Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search

Science

Volumn 274, Issue 5291, 1996, Pages 1371-1374

  Smith, Jeffrey R ^a   Freije, Diha ^a   Carpten, John D ^a   Grönberg, Henrik ^a   Xu, Jianfeng ^a   Isaacs, Sarah D ^a   Brownstein, Michael J ^a   Bova, G Steven ^a   Guo, Hong ^a   Bujnovszky, Piroska ^a   Nusskern, Deborah R ^a   Damber, Jan Erik ^a   Bergh, Anders ^a   Emanuelsson, Monika ^a   Kallioniemi, Olli P ^a   Walker Daniels, Jennifer ^a   Bailey Wilson, Joan E ^a   Beaty, Terri H ^a   Meyers, Deborah A ^a   Walsh, Patrick C ^a   Collins, Francis S ^a   Trent, Jeffrey M ^a   Isaacs, William B ^a   more..

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

ADULT; AGED; ARTICLE; CHROMOSOME 1Q; FAMILIAL CANCER; GENE LOCUS; GENETIC LINKAGE; GENETIC SUSCEPTIBILITY; HUMAN; MAJOR CLINICAL STUDY; MALE; NORTH AMERICA; PRIORITY JOURNAL; PROSTATE CANCER; SWEDEN;

ADULT; AGED; AGED, 80 AND OVER; CHROMOSOME MAPPING; CHROMOSOMES, HUMAN, PAIR 1; DINUCLEOTIDE REPEATS; GENES; GENETIC MARKERS; GENETIC PREDISPOSITION TO DISEASE; HUMANS; LIKELIHOOD FUNCTIONS; LINKAGE (GENETICS); MALE; MIDDLE AGED; NORTH AMERICA; ONCOGENES; PEDIGREE; PROSTATIC NEOPLASMS; RISK FACTORS; STATISTICS, NONPARAMETRIC; SWEDEN;

EID: 0000009909     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.274.5291.1371     Document Type: Article

References (23)

