Clinical characteristics of prostate cancer in an analysis of linkage to four putative susceptibility loci.

PURPOSE: Hereditary prostate cancer is an etiologically heterogeneous disease with six susceptibility loci mapped to date. We aimed to describe a collection of high-risk prostate cancer families and assess linkage to multiple markers at four loci: HPC1 (1q24-25), PCaP (1q42.2-43), HPCX (Xq27-28), and CAPB (1p36). EXPERIMENTAL DESIGN: Medical record data on 505 affected men in 149 multiply-affected prostate cancer families were reviewed, and correlations of clinical traits within each family were calculated. Logarithm of odds (LOD) score and nonparametric (NPL) linkage analyses were performed; white families were stratified by age of diagnosis, grade and stage of disease, and evidence of linkage to the other loci to increase genetic homogeneity. RESULTS: Age at diagnosis was the most correlated clinical trait within families. A maximum NPL score of 2.61 (P = 0.007) appeared to confirm HPC1 linkage for families that had a prevalence of high-grade or advanced-stage prostate cancer and which were not likely to be linked to PCaP, HPCX, or CAPB. Because the NPL scores improved when families more likely to be linked to the other loci were excluded, HPC1 may act independently of the other loci. The relationship of HPC1 and aggressive disease was strongest in families with median age at diagnosis > or =65 years (NPL, 3.48; P = 0.0008). CONCLUSIONS: The current results suggest that HPC1 linkage may be most common among families with more severe prostate cancer. Stratification by clinical characteristics may be a useful tool in prostate cancer linkage analyses and may increase our understanding of hereditary prostate cancer.

The importance of connections: joining components of the Hutterite pedigree.

We analyzed a quantitative trait (serum IgE levels), and a binary trait (asthma), in four Hutterite sub-pedigrees. A genome screen for asthma was performed using GENEHUNTER, and interesting regions were followed up using extended pedigrees and the FASTLINK package. Markov chain Monte Carlo (MCMC) methods were used to assess haplotype sharing among affected individuals (MORGAN/AUTOZYG), and to perform a combined oligogenic segregation and linkage analysis (LOKI) for log10(IgE). We found evidence for at least two susceptibility loci for asthma on chromosome 5, and a QTL for log10(IgE) on chromosome 1. Our analyses demonstrate that using the most complete pedigree structure possible is advisable, with attention to the possibility of heterogeneity among subunits of a very large pedigree.

Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival.

Several reports have suggested that one or both of the trinucleotide repeat polymorphisms in the human androgen receptor (hAR) gene, (CAG)n coding for polyglutamine and (GGC)n coding for polyglycine, may be associated with prostate cancer risk; but no study has investigated their association with disease progression. We present here a study of both hAR trinucleotide repeat polymorphisms not only as they relate to the initial diagnosis but also as they are associated with disease progression after therapy. Lymphocyte DNA samples from 178 British Caucasian prostate cancer patients and 195 control individuals were genotyped by PCR for the (CAG)n and (GGC)n polymorphisms in hAR. Univariate Cox proportional hazard analysis indicated that stage, grade and GGC repeat length were individually significant factors associated with disease-free survival (DFS) and overall survival (OS). The relative risk (RR) of relapse for men with more than 16 GGC repeats was 1.74 (95% CI 1. 08-2.79) and of dying from any cause, 1.98 (1.13-3.45). Adjusting for stage and grade, GGC effects remained but were not significant (RR(DFS)= 1.60, p = 0.052; RR(OS)= 1.65, p = 0.088). The greatest effects were in stage T1-T2 (RR(DFS)= 3.56, 95% CI 1.13-11.21) and grade 1 (RR(DFS)= 6.47, 95% CI 0.57-72.8) tumours. No differences between patient and control allele distributions were found by odds-ratio analysis, nor were trends with stage or grade evident in the proportion of short CAG alleles. Non-significant trends with stage and grade were found in the proportion of short GGC alleles. The (GGC)n polymorphism in this population is a significant predictor of disease outcome. Since the (GGC)(n) effect is strongest in early-stage tumours, this marker may help forecast aggressive behaviour and could be used to identify those patients meriting more radical treatment.

