PROGRESS Study

Published Articles

Authors: Gibbs M, Chakrabarti L, Stanford JL, Goode EL, Kolb S, Schuster EF, Buckley VA, Shook M, Hood L, Jarvik GP, Ostrander EA.

Title: Analysis of chromosome 1q42.2-43 in 152 families with high risk of prostate cancer.

Source: American Journal of Human Genetics 1999 Apr;64(4):1087-95.

Abstract: One hundred fifty-two families with prostate cancer were analyzed for linkage to markers spanning a 20-cM region of 1q42.2-43, the location of a putative prostate cancer-susceptibility locus (PCAP). No significant evidence for linkage was found, by use of both parametric and nonparametric tests, in our total data set, which included 522 genotyped affected men. Rejection of linkage may reflect locus heterogeneity or the confounding effects of sporadic disease in older-onset cases; therefore, pedigrees were stratified into homogeneous subsets based on mean age at diagnosis of prostate cancer and number of affected men. Analyses of these subsets also detected no significant evidence for linkage, although LOD scores were positive at higher recombination fractions, which is consistent with the presence of a small proportion of families with linkage. The most suggestive evidence of linkage was in families with at least five affected men (nonparametric linkage score of 1.2; P=.1). If heterogeneity is assumed, an estimated 4%-9% of these 152 families may show linkage in this region. We conclude that the putative PCAP locus does not account for a large proportion of these families with prostate cancer, although the linkage of a small subset is compatible with these data.


Authors: Gibbs M, Stanford JL, McIndoe RA, Jarvik GP, Kolb S, Goode EL, Chakrabarti L, Schuster EF, Buckley VA, Miller EL, Brandzel S, Li S, Hood L, Ostrander EA.

Title: Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36.

Source: American Journal of Human Genetics 1999 Mar;64(3):776-87.

Abstract: Combining data from a genomic screen in 70 families with a high risk for prostate cancer (PC) with data from candidate-region mapping in these families and an additional 71 families, we have localized a potential hereditary PC-susceptibility locus to chromosome 1p36. Because an excess of cases of primary brain cancer (BC) have been observed in some studies of families with a high risk for PC, and because loss of heterozygosity at 1p36 is frequently observed in BC, we further evaluated 12 families with both a history of PC and a blood relative with primary BC. The overall LOD score in these 12 families was 3.22 at a recombination fraction (theta) of .06, with marker D1S507. On the basis of an a priori hypothesis, this group was stratified by age at diagnosis of PC. In the younger age group (mean age at diagnosis <66 years), a maximum two-point LOD score of 3.65 at straight theta = .0 was observed, with D1S407. This linkage was rejected in both early- and late-onset families without a history of BC (LOD scores -7.12 and -6.03, respectively, at straight theta = .0). After exclusion of 3 of the 12 families that had better evidence of linkage to previously described PC-susceptibility loci, linkage to the 1p36 region was suggested by a two-point LOD score of 4.74 at straight theta = .0, with marker D1S407. We conclude that a significant proportion of these families with both a high risk for PC and a family member with BC show linkage to the 1p36 region. 

 


Authors: Jarvik GP, Stanford JL, Goode EL, McIndoe R, Kolb S, Gibbs M, Hood L, Ostrander EA.

Title: Confirmation of prostate cancer susceptibility genes using high-risk families.

Source: Journal of the National Cancer Institute. Monographs. 1999;(26):81-7.

Abstract: Data from many types of studies support the hypothesis that strong familial components are involved in the etiology of prostate cancer. One way to access such genes is through the study of families with multiple affected family members and, in particular, families with individuals affected comparatively early in life. Several prostate cancer susceptibility loci have been described to date. Confirmation of the linkage and estimation of the proportion of families who are linked in large independent datasets is essential to understanding the significance of susceptibility genes. We explore the methodology used to perform such studies and the factors that can limit the ability to confirm linkage results. We report specifically the example of the HPC1 gene on 1q24-25.


