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Early Age at Diagnosis in Families Providing Evidence of Linkage to the Hereditary Prostate Cancer Locus (HPC1) on Chromosome 1
BENIGN AND MALIGNANT NEOPLASMS OF PROSTATE
one nuclear family; affected individuals in three successive generations [maternal or paternal lineage]: and/or clustering of two or more individuals affected before the age of 55 years) revealed more convincing evidence of disease linkage t o chromosome 1q24-25 (maximum NPL Z score [at marker DlS4661 = 1.72; P = .0451). The 39 families (79 affected individuals) that did not meet the clinical criteria for hereditary prostate cancer exhibited no significant evidence of disease linkage to DNA sequences at chromosome 1q24-25 (maximum NPL Z score [at marker DlS4661 = 0.809; P = .208). The six African-American families in our study contributed disproportionately to the observation of linkage, with a maximum NPL Z score at marker DlS158 of 1.39 (P = ,0848) for these families. Conclusions and Implications: Our data confirm that chromosome 1q24-25 is likely to contain a prostate cancer susceptibility gene. Future efforts at positional cloning of the HPCl gene should focus on families who meet the proposed clinical criteria for hereditary prostate cancer.
Linkage Analysis of 49 High-Risk Families does not Support a Common Familial Prostate Cancer-Susceptibility at 1q24-25 R. A. MCINDOE, J. L. STANFORD, M. GIBBS,G. P. JARVIK, S. BRANDZEL, C. L. NEAL,S. LI, J. T. GAMMACK, A. A. GAY,E. L. GOODE,L. HOODAND E. A. OSTRANDER, Departments of Molecular Biotechnology and Epidemiology, School of Public Health and Community Medicine, University of Washington, Department of Medicine, Division of Medical Genetics, University of Washington Medical Center and Divisions of Public Health Sciences and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington Amer. J. Hum. Genet., 61: 347-353, 1997 Linkage of a putative prostate cancer-susceptibility locus (HPC1)to chromosome 1q24-25 has recently been reported. Confirmation of this linkage in independent data sets is essential because of the complex nature of this disease. Here we report the results of a linkage analysis using 10 polymorphic markers spanning -37 cM in the region of the putative HPCl locus in 49 high-risk prostate cancer families. Data were analyzed by use of two parametric models and a nonparametric method. For the parametric LOD-score method, the first model was identical to the original report by Smith and coworkers (“Hopkins”),and the second was based on a segregation analysis previously reported by Carter and coworkers (“Seattle”).In both cases, our results do not confirm the linkage reported for this region. Calculated LOD scores from the two-point analysis for each marker were highly negative a t small recombination fractions. Multipoint LOD scores for this linkage group were also highly negative. Additionally, we were unable to demonstrate heterogeneity within the data set, using HOMOG. Although these data do not formally exclude linkage of a prostate cancer-susceptibility locus a t HPC1, it is likely that other prostate cancer-susceptibility loci play a more critical role in the families that we studied.
