Prostate cancer is one of the most common malignancies of males in western countries, accounting for 36 percent of all male cancers and 13 percent of male cancer-related deaths. In spite of the magnitude of the problem which this malignancy presents, an understanding of the molecular mechanisms underlying susceptibility remains elusive. Complex segregation analyses suggest the existence of dominant high-penetrant susceptibility alleles, which may account for up to 10 percent of all prostate cancer. During this past grant period, the applicant has performed a genome-wide scan on 163 kindreds with three or more affected men with prostate cancer, as well as analyzed several chromosomal regions reported by others to demonstrate linkage. By the end of the current grant period, they will have completed the genome-wide scan of their families. Although linkage analysis of hereditary prostate cancer (HPC) is complicated by a number of barriers, including potentially extensive genetic heterogeneity, high phenocopy rates, and lack of fully informative pedigrees, a number of research groups (including the Mayo Clinic) have implicated four loci (three on chromosome 1 and one on the X chromosome) as harboring HPC genes. Additionally, the P.I. has demonstrated linkage to an unreported region on chromosome 20, at 20q13. In spite of the progress made, these five loci still account for less than half of the HPC cases. With the completion of the genome-wide scan, as well as the completion of similar analyses from other groups, it is likely that other chromosomal regions will be identified. It is noticed that none of the putative susceptibility genes from these regions have been identified. Thus, the P.I. proposed the following specific aims: 1) Complete the statistical analysis of the genome-wide scan and identify additional regions of linkage for more detailed analyses; 2) Define the narrowest genetic and physical interval for those regions demonstrating the strongest evidence of linkage in the Mayo families; 3) Identify candidate genes that map to these region(s), especially to chromosome 20ql3; and 4) Analyze and characterize genes from the regions of interest for their involvement in hereditary prostate cancer. The potential impact of the discoveries of cancer susceptibility genes on cancer prevention and early detection, leading to increased likelihood of cure is great. In the case of prostate cancer, it is clear that early, localized disease is highly curable.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA072818-05
Application #
6266238
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Seminara, Daniela
Project Start
1996-12-26
Project End
2005-11-30
Budget Start
2001-01-10
Budget End
2001-11-30
Support Year
5
Fiscal Year
2001
Total Cost
$333,648
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Saunders, Edward J; Dadaev, Tokhir; Leongamornlert, Daniel A et al. (2016) Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array. Br J Cancer 114:945-52
Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb et al. (2016) Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation. Nat Commun 7:10979
Southey, Melissa C (see original citation for additional authors) (2016) PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J Med Genet 53:800-811
Szulkin, Robert; Karlsson, Robert; Whitington, Thomas et al. (2015) Genome-wide association study of prostate cancer-specific survival. Cancer Epidemiol Biomarkers Prev 24:1796-800
Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I et al. (2014) A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet 46:1103-9
Bailey-Wilson, Joan E; Childs, Erica J; Cropp, Cheryl D et al. (2012) Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families. BMC Med Genet 13:46
Lu, Lingyi; Cancel-Tassin, Geraldine; Valeri, Antoine et al. (2012) Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG. Prostate 72:410-26
Kote-Jarai, Zsofia; Olama, Ali Amin Al; Giles, Graham G et al. (2011) Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nat Genet 43:785-91
Johanneson, Bo; McDonnell, Shannon K; Karyadi, Danielle M et al. (2010) Family-based association analysis of 42 hereditary prostate cancer families identifies the Apolipoprotein L3 region on chromosome 22q12 as a risk locus. Hum Mol Genet 19:3852-62
Schaid, Daniel J; McDonnell, Shannon K; Riska, Shaun M et al. (2010) Estimation of genotype relative risks from pedigree data by retrospective likelihoods. Genet Epidemiol 34:287-98

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