Author: Xu J.

Title: Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics.

Source: American Journal of Human Genetics 2000 Mar;66(3):945-57.

Abstract: A previous linkage study provided evidence for a prostate cancer-susceptibility locus at 1q24-25. Subsequent reports in additional collections of families have yielded conflicting results. In addition, evidence for locus heterogeneity has been provided by the identification of other putative hereditary prostate cancer loci on Xq27-28, 1q42-43, and 1p36. The present study describes a combined analysis for six markers in the 1q24-25 region in 772 families affected by hereditary prostate cancer and ascertained by the members of the International Consortium for Prostate Cancer Genetics (ICPCG) from North America, Australia, Finland, Norway, Sweden, and the United Kingdom. Overall, there was some evidence for linkage, with a peak parametric multipoint LOD score assuming heterogeneity (HLOD) of 1.40 (P=.01) at D1S212. The estimated proportion of families (alpha) linked to the locus was.06 (1-LOD support interval.01-.12). This evidence was not observed by a nonparametric approach, presumably because of the extensive heterogeneity. Further parametric analysis revealed a significant effect of the presence of male-to-male disease transmission within the families. In the subset of 491 such families, the peak HLOD was 2.56 (P=.0006) and alpha =.11 (1-LOD support interval.04-.19), compared with HLODs of 0 in the remaining 281 families. Within the families with male-to-male disease transmission, alpha increased with the early mean age at diagnosis (<65 years, alpha =.19, with 1-LOD support interval.06-.34) and the number of affected family members (five or more family members, alpha =.15, with 1-LOD support interval.04-.28). The highest value of alpha was observed for the 48 families that met all three criteria (peak HLOD = 2.25, P=.001, alpha=.29, with 1-LOD support interval.08-.53). These results support the finding of a prostate cancer-susceptibility gene linked to 1q24-25, albeit in a defined subset of prostate cancer families. Although HPC1 accounts for only a small proportion of all families affected by hereditary prostate cancer, it appears to play a more prominent role in the subset of families with several members affected at an early age and with male-to-male disease transmission. 


Authors: Gibbs M, Stanford JL, Jarvik GP, Janer M, Badzioch M, Peters MA, Goode EL, Kolb S, Chakrabarti L, Shook M, Basom R, Ostrander EA, Hood L.

Title: A genomic scan of families with prostate cancer identifies multiple regions of interest.

Source: American Journal of Human Genetics 2000 Jul;67(1):100-9.

Abstract: A 10-cM genomewide scan of 94 families with hereditary prostate cancer, including 432 affected men, was used to identify regions of putative prostate cancer-susceptibility loci. There was an average of 3.6 affected, genotyped men per family, and an overall mean age at diagnosis of 65.4 years. A total of 50 families were classified as early onset (mean age at diagnosis <66 years), and 44 families were classified as later onset (mean age at diagnosis > or =66 years). When the entire data set is considered, regions of interest (LOD score > or =1.5) were identified on chromosomes 10, 12, and 14, with a dominant model of inheritance. Under a recessive model LOD scores > or =1.5 were found on chromosomes 1, 8, 10, and 16. Stratification by age at diagnosis highlighted a putative susceptibility locus on chromosome 11, among the later-onset families, with a LOD score of 3. 02 (recombination fraction 0) at marker ATA34E08. Overall, this genomic scan suggests that there are multiple prostate cancer loci responsible for the hereditary form of this common and complex disease and that stratification by a variety of factors will be required for identification of all relevant genes.

 


Authors: Goode EL, Stanford JL, Chakrabarti L, Gibbs M, Kolb S, McIndoe RA, Buckley VA, Schuster EF, Neal CL, Miller EL, Brandzel S, Hood L, Ostrander EA, Jarvik GP.

Title: Linkage analysis of 150 high-risk prostate cancer families at 1q24-25.