Early Age at Diagnosis in Families Providing Evidence of Linkage to the Hereditary Prostate Cancer Locus (HPC1) on Chromosome 1 H. GRONBERG, J. Xu, J. R. SMITH,J. D. CARPTEN,S. D. ISAACS,D. FREIJE,G. S. BOVA,P. C. WALSH,F. S. COLLINS, J. M. TRENT, D. A. MEYERS AND W. B. ISAACS, James Buchanan Brady Urological Institute, Johns Hopkins University, School of Medicine, Center for Genetics of Asthma and Complex Diseases, University of Maryland, School of Medicine, Baltimore and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, and Department of Oncology, Umed University, Umed, Sweden Cancer Res., 57: 4707-4709, 1997 In a recent study of 91 families having at least three first degree relatives with prostate cancer, we reported the localization of a major susceptibility locus for prostate cancer (HPC1) to chromosome 1 [band q24; J. R. Smith et al., Science (Washington DC), 274: 1371-1373,19961. There was significant evidence for locus heterogeneity, with an estimate of 34% of the families being linked to this locus. In this report, we investigate the importance of age at diagnosis of prostate cancer and number of affected individuals within a family as variables in the linkage analysis of an expanded set of markers on lq24. Under two different models for the prostate cancer locus, we find that the evidence for linkage to HPCl is provided primarily by large (five or more members affected) families with an early average age at diagnosis. Specifically, for 40 North American families with an average age at diagnosis <65 years, the multipoint lod score is 3.96, whereas for 39 families with an older average age at diagnosis, this value is -0.84. Assuming heterogeneity, the proportion of families linked is 66% for the 14 families with the earliest average ages at diagnoses, but it decreases to 7% for the families with the latest ages at diagnoses. A similar age effect is observed in 12 Swedish pedigrees analyzed. To test the hypotheses generated by these analyses, we examined an additional group of 13 newly identified prostate cancer families. Overall, these families provided additional evidence for linkage to this region (nonparametric linkage Z = 1.91; P = 0.04 at marker DlS1660), contributed primarily by the families in this group with early age at diagnosis [nonparametric linkage Z =
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BENIGN AND MALIGNANT NEOPLASMS OF PROSTATE
2.50 (P = 0.01) at DlS4221. These results are consistent with the existence of a locus in this region that predisposes men to develop early-onset prostate cancer.
Editorial Comment: The identification of the first prostate cancer susceptibility locus linked to chromosome 1 was a major step forward in unraveling the molecular genetics of prostate cancer. Potentially, this observation will lead to cloning of the gene and the development of diagnostic markers for the identification of carriers in high risk families. However, it has not been without controversy. The findings have been difficult to reproduce in other laboratories. These 3 articles help explain some of the controversy. Cooney et al provide a confirmatory study. One reason for their success was the inclusion of 6 black families. In the original study of Smith et al the only 2 black families included linked strongly to the locus on chromosome 1.' In contrast, McIndoe et al were unable to confirm linkage to chromosome 1. They emphasize that conflicting evidence regarding linkage to a chromosomal region is not unexpected in common diseases for various reasons. One of these reasons is the population studied. For example, their study contained no black patients. Also, their study was not initiated until July 1995,whereas the original study of Smith et al includes families who were recruited during the previous 10 years, which has important implications.Patients recruited before the prostate specific antigen era are more likely to have real disease as opposed to patients recruited more recently who may be phenocopies (men with sporadic or low volume incidental cancer not linked to the gene). Furthermore, in the study of Smith et a1 archival tissue was obtained post mortem for deoxyribonucleic acid analysis, whereas in the study of McIndoe et a1 deoxyribonucleic acid was obtained only from living members. According to an article by Gronberg et al, patients who linked to chromosome 1 presented at a younger age with more advanced disease and were more likely to die of the disease.2 Thus, if one did not obtain material from archival specimens, it is possible that the truly informative members of the family were not evaluated. Finally, Gronberg et al emphasize in the Cancer Research article how difficult it is to find this locus. At Johns Hopkins we collected information on 2,500 families who met the definition of hereditary prostate cancer. We entered data of 91 of the best families into this linkage analysis. However, 40 families with an average age at diagnosis of younger than 65 years gave the greatest information. Other families with an older average age of onset were uninformative. Finally, the truly most informative families had an average age at diagnosis of younger than 65 years with 5 or more affected individuals. These families gave a logarithm of the odds score of 6.6, which means that the odds ratio that linkage truly exists is greater than 1 in 10 million. Patrick C. Walsh, M.D. 1. Smith, J. R., Freije, D., Carpten, J. D., Griinberg, H., Xu, J., Isaacs, S. D., Brownstein, M. J., Bova, G. S., Guo,H., Bujnovszky, P., Nusskern, D. R, Damber, J. E., Bergh, A, Emanuelsson, M., Kallioniemi, 0. P., Walker-Daniels,J., Bailey-Wilson,J. E., Beaty, T. H., Meyers, D. A, Walsh, P. C., Collins, F. S., Trent, J. M.
and Isaacs, W. B.: M 'or susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search.%ience, 274 1371,1996. 2. Gronberg, H., Isaacs, S. D., Smith, J. R,Carpten, J. D., Bova, G . S., Freije,D.,Xu, J., Meyers, D. A, Collins, F. S., Trent, J. M., Walsh, P. C. and Isaacs, W. B.: Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAM& 278 1251, 1997.