Familial effects of prostate and other cancers on lifetime breast cancer risk.

Lifetime probabilities of developing breast cancer were calculated for first-degree female relatives of three groups of breast cancer patients: 114 with bilateral cancer, 186 unselected, and 88 males. The patients were classified according to whether they had a family history of prostate, endometrial, or ovarian cancer, or no family history of these cancers. In families of unselected female and male patients with no family history of prostate, endometrial, or ovarian cancer, the lifetime probability of developing breast cancer was 11.4%. The risk increased slightly to 13.5% when these other cancers may or may not have present (i.e., they were ignored, which is the usual method in computing risks) and increased further to 25.5% when prostate, endometrial, or ovarian cancer was present in the family. In families of patients with bilateral cancer the respective risks were 10.9%, 17.3%, and 34.4%. A family history of prostate cancer increased lifetime risk consistently in each of the groups, to 29.0% in the unselected and male groups and to 38.2% in the bilateral group. Endometrial cancer increased risk only in the bilateral group (to 41.8%) as did ovarian cancer (to 54.6%). Increased risk of breast cancer with a family history of endometrial or ovarian cancer appeared to be influenced by families with hereditary breast-ovarian cancer or the cancer family syndrome. The results indicate that prostate cancer, and endometrial and ovarian cancers in some families, can significantly increase breast cancer risk and should be taken into account when counseling women about their breast cancer risk.

Familial breast cancer risks. Effects of prostate and other cancers.

BACKGROUND: Previous studies have provided conflicting results concerning the effects of a family history of prostate and other cancers on breast cancer risks. METHODS: Three groups of families were studied to determine the effects of a family history of prostate cancer on breast cancer risks. Also considered were the effects of a family history of melanoma, colon, lung, ovarian, and endometrial cancers. Included were 422 first-degree female relatives of 114 patients with bilateral breast cancer, 320 first-degree relatives of 88 male patients with breast cancer, and 633 relatives of 186 unselected female patients. For estimating relative risks, observed numbers of breast cancers in relatives were compared with expected numbers based on population incidence data. Multiple logistic-regression also provided odds ratios of relatives affected with breast cancer. RESULTS: A family history of prostate cancer increased the breast cancer risks in each of the groups, compared with families without prostate cancer. Ovarian cancer in a family increased the breast cancer risks only in the bilateral breast cancer group, and endometrial cancer increased the risks in the bilateral and unselected groups. These increases in risk appeared to be the consequence of families with multiple cancers, including those with hereditary breast-ovarian cancers and the cancer family syndrome. A family history of melanoma, lung, or colon cancer did not increase breast cancer risks. CONCLUSIONS: A family history of prostate cancer, as well as endometrial and ovarian cancer, significantly increases the risk of breast cancer.

Breast cancer risks in relatives of male breast cancer patients.

BACKGROUND: Previous studies have provided conflicting results concerning the familial effect of male breast cancer on breast cancer risks in female relatives. PURPOSE: We studied breast cancer risks in first-degree relatives of male patients and compared them with relatives of female patients. METHODS: Our study included 88 consecutively ascertained male patients and 320 of their first-degree relatives as well as 186 consecutively ascertained female patients and 633 of their first-degree relatives. Observed numbers of breast cancers in relatives were compared with the expected number derived from the Connecticut Tumor Registry. Multiple logistic regression analysis was also performed. RESULTS: Relatives of male patients exhibited a significant twofold increased risk when compared with expected rates and no difference in risk when compared with that of relatives of female patients. Prostate cancer in the family of a male patient resulted in a significant fourfold increased breast cancer risk compared with a risk of 1.4 in families with no history of prostate cancer. A family history of lung cancer, colon cancer, or melanoma had no effect on increasing risks of breast cancer. CONCLUSION: The familial effect of male breast cancer is the same as that of female breast cancer. IMPLICATIONS: Any estimates of breast cancer risk provided to individuals should also consider the occurrence of prostate cancer in the family, since prostate cancer appears capable of at least doubling the underlying twofold risk.