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13. In response to an article in Parade magazine (3 March 1996) describing this study, individuals in 1904 different families reported having three or more family members affected with prostate cancer. Of these, 6% reported having five affected family members, 1.4% reported having six affected members, and 1.4% reported having seven or more affected members.
14. North American prostate cancer families were obtained from three sources: 65% of the families were identified by referrals generated as a response to a letter sent by one of us (PCW) to 8000 urologists throughout the country; the second source, accounting for 23% of the families, was identified by family history records of the patient population seen at Johns Hopkins Hospital for treatment of prostate cancer; the remainder of the families responded to articles published in a variety of lay publications describing this study. Prostate cancer diagnosis was verified by medical records for each affected male studied. Swedish families were obtained as a result of a nationwide search of cancer registries, and from referrals from urologists. All individuals in this study gave full informed consent.
15. 4.
16. In the model used, affected men were assumed to be carriers of a rare autosomal dominant gene frequency q = 0.003) (6), with a fixed 15% phenocopy rate, while all unaffected men under 75 and all women were assumed to be of unknown phenotype. In men over age 75, the lifetime penetrance of genecarriers was estimated to be 63% (based on a population based segregation analysis performed by H.G., in preparation, and the lifetime risk of prostate cancer for non-carriers was 16% in this age class (based on SEER data) [C. L. Kosary, L. A. G. Ries, B. A. Miller, B. F. Hankey, A. Harras, B. K. Edwards (Eds.), SEER Cancer Statistics Review, 1973-1992: Tables and Graphs, National Cancer Institute. NIH Pub. No. 96-2789. Bethesda, MD, 1995]. This is a conservative model as it minimizes the chances of incorrectly assuming that a young unaffected male is a noncarrier. The fact that nonparametric methods produce results of similar statistical significance (Table 2) adds confidence to the conclusion that the observed linkage is not strongly dependent on the choice of this particular model.
17. Standard parametric likelihood analysis was performed by means of FASTLINK [R. W. Cottingham Jr., R. M. Idury, A. A. Schaffer, Am. J. Hum. Genet. 53, 252 (1993)] for two-point linkage and VITESSE [J. R. O'Connel and D. E. Weeks, Nature Genet. 11,402 (1995)] for multipoint linkage analysis. Multipoint analysis has the advantage of utilizing data from multiple linked markers to maximize the information in a given pedigree. Nonparametric multipoint analysis, which is robust even when the mode of inheritance is not known, was also performed, with GENEHUNTER [L. Kruglayk and E. S. Lander, Am. J. Hum. Genet. 57, 439 (1995)] to calculate normalized Z scores and associated P values. In all of the linkage analyses, allele frequencies for the markers were estimated from independent individuals in the families and unrelated individuals separately for the North American and Swedish families. CRIMAP [E. S. Lander and P. Green, Proc. Natl. Acad, Sci. U.S.A. 84, 2363 (1987)] was used to order the multiple markers on chromosome 1 using the genotype data from all pedigrees. The BUILD option of CRIMAP was first used to establish the order of markers with at least a likelihood ratio of 1000:1. The FLIP option was then used to calculate the likelihood of alternative marker orders by permuting adjacent loci (five flanking markers). The most likely order thus determined is the same as the published order (http: //cedar.soton.ac,uk/pub). The admixture test as implemented in HOMOG [J. Ott, Analysis of Human Genetic Linkage (Johns Hopkins Univ. Press, Baltimore, 1985), pp. 200-203] was used to test for genetic heterogeneity in the context of the two-point parametric analysis.
18. Standard parametric likelihood analysis was performed by means of FASTLINK [R. W. Cottingham Jr., R. M. Idury, A. A. Schaffer, Am. J. Hum. Genet. 53, 252 (1993)] for two-point linkage and VITESSE [J. R. O'Connel and D. E. Weeks, Nature Genet. 11,402 (1995)] for multipoint linkage analysis. Multipoint analysis has the advantage of utilizing data from multiple linked markers to maximize the information in a given pedigree. Nonparametric multipoint analysis, which is robust even when the mode of inheritance is not known, was also performed, with GENEHUNTER [L. Kruglayk and E. S. Lander, Am. J. Hum. Genet. 57, 439 (1995)] to calculate normalized Z scores and associated P values. In all of the linkage analyses, allele frequencies for the markers were estimated from independent individuals in the families and unrelated individuals separately for the North American and Swedish families. CRIMAP [E. S. Lander and P. Green, Proc. Natl. Acad, Sci. U.S.A. 84, 2363 (1987)] was used to order the multiple markers on chromosome 1 using the genotype data from all pedigrees. The BUILD option of CRIMAP was first used to establish the order of markers with at least a likelihood ratio of 1000:1. The FLIP option was then used to calculate the likelihood of alternative marker orders by permuting adjacent loci (five flanking markers). The most likely order thus determined is the same as the published order (http: //cedar.soton.ac,uk/pub). The admixture test as implemented in HOMOG [J. Ott, Analysis of Human Genetic Linkage (Johns Hopkins Univ. Press, Baltimore, 1985), pp. 200-203] was used to test for genetic heterogeneity in the context of the two-point parametric analysis.