Serum Androgens: Associations With Prostate Cancer Risk and Hair Patterning W. DEMAF~K-WAHNEFRIED, S. M. LESKO,M. R. CONAWAY, C. N. ROBERTSON, R. V. CLARK,B. LOBAUGH, B. J. MATHIAS, T. S. STRIGO AND D. F. PAULSON, Divisions of Urology, Biometry and Endocrinology, Metabolism and Nutrition, Program of Cancer Prevention, Detection and Control Research, Duke University Medical Center, Durham, North Carolina and School of Public Health, Boston University School of Medicine, Boston, Massachusetts J. Androl., 18: 495-500, 1997 Cancer of the prostate is the leading cancer among American men, yet few risk factors have been established. Hair growth and development are influenced by androgens, and it has long been suspected that prostate cancer also is responsive to these hormones. A blinded, case-control study was undertaken to determine if hair patterning is associated with risk of prostate cancer, as well as specific hormonal profiles. The study accrued 315 male subjects who were stratified with regard to age, race, and case-control status (159 prostate cancer cased156 controls). Hair-patterning classification and serum levels of total and free testosterone (T), sex hormone binding globulin, and dihydrotestosterone (DHT) were performed. Data indicate that hair patterning did not differ between prostate cancer cases and controls; however, significant hormonal differences were detected between the two groups. Free T was greater among cases than in controls (16.4 ? 6.1 vs. 14.9 t 4.8 pg/ml, P = 0.02). Conversely, DHT-related ratios were greater among controls !P = 0.03 for DHTPT and P = 0.01 for DHT/free T).Several strong associations also were found between hormone levels and hair patterning. Men with vertex and frontal baldness had higher levels of free T (16.5 2 5.5 and 16.2 t 8.0 pg/ml, respectively) when compared to men with either little or no hair loss (14.8 t 4.7 pg/ml) (P = 0.01). Data suggest that increased levels of free T may be a risk factor for prostatic carcinoma.
one nuclear family; affected individuals in three successive generations [maternal or paternal lineage]: and/or clustering of two or more individuals affected before the age of 55 years) revealed more convincing evidence of disease linkage t o chromosome 1q24-25 (maximum NPL Z score [at marker DlS4661 = 1.72; P = .0451). The 39 families (79 affected individuals) that did not meet the clinical criteria for hereditary prostate cancer exhibited no significant evidence of disease linkage to DNA sequences at chromosome 1q24-25 (maximum NPL Z score [at marker DlS4661 = 0.809; P = .208). The six African-American families in our study contributed disproportionately to the observation of linkage, with a maximum NPL Z score at marker DlS158 of 1.39 (P = ,0848) for these families. Conclusions and Implications: Our data confirm that chromosome 1q24-25 is likely to contain a prostate cancer susceptibility gene. Future efforts at positional cloning of the HPCl gene should focus on families who meet the proposed clinical criteria for hereditary prostate cancer.
Linkage Analysis of 49 High-Risk Families does not Support a Common Familial Prostate Cancer-Susceptibility at 1q24-25 R. A. MCINDOE, J. L. STANFORD, M. GIBBS,G. P. JARVIK, S. BRANDZEL, C. L. NEAL,S. LI, J. T. GAMMACK, A. A. GAY,E. L. GOODE,L. HOODAND E. A. OSTRANDER, Departments of Molecular Biotechnology and Epidemiology, School of Public Health and Community Medicine, University of Washington, Department of Medicine, Division of Medical Genetics, University of Washington Medical Center and Divisions of Public Health Sciences and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington Amer. J. Hum. Genet., 61: 347-353, 1997 Linkage of a putative prostate cancer-susceptibility locus (HPC1)to chromosome 1q24-25 has recently been reported. Confirmation of this linkage in independent data sets is essential because of the complex nature of this disease. Here we report the results of a linkage analysis using 10 polymorphic markers spanning -37 cM in the region of the putative HPCl locus in 49 high-risk prostate cancer families. Data were analyzed by use of two parametric models and a nonparametric method. For the parametric LOD-score method, the first model was identical to the original report by Smith and coworkers (“Hopkins”),and the second was based on a segregation analysis previously reported by Carter and coworkers (“Seattle”).In both cases, our results do not confirm the linkage reported for this region. Calculated LOD scores from the two-point analysis for each marker were highly negative a t small recombination fractions. Multipoint LOD scores for this linkage group were also highly negative. Additionally, we were unable to demonstrate heterogeneity within the data set, using HOMOG. Although these data do not formally exclude linkage of a prostate cancer-susceptibility locus a t HPC1, it is likely that other prostate cancer-susceptibility loci play a more critical role in the families that we studied.