Hereditary cutaneous malignant melanoma: a 20-year family update.

A family is reported in which 28 members developed cutaneous melanoma. Segregation of the neoplasm suggested an autosomal dominant mode of inheritance but with a sex difference in penetrance and disease expression. Men developed the neoplasm less frequently and at a slightly later age than women and fathers were unaffected carriers more frequently than mothers. Children of affected or carrier fathers developed the disease less frequently than children of affected or carrier mothers. The highest frequency of melanoma occurred in daughters of affected or carrier mothers. Further study of the genetic basis for the development of melanoma is warranted.

Combined effect of family history and reproductive factors on breast cancer risk.

This study evaluated the combined effect of a family history of breast cancer and each of three reproductive factors on breast cancer risk in the sisters of 404 breast cancer patients. The patients had a family history of breast cancer in a sister and mother or in two sisters. Risks were highest in sisters who had menarche at an early age or who first gave birth at a late age whether the patient had unilateral or bilateral disease, and with low parity only when the patient had bilateral disease. The bilateral group may have included a higher fraction of hereditary forms of breast cancer than the unilateral group. Because similar findings have been reported previously for breast cancer patients in general, the current results suggest that these reproductive factors have an effect on breast cancer risk independent of a family history of the disease. It is important, therefore, that the combined effects of these risk factors be taken into account when counseling women about their breast cancer risks.

Survival in familial breast cancer patients.

This study was conducted to measure survival in breast cancer patients differing in their familiarity of the disease. A total of 556 familial patients and 4551 general patients were evaluated. Survival was higher with bilateral than unilateral disease in both groups of patients. This difference was observed only when survival was measured from the first primary; it disappeared when survival was measured from the second primary. Three groups of familial patients, who likely differed in genetic risk, had similar survival curves. They were also similar to a general series patients when stage of disease was controlled and the comparison involved primarily unilateral patients. Previous reports of increased survival in familial and bilateral patients were thus not confirmed. The previous results were likely the consequence of bias arising from measuring survival from the first primary. Survival does not appear to be influenced by family history or laterality of breast cancer.

Bilaterality in familial breast cancer patients.

The authors conducted this study to determine the probability of a second primary developing in the contralateral breast of a patient, based on her present age, age at her first breast primary, and family history of breast cancer in her mother, sister, or second-degree relative. The study involved 556 patients. With premenopausal diagnosis of the first primary, the probabilities to the 19th year for the three types of family histories ranged from 35% to 38%; with postmenopausal diagnosis, they ranged from 11% to 26%. The probability for all familial patients was 28%. This contrasts with a probability of 13% reported for a general series of patients. An early age at diagnosis and family history of the disease thus have important enhancing effects on the development of second primaries. This information could be useful to physicians in deciding how best to manage the treatment of their patients.

Risk of familial breast cancer.

The probabilities of developing breast cancer to and between various ages were estimated for 699 sisters of patients from three pedigree groups: sisters of patients whose (1) mothers, (2) sisters, or (3) second-degree relatives had previous breast cancer. The pedigree source of the patient and the laterality of disease had important effects on her sister's risk, whereas her age at diagnosis had virtually no effect. The highest life-time risks to sisters occurred when the patient had bilateral disease, an affected mother (25 +/- 7.2%), or an affected sister (28 +/- 11%). The risks reduced to 18 +/- 3.3% and 14 +/- 2.6%, respectively, with unilateral disease. Sisters of patients with an affected second-degree relative manifested a risk of 4 +/- 1.8% only with unilateral disease. Although the sisters' probabilities to age 70 were similar in pedigrees with affected mothers and sisters, the interval probabilities for successive 10-year periods suggested an earlier disease occurrence in the mother than sister pedigree groups when the patient had bilateral disease. The current results and those of others underscore the need for caution in applying probabilities for counseling women about their breast cancer risks.