACS, W., SCHLEUTKER, J., MATIKAINEN, M., TAMMELA, T., VISAKORPI, T., KALLIONIEMI, O-P., BERRY, R., SCHAID, D., FRENCH, A., MCDONNELL, S., SCHROEDER, J., BLUTE, M., THIBODEAU, S., GRÖNBERG, H., EMANUELSSON, M., DAMBER, J-E., BERGH, A., JONSSON, BJ., SMITH, J., BAILEY-WILSON, J., CARPTEN, J., STEPHAN, D., GILLANDERS, E., AMUNDSON, I., KAINU, T., FREAS-LUTZ, D., BAFFOE-BONNIE, A., VAN AUCKEN, A., SOOD, R., COLLINS, F., BROWNSTEIN, M., TRENT, J. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nature Genet. 20:175-79, 1998.

2.   WATKINS-BRUNNER, D., BAFFOE-BONNIE A., MILLER, S., DIEFENBACH, M., TRICOLI, J.V., DALY, M., PINOVER, W., GRUMET, S.C., STOFEY, J., ROSS, E., RAYSOR, S., BALSHEM, A., MALICK, J., MIRCHANDANI, I., ENGSTROM, P., HANKS, G. A prostate cancer risk assessment program. A model for early detection of prostate cancer. Oncology (in press).

3.   BAFFOE-BONNIE, A., BEATY, T.H., BAILEY-WILSON, J.E., KIEMENEY, L.A.L.M., SIGVADASSON, H., OLAFSDOTTIR, G., TRYGGVADOTTIR, L., TULINIUS, H. The genetic epidemiology of breast cancer: Segregation analyses of 389 Icelandic Pedigrees. Genet. Epidemiol. (in press).

^§   Fox Chase researcher

^a   J.R. Smith, L. Gillanders, O-P. Kallioniemi, J. Trent, J.E. Bailey-Wilson: Prostate Cancer Investigation Group, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892

^b   J. Schleutker: Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland

Illustrations or unpublished data in these reports should not be used without permission of the author.

Fox Chase Cancer Center

Scientific Report 1998