Early Age at Diagnosis in Families Providing Evidence of Linkage to the Hereditary Prostate Cancer Locus (HPC1) on Chromosome 1 H. GRONBERG, J. Xu, J. R. SMITH,J. D. CARPTEN,S. D. ISAACS,D. FREIJE,G. S. BOVA,P. C. WALSH,F. S. COLLINS, J. M. TRENT, D. A. MEYERS AND W. B. ISAACS, James Buchanan Brady Urological Institute, Johns Hopkins University, School of Medicine, Center for Genetics of Asthma and Complex Diseases, University of Maryland, School of Medicine, Baltimore and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, and Department of Oncology, Umed University, Umed, Sweden Cancer Res., 57: 4707-4709, 1997 In a recent study of 91 families having at least three first degree relatives with prostate cancer, we reported the localization of a major susceptibility locus for prostate cancer (HPC1) to chromosome 1 [band q24; J. R. Smith et al., Science (Washington DC), 274: 1371-1373,19961. There was significant evidence for locus heterogeneity, with an estimate of 34% of the families being linked to this locus. In this report, we investigate the importance of age at diagnosis of prostate cancer and number of affected individuals within a family as variables in the linkage analysis of an expanded set of markers on lq24. Under two different models for the prostate cancer locus, we find that the evidence for linkage to HPCl is provided primarily by large (five or more members affected) families with an early average age at diagnosis. Specifically, for 40 North American families with an average age at diagnosis <65 years, the multipoint lod score is 3.96, whereas for 39 families with an older average age at diagnosis, this value is -0.84. Assuming heterogeneity, the proportion of families linked is 66% for the 14 families with the earliest average ages at diagnoses, but it decreases to 7% for the families with the latest ages at diagnoses. A similar age effect is observed in 12 Swedish pedigrees analyzed. To test the hypotheses generated by these analyses, we examined an additional group of 13 newly identified prostate cancer families. Overall, these families provided additional evidence for linkage to this region (nonparametric linkage Z = 1.91; P = 0.04 at marker DlS1660), contributed primarily by the families in this group with early age at diagnosis [nonparametric linkage Z =
265
266
BENIGN AND MALIGNANT NEOPLASMS OF PROSTATE
2.50 (P = 0.01) at DlS4221. These results are consistent with the existence of a locus in this region that predisposes men to develop early-onset prostate cancer.