19. Standard parametric likelihood analysis was performed by means of FASTLINK [R. W. Cottingham Jr., R. M. Idury, A. A. Schaffer, Am. J. Hum. Genet. 53, 252 (1993)] for two-point linkage and VITESSE [J. R. O'Connel and D. E. Weeks, Nature Genet. 11,402 (1995)] for multipoint linkage analysis. Multipoint analysis has the advantage of utilizing data from multiple linked markers to maximize the information in a given pedigree. Nonparametric multipoint analysis, which is robust even when the mode of inheritance is not known, was also performed, with GENEHUNTER [L. Kruglayk and E. S. Lander, Am. J. Hum. Genet. 57, 439 (1995)] to calculate normalized Z scores and associated P values. In all of the linkage analyses, allele frequencies for the markers were estimated from independent individuals in the families and unrelated individuals separately for the North American and Swedish families. CRIMAP [E. S. Lander and P. Green, Proc. Natl. Acad, Sci. U.S.A. 84, 2363 (1987)] was used to order the multiple markers on chromosome 1 using the genotype data from all pedigrees. The BUILD option of CRIMAP was first used to establish the order of markers with at least a likelihood ratio of 1000:1. The FLIP option was then used to calculate the likelihood of alternative marker orders by permuting adjacent loci (five flanking markers). The most likely order thus determined is the same as the published order (http: //cedar.soton.ac,uk/pub). The admixture test as implemented in HOMOG [J. Ott, Analysis of Human Genetic Linkage (Johns Hopkins Univ. Press, Baltimore, 1985), pp. 200-203] was used to test for genetic heterogeneity in the context of the two-point parametric analysis.
20. Standard parametric likelihood analysis was performed by means of FASTLINK [R. W. Cottingham Jr., R. M. Idury, A. A. Schaffer, Am. J. Hum. Genet. 53, 252 (1993)] for two-point linkage and VITESSE [J. R. O'Connel and D. E. Weeks, Nature Genet. 11,402 (1995)] for multipoint linkage analysis. Multipoint analysis has the advantage of utilizing data from multiple linked markers to maximize the information in a given pedigree. Nonparametric multipoint analysis, which is robust even when the mode of inheritance is not known, was also performed, with GENEHUNTER [L. Kruglayk and E. S. Lander, Am. J. Hum. Genet. 57, 439 (1995)] to calculate normalized Z scores and associated P values. In all of the linkage analyses, allele frequencies for the markers were estimated from independent individuals in the families and unrelated individuals separately for the North American and Swedish families. CRIMAP [E. S. Lander and P. Green, Proc. Natl. Acad, Sci. U.S.A. 84, 2363 (1987)] was used to order the multiple markers on chromosome 1 using the genotype data from all pedigrees. The BUILD option of CRIMAP was first used to establish the order of markers with at least a likelihood ratio of 1000:1. The FLIP option was then used to calculate the likelihood of alternative marker orders by permuting adjacent loci (five flanking markers). The most likely order thus determined is the same as the published order (http: //cedar.soton.ac,uk/pub). The admixture test as implemented in HOMOG [J. Ott, Analysis of Human Genetic Linkage (Johns Hopkins Univ. Press, Baltimore, 1985), pp. 200-203] was used to test for genetic heterogeneity in the context of the two-point parametric analysis.
21. Standard parametric likelihood analysis was performed by means of FASTLINK [R. W. Cottingham Jr., R. M. Idury, A. A. Schaffer, Am. J. Hum. Genet. 53, 252 (1993)] for two-point linkage and VITESSE [J. R. O'Connel and D. E. Weeks, Nature Genet. 11,402 (1995)] for multipoint linkage analysis. Multipoint analysis has the advantage of utilizing data from multiple linked markers to maximize the information in a given pedigree. Nonparametric multipoint analysis, which is robust even when the mode of inheritance is not known, was also performed, with GENEHUNTER [L. Kruglayk and E. S. Lander, Am. J. Hum. Genet. 57, 439 (1995)] to calculate normalized Z scores and associated P values. In all of the linkage analyses, allele frequencies for the markers were estimated from independent individuals in the families and unrelated individuals separately for the North American and Swedish families. CRIMAP [E. S. Lander and P. Green, Proc. Natl. Acad, Sci. U.S.A. 84, 2363 (1987)] was used to order the multiple markers on chromosome 1 using the genotype data from all pedigrees. The BUILD option of CRIMAP was first used to establish the order of markers with at least a likelihood ratio of 1000:1. The FLIP option was then used to calculate the likelihood of alternative marker orders by permuting adjacent loci (five flanking markers). The most likely order thus determined is the same as the published order (http: //cedar.soton.ac,uk/pub). The admixture test as implemented in HOMOG [J. Ott, Analysis of Human Genetic Linkage (Johns Hopkins Univ. Press, Baltimore, 1985), pp. 200-203] was used to test for genetic heterogeneity in the context of the two-point parametric analysis.
22. The evaluation of age as a variable is confounded because of the changing methods used to diagnose this disease, and increased interest in screening for this disease. For the years prior to the use of prostate-specific antigen (PSA), diagnosis of prostate cancer was often not made until men presented with advanced disease, whereas today most men are diagnosed younger and at an earlier stage.
23. The expert technical assistance of C. Ewing and J. Robinson, and the help of X. Chen, D. Schwengel, R. Paul, C. Engstrand, A. Kallioniemi, L. Hardie, and B. Carter during the early phases of this work is acknowledged. We also thank B. Childs, J. Isaacs, and D. Coffey for helpful advice. We acknowledge the assistance of L. Middelton, C. Francomano, and the Family Studies Core of the National Center for Human Genome Research (NCHGR), and the Genetic Resources Core Facility (JHU). We also acknowledge A. Lowe and D. Gilbert at the Applied Biosystems Division of Perkin-Elmer for providing valuable genotyping technical support. We wish to thank all the physicians who referred families for this study. Supported by grants from U.S. Public Health Service SPORE CA58236; The Fund for Research and Progress in Urology; The Johns Hopkins University; Swedish Cancer Society (Cancerfonden); Lion's Cancer Foundation, Department of Oncology, Umeå Universitet, and a 1995 CaPCURE award. D.F. is supported by a grant from American Foundation for Urologic Disease.