Source: Genetic Epidemiology 2000 Mar;18(3):251-75.

Abstract: Confirmation of linkage and estimation of the proportion of families who are linked in large independent datasets is essential to understanding the significance of cancer susceptibility genes. We report here on an analysis of 150 high-risk prostate cancer families (2,176 individuals) for potential linkage to the HPC1 prostate cancer susceptibility locus at 1q24-25. This dataset includes 640 affected men with an average age at prostate cancer diagnosis of 66. 8 years (range, 39-94), representing the largest collection of high-risk families analyzed for linkage in this region to date. Linkage to multiple 1q24-25 markers was strongly rejected for the sample as a whole (lod scores at theta = 0 ranged from -30.83 to -18. 42). Assuming heterogeneity, the estimated proportion of families linked (alpha) at HPC1 in the entire dataset was 2.6%, using multipoint analysis. Because locus heterogeneity may lead to false rejection of linkage, data were stratified based on homogeneous subsets. When restricted to 21 Caucasian families with five or more affected family members and mean age at diagnosis < = 65 years, the lod scores at theta = 0 remained less than -4.0. These results indicate that the overall portion of hereditary prostate cancer families whose disease is due to inherited variation in HPC1 may be less than originally estimated. 

 


 

Authors: Ostrander EA, Stanford JL.

Title: Genetics of prostate cancer: too many loci, too few genes.

Source: American Journal of Human Genetics 2000 Dec;67(6):1367-75.


Authors: Stanford JL, Ostrander EA.

Title: Familial prostate cancer.

Source: Epidemiologic Reviews 2001;23(1):19-23. 


Authors: Goode EL, Stanford JL, Peters MA, Janer M, Gibbs M, Kolb S, Badzioch MD, Hood L, Ostrander EA, Jarvik GP.

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

Source: Clinical Cancer Research 2001 Sep;7(9):2739-49.

Abstract: 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.


Authors: Miller EA, Stanford JL, Hsu L, Noonan E, Ostrander EA.

Title: Polymorphic repeats in the androgen receptor gene in high-risk sibships.

Source: Prostate 2001 Aug;48(3):200-5.

Abstract: BACKGROUND: Genetic susceptibility may explain some familial clusters of prostate cancer. The polymorphic androgen receptor (AR) gene, which mediates androgen activity in the prostate, is a candidate gene that may influence predisposition to the disease. METHODS: We analyzed the polymorphic (CAG)n and (GGN)n repeats within the AR gene in men from 51 high-risk prostate cancer sibships, which included at least one affected and one unaffected man (n = 210). We compared repeat lengths of men with prostate cancer (n = 140) to their brothers (n = 70) without disease, stratified by median age at diagnosis of affected men within each sibship. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals to evaluate associations between prostate cancer and repeat length. RESULTS: The OR for prostate cancer associated with short (CAG)n repeats (< 22) compared to longer repeats (> or =22) was 1.13 (95% CI 0.5-2.4) overall, but was higher in sibships with a median age of <66 years at diagnosis (OR = 1.72, 95% CI 0.5-6.0). The (GGN)n array also was not associated with prostate cancer in general. However, in older men (> or = 66 years), there was a modest elevation in risk (OR = 1.56, 95% CI 0.6-4.1) among those with short repeats (GGN of < or =16). Men with both a short (CAG)n (< 22) and a short (GGN)n (< or =16) array were not at higher risk (OR = 1.06) compared to men with two long repeats [(CAG)n > or =22 and (GGN)n >16)]. CONCLUSIONS: These results suggest that the (CAG)n and (GGN)n repeats in the AR gene do not play a major role in familial prostate cancer.


Authors: Nelson PS, Stanford JL, Ostrander EA.

Title: Prostate cancer research in the post-genome era.

Source: Epidemiologic Reviews 2001;23(1):187-90. 