Editorial Comment: The identification of the first prostate cancer susceptibility locus linked to chromosome 1 was a major step forward in unraveling the molecular genetics of prostate cancer. Potentially, this observation will lead to cloning of the gene and the development of diagnostic markers for the identification of carriers in high risk families. However, it has not been without controversy. The findings have been difficult to reproduce in other laboratories. These 3 articles help explain some of the controversy. Cooney et al provide a confirmatory study. One reason for their success was the inclusion of 6 black families. In the original study of Smith et al the only 2 black families included linked strongly to the locus on chromosome 1.' In contrast, McIndoe et al were unable to confirm linkage to chromosome 1. They emphasize that conflicting evidence regarding linkage to a chromosomal region is not unexpected in common diseases for various reasons. One of these reasons is the population studied. For example, their study contained no black patients. Also, their study was not initiated until July 1995,whereas the original study of Smith et al includes families who were recruited during the previous 10 years, which has important implications.Patients recruited before the prostate specific antigen era are more likely to have real disease as opposed to patients recruited more recently who may be phenocopies (men with sporadic or low volume incidental cancer not linked to the gene). Furthermore, in the study of Smith et a1 archival tissue was obtained post mortem for deoxyribonucleic acid analysis, whereas in the study of McIndoe et a1 deoxyribonucleic acid was obtained only from living members. According to an article by Gronberg et al, patients who linked to chromosome 1 presented at a younger age with more advanced disease and were more likely to die of the disease.2 Thus, if one did not obtain material from archival specimens, it is possible that the truly informative members of the family were not evaluated. Finally, Gronberg et al emphasize in the Cancer Research article how difficult it is to find this locus. At Johns Hopkins we collected information on 2,500 families who met the definition of hereditary prostate cancer. We entered data of 91 of the best families into this linkage analysis. However, 40 families with an average age at diagnosis of younger than 65 years gave the greatest information. Other families with an older average age of onset were uninformative. Finally, the truly most informative families had an average age at diagnosis of younger than 65 years with 5 or more affected individuals. These families gave a logarithm of the odds score of 6.6, which means that the odds ratio that linkage truly exists is greater than 1 in 10 million. Patrick C. Walsh, M.D. 1. Smith, J. R., Freije, D., Carpten, J. D., Griinberg, H., Xu, J., Isaacs, S. D., Brownstein, M. J., Bova, G. S., Guo,H., Bujnovszky, P., Nusskern, D. R, Damber, J. E., Bergh, A, Emanuelsson, M., Kallioniemi, 0. P., Walker-Daniels,J., Bailey-Wilson,J. E., Beaty, T. H., Meyers, D. A, Walsh, P. C., Collins, F. S., Trent, J. M.
and Isaacs, W. B.: M 'or susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search.%ience, 274 1371,1996. 2. Gronberg, H., Isaacs, S. D., Smith, J. R,Carpten, J. D., Bova, G . S., Freije,D.,Xu, J., Meyers, D. A, Collins, F. S., Trent, J. M., Walsh, P. C. and Isaacs, W. B.: Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAM& 278 1251, 1997.
Serum Androgens: Associations With Prostate Cancer Risk and Hair Patterning W. DEMAF~K-WAHNEFRIED, S. M. LESKO,M. R. CONAWAY, C. N. ROBERTSON, R. V. CLARK,B. LOBAUGH, B. J. MATHIAS, T. S. STRIGO AND D. F. PAULSON, Divisions of Urology, Biometry and Endocrinology, Metabolism and Nutrition, Program of Cancer Prevention, Detection and Control Research, Duke University Medical Center, Durham, North Carolina and School of Public Health, Boston University School of Medicine, Boston, Massachusetts J. Androl., 18: 495-500, 1997 Cancer of the prostate is the leading cancer among American men, yet few risk factors have been established. Hair growth and development are influenced by androgens, and it has long been suspected that prostate cancer also is responsive to these hormones. A blinded, case-control study was undertaken to determine if hair patterning is associated with risk of prostate cancer, as well as specific hormonal profiles. The study accrued 315 male subjects who were stratified with regard to age, race, and case-control status (159 prostate cancer cased156 controls). Hair-patterning classification and serum levels of total and free testosterone (T), sex hormone binding globulin, and dihydrotestosterone (DHT) were performed. Data indicate that hair patterning did not differ between prostate cancer cases and controls; however, significant hormonal differences were detected between the two groups. Free T was greater among cases than in controls (16.4 ? 6.1 vs. 14.9 t 4.8 pg/ml, P = 0.02). Conversely, DHT-related ratios were greater among controls !P = 0.03 for DHTPT and P = 0.01 for DHT/free T).Several strong associations also were found between hormone levels and hair patterning. Men with vertex and frontal baldness had higher levels of free T (16.5 2 5.5 and 16.2 t 8.0 pg/ml, respectively) when compared to men with either little or no hair loss (14.8 t 4.7 pg/ml) (P = 0.01). Data suggest that increased levels of free T may be a risk factor for prostatic carcinoma.