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Prostate Cancer Susceptibility Locus on Chromosome 1q: A Confirmatory Study
0022-5347/98/1601-0264$03.00/0
Vol. 160. 264-293.July 1998 Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright @ 1998 by AVERICAN UROL~CICAL ASSOCUTION, INC.
ABSTRACTS BENIGN AND MALIGNANT NEOPLASMS OF PROSTATE Heredity and Prostate Cancer: A Study of World War I1 Veteran Twins W. F. PAGE,M. M. BRAUN, A. W. PARTIN, N. CAPORASO AND P. WALSH,Medical Followup Agency, Institute of Medicine, National Academy of Sciences and Division of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration, Washington, D. C., and James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore and Genetic Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Prostate, 3 3 240-245, 1997 BACKGROUND. Increased risk of prostate cancer among men with a family history of the disease has been observed in several epidemiological studies, and family studies have identified hereditary prostate cancer characterized by early onset and autosomal dominant inheritance. METHODS. In this study, we examine prostate cancer heritability among twins in the NAS-NRC Twin Registry, with cases ascertained from a number of sources: recent telephone interviews, Medicare and Department of Veterans Af€airs hospitalizations, previous mail questionnaires, and death certificates. A total of 1,009 prostate cancer cases were identified among the cohort of 31,848 veteran twins born in the years 1917-1927. RESULTS. Probandwise concordance for prostate cancer was substantially higher among monozygous twin pairs, 27.1%, than among dizygous twin pairs, 7.1% (P < 0.001). CONCLUSIONS. These data suggest that genetic influences account for approximately 57%, and environmental influences for 43%, of the variability in twin liability for prostate cancer. Editorial Comment: This study compares the development of prostate cancer in monozygotic and dizygotic twins. Twin studies are important because they enable one to estimate the influence of genetic factors. Monozygotic twins are genetically identical, whereas dizygotic twins are no more alike than brothers. This study has 2 important messages. Not all identical twins are destined to have prostate cancer. In this study of men born between the years 1917 and 1927 only 27% of the monozygotic twins were concordant for the disease. However, this rate was 4-fold higher than dizygotic twins (7.1%). Using these data one can estimate that genetic influences account for approximately 57% and environmental influences 43%of the variability in twin liability for prostate cancer. Patrick C. Walsh, M.D.
Prostate Cancer Susceptibility Locus on Chromosome lq:A Confirmatory Study K. A. COONEY, J. D. MCCARTHY, E. JANGE, L. HUANG, S. MIESFELDT, J. E. MONTIE, J. E. OESTERLING, H. M. SANDLER AND K. LANGE, Departments of Internal Medicine, Surgery and Radiation Oncology, University of Michigan Medical School and Ann Arbor VeteransAffairs Medical Center, and Department of Biostatistics and Mathematics, University of Michigan, Ann Arbor, Michigan and Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesuille, Virginia J. Natl. Cancer Inst., 8 9 955-959, 1997 Background: Recent recognition that a predisposition to prostate cancer can be inherited has led to a search for specific genes associated with the disease. Through a study of families with three or more affected first-degree relatives, a region on the long arm of chromosome 1 (i.e., 1q24-25) has been tentatively identified as containing a gene, HPC1, involved in the development of hereditary prostate cancer. Confirmation of this finding is needed, however, before attempts are made to isolate and characterize the putative HPCl gene. Purpose: To confirm that chromosome 1q24-25 contains a gene relevant to hereditary prostate cancer, we analyzed an independent set of families, each with two or more affected individuals. Methods: Fifty-nine unrelated families were selected for analysis on the sole criterion that more than one living family member was affected by prostate cancer. DNA samples were subsequently isolated from 130 individuals with the disease. These samples were genotyped at six polymorphic marker sequences (DlS215, DlS2883, DlS466, DlS158, DlS518, and DlS2757) covering the chromosomal region proposed to contain HPC1. The resulting data were analyzed by nonparametric multipoint linkage (NPL) methods, yielding NPL Z scores and corresponding one-sided P values. Results: When the entire set of 59 families was considered, the occurrence of prostate cancer (and, presumably, the HPCl gene) was most tightly linked to marker DlS466 (NPL Z score = 1.58; P = .0574). Analysis of the 20 families (51 affected individuals) fulfilling one or more of the proposed clinical criteria for hereditary prostate cancer (i.e., three or more affected individuals within 264
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 =
265
Vol. 160. 264-293.July 1998 Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright @ 1998 by AVERICAN UROL~CICAL ASSOCUTION, INC.