Authors: Conlon EM, Goode EL, Gibbs M, Stanford JL, Badzioch M, Janer M, Kolb S, Hood L, Ostrander EA, Jarvik GP, Wijsman EM.

Title: Oligogenic segregation analysis of hereditary prostate cancer pedigrees: evidence for multiple loci affecting age at onset.

Source: International Journal of Cancer 2003 Jul;105(5):630-5.

Abstract: Previous studies have suggested strong evidence for a hereditary component to prostate cancer (PC) susceptibility. Here, we analyze 3,796 individuals in 263 PC families recruited as part of the ongoing Prostate Cancer Genetic Research Study (PROGRESS). We use Markov chain Monte Carlo (MCMC) oligogenic segregation analysis to estimate the number of quantitative trait loci (QTLs) and their contribution to the variance in age at onset of hereditary PC (HPC). We estimate 2 covariate effects: diagnosis of PC before and after prostate-specific antigen (PSA) test availability, and presence/absence of at least 1 blood relative with primary neuroepithelial brain cancer (BC). We find evidence that 2 to 3 QTLs contribute to the variance in age at onset of HPC. The 2 QTLs with the largest contribution to the total variance are both effectively dominant loci. We find that the covariate for diagnosis before and after PSA test availability is important. Our findings for the number of QTLs contributing to HPC and the variance contribution of these QTLs will be instructive in mapping and identifying these genes. 


Authors: Friedrichsen DM, Stanford JL, Isaacs SD, Janer M, Chang BL, Deutsch K, Gillanders E, Kolb S, Wiley KE, Badzioch MD, Zheng SL, Walsh PC, Jarvik GP, Hood L, Trent JM, Isaacs WB, Ostrander EA, Xu J.

Title: Identification of a prostate cancer susceptibility locus on chromosome 7q11-21 in Jewish families.

Source: Proceedings of the National Academy of Sciences of the United States of America 2004 Feb;101(7):1939-44.

Abstract: Results from over a dozen prostate cancer susceptibility genome-wide scans, encompassing some 1,500 hereditary prostate cancer families, indicate that prostate cancer is an extremely heterogeneous disease with multiple loci contributing to overall susceptibility. In an attempt to reduce locus heterogeneity, we performed a genomewide linkage scan for prostate cancer susceptibility genes with 36 Jewish families, which represent a stratification of hereditary prostate cancer families with potentially increased locus homogeneity. The 36 Jewish families represent a combined dataset of 17 Jewish families from Fred Hutch-based Prostate Cancer Genetic Research Study dataset and 19 Ashkenazi Jewish families collected at Johns Hopkins University . All available family members, including 94 affected men, were genotyped at markers distributed across the genome with an average interval of <10 centimorgans. Nonparametric multipoint linkage analyses were the primary approach, although parametric analyses were performed as well. Our strongest signal was a significant linkage peak at 7q11-21, with a nonparametric linkage (NPL) score of 3.01 (P = 0.0013). Simulations indicated that this corresponds to a genomewide empirical P = 0.006. All other regions had NPL P values >/=0.02. After genotyping additional markers within the 7q11-21 peak, the NPL score increased to 3.35 (P = 0.0004) at D7S634 with an allele-sharing logarithm of odds of 3.12 (P = 0.00007). These studies highlight the utility of analyzing defined sets of families with a common origin for reducing locus heterogeneity problems associated with studying complex traits. 


Authors: Janer M, Friedrichsen DM, Stanford JL, Badzioch MD, Kolb S, Deutsch K, Peters MA, Goode EL, Welti R, DeFrance HB, Iwasaki L, Li S, Hood L, Ostrander EA, Jarvik GP.

Title: Genomic scan of 254 hereditary prostate cancer families. Prostate 2003 Dec;57(4):309-19.

