Mendelian inheritance of familial prostate cancer.

Abstract

Previous studies have demonstrated familial clustering of prostate cancer. To define the nature of this familial aggregation and to assess whether Mendelian inheritance can explain prostate cancer clustering, proportional hazards and segregation analyses were performed on 691 families ascertained through a single prostate cancer proband. The proportional hazards analyses revealed that two factors, early age at onset of disease in the proband and multiple affected family members, were important determinants of risk of prostate cancer in these families. Furthermore, segregation analyses revealed that this clustering can be best explained by autosomal dominant inheritance of a rare (q = 0.0030) highrisk aflele leading to an early onset of prostate cancer. The estimated cumulative risk of prostate cancer for carriers revealed that the allele was highly penetrant: by age 85, 88% of carriers compared to only 5% of noncarriers are projected to be affected with prostate cancer. The best fitting autosomal dominant model further suggested that this inherited form of prostate cancer accounts for a significant proportion of early onset disease but overall is responsible for a small proportion of prostate cancer occurrence (9% by age 85). These data provide evidence that prostate cancer is inherited in Mendelian fashion in a subset offamilies and provide a foundation for gene mapping studies of heritable prostate cancer. Characterization of genes involved in inherited prostate cancer could provide important insight into the development of this disease in general.Molecular approaches to the understanding of human neoplastic disease have revealed that multiple genetic alterations are an essential component of tumorigenesis (1, 2). Both inherited and somatic genetic alterations can be involved in the malignant transformation of normal cells (3). Identification of the genes involved in neoplastic transformation has been approached through the molecular analysis of sporadic cancers and the genetic study of families with an inherited predisposition for cancer. The interplay of these two approaches has led to the characterization of genes such as the retinoblastoma gene, the p53 gene, and the APC gene that are each involved in the development of both hereditary, and nonhereditary forms of cancer (4-15). Because inherited and noninherited cancers can share common genetic lesions, the study of inherited cancer syndromes can provide insights into understanding the development of cancer in general.Prostate cancer is the most common cancer diagnosed and the second leading cause of cancer mortality in United States men (16). As with breast, colon, and other cancers for which Mendelian syndromes have been described and susceptibility genes have been mapped and cloned (14,15,17), family history is known to be a risk factor for prostate cancer (18-21), which raises the possibility that transmissible genetic factors may be involved in the development of this disease in a subset of men. The genetic contribution to diseases of complex ...

Clinical characteristics of African-American men with hereditary prostate cancer: the AAHPC study

“…This elaborate multi-institutional network was designed to recruit African-American families that fulfill very stringent criteria for hereditary prostate cancer, exceeding those originally proposed by Carter et al 10 The AAHPC inclusion criteria were as follows: (a) African-American families with four or more members diagnosed with prostate cancer, (b) the combined age at diagnosis of all affected members in the family should average 65 y or less, (c) at least three affected members must donate a sample of blood for genotyping. These criteria differ from the original HPC definition proposed by Carter et al, 7,10 in which the hereditary subgroup consisted of three successive generations with prostate cancer, a clustering of three or more affected individuals in a nuclear family and/or two relatives with early onset (less than 55 y) of prostate cancer. The details of the AAHPC network infrastructure and recruitment protocols have been previously reported.…”

“…Affected males from families with hereditary prostate cancer (HPC) account for 5-10% of all reported cases of prostate cancer in the United States and Europe. [7][8][9] It is against this background that the African-American Hereditary Prostate Cancer Study (AAHPC) was initiated to recruit African-American families to a hereditary prostate cancer study. This is the first large-scale study to describe the clinical characteristics of hereditary prostate cancer in affected African-American men from multiplex families.…”

Prospective comparison of family medical history with personal genome screening for risk assessment of common cancers

“…19 Colorectal cancer risk assessment was based on the Scheuner criteria, which classifies individuals as general population, moderate and high risk (Supplementary Table 1). Participants' medical and family histories were then re-examined for evidence of hereditary risk.…”

The influence of dietary and environmental factors on prostate cancer risk

“…However, it is clear that there are subtypes of the disease involving familial clustering 2 and a hereditary form accounts for about 9% of cases. 3 The marked variation in the incidence and mortality from prostate cancer across geographic and ethnic groups and the observed changes in risk in migrants 4 suggest that dietary and/or lifestyle factors affect prostate cancer development. Dietary factors may prove to be directly protective against prostate cancer development or may protect against tumour progression as proposed by Carter et al 5 They reported that histological prostate cancer was as common in Japan as in the United States, but that in Japan the cancer remained latent and rarely progressed to clinically manifested disease.…”