ABSTRACTS BENIGN AND MALIGNANT NEOPLASMS OF PROSTATE Heredity and Prostate Cancer: A Study of World War I1 Veteran Twins W. F. PAGE,M. M. BRAUN, A. W. PARTIN, N. CAPORASO AND P. WALSH,Medical Followup Agency, Institute of Medicine, National Academy of Sciences and Division of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration, Washington, D. C., and James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore and Genetic Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Prostate, 3 3 240-245, 1997 BACKGROUND. Increased risk of prostate cancer among men with a family history of the disease has been observed in several epidemiological studies, and family studies have identified hereditary prostate cancer characterized by early onset and autosomal dominant inheritance. METHODS. In this study, we examine prostate cancer heritability among twins in the NAS-NRC Twin Registry, with cases ascertained from a number of sources: recent telephone interviews, Medicare and Department of Veterans Af€airs hospitalizations, previous mail questionnaires, and death certificates. A total of 1,009 prostate cancer cases were identified among the cohort of 31,848 veteran twins born in the years 1917-1927. RESULTS. Probandwise concordance for prostate cancer was substantially higher among monozygous twin pairs, 27.1%, than among dizygous twin pairs, 7.1% (P < 0.001). CONCLUSIONS. These data suggest that genetic influences account for approximately 57%, and environmental influences for 43%, of the variability in twin liability for prostate cancer. Editorial Comment: This study compares the development of prostate cancer in monozygotic and dizygotic twins. Twin studies are important because they enable one to estimate the influence of genetic factors. Monozygotic twins are genetically identical, whereas dizygotic twins are no more alike than brothers. This study has 2 important messages. Not all identical twins are destined to have prostate cancer. In this study of men born between the years 1917 and 1927 only 27% of the monozygotic twins were concordant for the disease. However, this rate was 4-fold higher than dizygotic twins (7.1%). Using these data one can estimate that genetic influences account for approximately 57% and environmental influences 43%of the variability in twin liability for prostate cancer. Patrick C. Walsh, M.D.
Prostate Cancer Susceptibility Locus on Chromosome lq:A Confirmatory Study K. A. COONEY, J. D. MCCARTHY, E. JANGE, L. HUANG, S. MIESFELDT, J. E. MONTIE, J. E. OESTERLING, H. M. SANDLER AND K. LANGE, Departments of Internal Medicine, Surgery and Radiation Oncology, University of Michigan Medical School and Ann Arbor VeteransAffairs Medical Center, and Department of Biostatistics and Mathematics, University of Michigan, Ann Arbor, Michigan and Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesuille, Virginia J. Natl. Cancer Inst., 8 9 955-959, 1997 Background: Recent recognition that a predisposition to prostate cancer can be inherited has led to a search for specific genes associated with the disease. Through a study of families with three or more affected first-degree relatives, a region on the long arm of chromosome 1 (i.e., 1q24-25) has been tentatively identified as containing a gene, HPC1, involved in the development of hereditary prostate cancer. Confirmation of this finding is needed, however, before attempts are made to isolate and characterize the putative HPCl gene. Purpose: To confirm that chromosome 1q24-25 contains a gene relevant to hereditary prostate cancer, we analyzed an independent set of families, each with two or more affected individuals. Methods: Fifty-nine unrelated families were selected for analysis on the sole criterion that more than one living family member was affected by prostate cancer. DNA samples were subsequently isolated from 130 individuals with the disease. These samples were genotyped at six polymorphic marker sequences (DlS215, DlS2883, DlS466, DlS158, DlS518, and DlS2757) covering the chromosomal region proposed to contain HPC1. The resulting data were analyzed by nonparametric multipoint linkage (NPL) methods, yielding NPL Z scores and corresponding one-sided P values. Results: When the entire set of 59 families was considered, the occurrence of prostate cancer (and, presumably, the HPCl gene) was most tightly linked to marker DlS466 (NPL Z score = 1.58; P = .0574). Analysis of the 20 families (51 affected individuals) fulfilling one or more of the proposed clinical criteria for hereditary prostate cancer (i.e., three or more affected individuals within 264
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 =
265