Abstract: Hereditary prostate cancer (HPC) is a genetically heterogeneous disease, complicating efforts to map and clone susceptibility loci. We have used stratification of a large dataset of 254 HPC families in an effort to improve power to detect HPC loci and to understand what types of family features may improve locus identification. The strongest result is that of a dominant locus at 6p22.3 (heterogeneity LOD (HLOD) = 2.51), the evidence for which is increased by consideration of the age of PC onset (HLOD = 3.43 in 214 families with median age-of-onset 56-72 years) and co-occurrence of primary brain cancer (HLOD = 2.34 in 21 families) in the families. Additional regions for which we observe modest evidence for linkage include chromosome 7q and 17p. Only weak evidence of several previously implicated HPC regions is detected. These analyses support the existence of multiple HPC loci, whose presence may be best identified by analyses of large, including pooled, datasets which consider locus heterogeneity.


Authors: Peters MA, Janer M, Kolb S, Jarvik GP, Ostrander EA, Stanford JL.

Title: Germline mutations in the p73 gene do not predispose to familial prostate-brain cancer.

Source: Prostate 2001 Sep;48(4):292-6.

Abstract: BACKGROUND: Analysis of high-risk prostate cancer (PC) families with at least one confirmed case of primary brain cancer (BC) has identified a region of genetic linkage on chromosome 1p36 termed CAPB. The p36 region of chromosome one has been reported to have frequent loss of heterozygosity (LOH) in brain and central nervous system (CNS) tumors and epidemiological studies have shown an increased relative risk of BC and tumors of the CNS in PC families. In 1997 a reported tumor suppressor with high homology to p53, termed p73, was mapped to the p36 region of chromosome one. Here, we examine the p73 gene as a potential candidate for CAPB. METHODS: Ninety-four members from the 12 prostate-brain cancer families in which linkage was originally found were examined. The complete coding region and intron-exon boundaries of the p73 gene were analyzed for germline mutations by Single Stranded Conformational Polymorphism analysis (SSCP) and direct DNA sequencing. RESULTS: Silent nucleotide substitutions only were detected within the coding regions of the gene in affected individuals. Nucleotide changes were detected in introns 1, 6, 8, 9, and 10, but all were located >or=16 base pairs from the splice site, and are thus unlikely to be deleterious mutations. CONCLUSIONS: Germline mutations in the p73 gene are unlikely to be critical for inherited susceptibility to PC in this specified subset of families.


Authors: Peters MA, Jarvik GP, Janer M, Chakrabarti L, Kolb S, Goode EL, Gibbs M, DuBois CC, Schuster EF, Hood L, Ostrander EA, Stanford JL.

Title: Genetic linkage analysis of prostate cancer families to Xq27-28.

Source: Human Heredity 2001;51(1-2):107-13.

Abstract: OBJECTIVES: A recent linkage analysis of 360 families at high risk for prostate cancer identified the q27-28 region on chromosome X as the potential location of a gene involved in prostate cancer susceptibility. Here we report on linkage analysis at this putative HPCX locus in an independent set of 186 prostate cancer families participating in the Prostate Cancer Genetic Research Study (PROGRESS). METHODS: DNA samples from these families were genotyped at 8 polymorphic markers spanning 14.3 cM of the HPCX region. RESULTS: Two-point parametric analysis of the total data set resulted in positive lod scores at only two markers, DXS984 and DXS1193, with scores of 0.628 at a recombination fraction (theta) of 0.36 and 0.012 at theta = 0.48, respectively. The stratification of pedigrees according to the assumed mode of transmission increased the evidence of linkage at DXS984 in 81 families with no evidence of male-to-male transmission (lod = 1.062 at theta = 0.28). CONCLUSIONS: Although this analysis did not show statistically significant evidence for the linkage of prostate cancer susceptibility to Xq27-28, the results are consistent with a small percentage of families being linked to this region. The analysis further highlights difficulties in replicating linkage results in an etiologically heterogeneous, complexly inherited disease.


Authors: Ostrander EA, Markianos K, Stanford JL.

Title: Finding prostate cancer susceptibility genes.

Source: Annu Rev Genomics Hum Genet 2004;5:151-75.

Abstract: Prostate cancer is a heterogeneous disease with multiple loci contributing to susceptibility. Traditionally, genome-wide scans using high-risk families have utilized stratification by number of affected individuals, family history of other cancers, or family age at diagnosis to improve genetic homogeneity. In addition to locus heterogeneity, for later onset diseases such as prostate cancer, a major limitation to mapping efforts is that key parental DNA samples are rarely available. The lack of available samples from upper generations reduces inheritance information, and as a result, the standard 10-cM genome scan does not provide full power to detect linkage. To increase the ability to find disease-associated loci, much denser genome-wide scans must be undertaken in multiple ethnic groups. In addition, new ways of defining homogenous subsets of families need to be developed. 


Authors: Schaid DJ, Chang BL.

Title: Description of the International Consortium For Prostate Cancer Genetics, and failure to replicate linkage of hereditary prostate cancer to 20q13.

Source: Prostate 2005 May;63(3):276-90.

Abstract: The International Consortium for Prostate Cancer Genetics (ICPCG) is an international collaborative effort to pool pedigrees with hereditary prostate cancer (PC) in order to replicate linkage findings for PC. A strength of the ICPCG is the large number of well-characterized pedigrees, allowing linkage analyses within large subsets. Given the heterogeneity and complexity of PC, the historical difficulties of synthesizing different studies reporting positive and negative linkage replication, and the use of different statistical analysis methods and different stratification criteria, the ICPCG provides a valuable resource to evaluate linkage for hereditary PC. To date, linkage of chromosome 20 (HPC20) to hereditary PC has been one of the strongest linkage signals, yet the efforts to replicate this linkage have been limited. This paper reports a linkage analysis of chromosome 20 markers for 1,234 pedigrees with multiple cases of PC ascertained through the ICPCG, and represents the most thorough attempt to confirm or refute linkage to chromosome 20. From the original 158 Mayo pedigrees in which linkage was detected, the maximum heterogeneity LOD (HLOD) score, under a recessive model, was 2.78. In contrast, for the 1,076 pedigrees not included in the original study, the maximum HLOD score (recessive model) was 0.06. Although, a few small linkage signals for chromosome 20 were found in various strata of this pooled analysis, this large study failed to replicate linkage to HPC20. This study illustrates the value of the ICPCG family collection to evaluate reported linkage signals and suggests that the HPC20 region does not make a major contribution to PC susceptibility.


Authors: Xu J, Dimitrov L, Chang BL, Adams TS, Turner AR, et al.

Title: A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics.

Source: American Journal of Human Genetics 2005 Aug;77(2):219-29.

Abstract: Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.


Authors: Stanford JL, McDonnell SK, Friedrichsen DM, Carlson EE, Kolb S, Deutsch K, Janer M, Hood L, Ostrander EA, Schaid DJ.

Title: Prostate cancer and genetic susceptibility: a genome scan incorporating disease aggressiveness.

Source: Prostate 2006 Feb;66(3):317-25.

Abstract: BACKGROUND: Prostate cancer is a heterogeneous disease, both genetically and phenotypically. Linkage studies attempting to map genes for hereditary prostate cancer (HPC) have proved challenging, and one potential problem contributing to this challenge is the variability in disease phenotypes. METHODS: We collected clinical data on 784 affected men with prostate cancer from 248 HPC families for whom a genomic screen was performed. Disease characteristics (i.e., Gleason score, stage, prostate-specific antigen (PSA)) were used to classify affected men into categories of clinically insignificant, moderate, or aggressive prostate cancer. To potentially enrich for a genetic etiology, we restricted linkage analyses to only men with aggressive disease, although we used genotype information from all family members; linkage analyses used both dominant and recessive models. In addition, subset analyses considered age at diagnosis, number of affected men per family and other stratifications to try to increase genetic homogeneity. RESULTS: Several regions of interest (heterogeneity LOD score, HLOD>1.0) were identified in families (n=123) with >or=2 affecteds with aggressive prostate cancer. "Suggestive" linkage was observed at chromosome 22q11.1 (Dominant model HLOD=2.18) and the result was stronger (Dominant HLOD=2.75) in families with evidence of male-to-male transmission. A second region at 22q12.3-q13.1 was also highlighted (Recessive model HLOD=1.90) among men with aggressive disease, as was a region on chromosome 18. CONCLUSIONS: These analyses suggest that using clinically defined phenotypes may be a useful approach for simplifying the locus heterogeneity problems that confound the search for prostate cancer susceptibility genes.


Authors: Schaid DJ and the International Consortium for Prostate Cancer Genetics.

Title: Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics

Source: Human Genetics 2006; 120:471-485


Authors: Pierce BL, Friedrichsen DM, McIntosh L, Deutsch K, Hood L, Ostrander EA, Austin MA, Stanford JL.  

Title: Genomic scan of 12 hereditary prostate cancer families having an occurrence of pancreas cancer.

Source: The Prostate 2007; 67(4) : 410-5.


Authors: Johanneson B, Deutsch K, McIntosh L, Friedrichsen-Karyadi DM, Janer M, Kwon EM, Iwasaki L, Hood L, Ostrander EA, Stanford JL.

Title: Suggestive genetic linkage to chromosome 11p11.2-q12.2 in hereditary prostate cancer families with primary kidney cancer.

Source: The Prostate 2007; 67:732-742.


Authors: Schaid DJ, Stanford JL, McDonnell SK, Suuriniemi M, McIntosh L, Friedrichsen-Karyadi DM, Carlson EE, Deutsch K, Janer M, Hood L, Ostrander EA.

Title: Genome-wide Linkage Scan  of Prostate Cancer Gleason Score and Confirmation of Chromosome 19q.

Source: Human Genetics 2007; 121(6): 729-35.


Authors: Camp NJ, Cannon-Albright LA, et al.

Title: Compelling evidence for a prostate cancer gene at 22q12.3 by the International Consortium for Prostate Cancer Genetics.

Source: Human Molecular Genetics 2007; 16(11):1271-78.


Authors: Stanford JL, Fitzgerald L, McDonnell SK, Carlson EE, McIntosh L, Deutsch K, Hood L, Ostrander EA, Schaid DJ.

Title: Dense genome-wide SNP linkage scan in 301 hereditary prostate cancer families identifies multiple regions with suggestive evidence for linkage.

Source: Human Molecular Genetics 2009; 18(10):1839-48.


Authors: Christensen GB, Baffoe-Bonnie AB, et al.

Title: Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for Prostate Cancer Genetics using novel sumLINK and sumLOD analyses.

Source: Prostate 2010; 70(7): 735-44.


Authors: Fitzgerald LF, McDonnell SK, Carlson EE, Langeberg W, McIntosh L, Deutsch K, Ostrander EA, Schaid DJ, Stanford JL.

Title: Genome-wide linkage analyses of hereditary prostate cancer families with colon cancer provide further evidence for a susceptibility locus on 15q11-q14.

Source: Eur J Hum Genet 2010; 18(10): 1141-7.


Authors: Johanneson B, McDonnell SK, Karyadi DM, Stanford JL, Kwon EM, Quignon P, Schaid DJ, McIntosh L, Cerhan JR, Johnson G, Deutsch K, St. Sauver JL, Williams G, Thibodeau SN, Ostrander EA.

Title: Family-based Association Analysis of 42 Hereditary Prostate Cancer Families Identifies the Apolipoprotein L3 Region on Chromosome 22q12 as a Risk Locus.

Source: Human Molecular Genetics 2010; 19(19): 3852-62.