title: A population-based analysis of clustering identifies a strong genetic contribution to lethal prostate cancer.
abstract: BACKGROUND
  Prostate cancer is a common and often deadly cancer. Decades of study have yet to identify genes that explain much familial prostate cancer. Traditional linkage analysis of pedigrees has yielded results that are rarely validated. We hypothesize that there are rare segregating variants responsible for high-risk prostate cancer pedigrees, but recognize that within-pedigree heterogeneity is responsible for significant noise that overwhelms signal. Here we introduce a method to identify homogeneous subsets of prostate cancer, based on cancer characteristics, which show the best evidence for an inherited contribution.
  
  
  METHODS
  We have modified an existing method, the Genealogical Index of Familiality (GIF) used to show evidence for significant familial clustering. The modification allows a test for excess familial clustering of a subset of prostate cancer cases when compared to all prostate cancer cases.
  
  
  RESULTS
  Consideration of the familial clustering of eight clinical subsets of prostate cancer cases compared to the expected familial clustering of all prostate cancer cases identified three subsets of prostate cancer cases with evidence for familial clustering significantly in excess of expected. These subsets include prostate cancer cases diagnosed before age 50 years, prostate cancer cases with body mass index (BMI) greater than or equal to 30, and prostate cancer cases for whom prostate cancer contributed to death.
  
  
  CONCLUSIONS
  This analysis identified several subsets of prostate cancer cases that cluster significantly more than expected when compared to all prostate cancer familial clustering. A focus on high-risk prostate cancer cases or pedigrees with these characteristics will reduce noise and could allow identification of the rare predisposition genes or variants responsible.
authors: Internal Medicine, University of Utah School of Medicine Salt Lake City, UT, USA.
authors: Quentin
authors: Q
authors: Nelson
authors: Neeraj
authors: N
authors: Agarwal
authors: Robert
authors: R
authors: Stephenson
authors: Lisa A
authors: LA
authors: Cannon-Albright
keywords: UPDB; familiality; lethal; prostate cancer
references: Hum Hered. 2008;65(4):209-20
references: 18073491
references: Hum Genet. 2006 Nov;120(4):471-85
references: 16932970
references: Genomics. 1994 Sep 1;23(1):265-8
references: 7829086
references: Epidemiol Rev. 2001;23(1):19-23
references: 11588848
references: Hum Genet. 2006 May;119(4):400-7
references: 16508751
references: Nat Genet. 1996 Mar;12(3):333-7
references: 8589730
references: Prostate. 2005 Sep 1;64(4):347-55
references: 15754348
references: J Urol. 1993 Sep;150(3):797-802
references: 8345587
references: BMC Cancer. 2012 Apr 03;12:138
references: 22471249
references: N Engl J Med. 2012 Jan 12;366(2):141-9
references: 22236224
references: Ann Hum Genet. 1989 Oct;53(4):339-55
references: 2624429
references: Ann Oncol. 2008 Dec;19(12):2084-8
references: 18653701
references: Nat Genet. 2001 Feb;27(2):172-80
references: 11175785
references: Eur J Hum Genet. 2003 Jan;11(1):17-22
references: 12529701
references: Am J Hum Genet. 1984 Jul;36(4):836-57
references: 6591796
references: Nat Genet. 1994 Sep;8(1):23-6
references: 7987388
references: Science. 1994 Oct 7;266(5182):66-71
references: 7545954
references: Front Biosci. 2007 May 01;12:4101-10
references: 17485361
references: Science. 1994 Sep 30;265(5181):2088-90
references: 8091231
references: Genet Med. 2012 Jan;14(1):107-14
references: 22237439
references: J Invest Dermatol. 2007 Jan;127(1):183-8
references: 16902418
references: Ann Hum Genet. 2008 Mar;72(Pt 2):279-87
references: 18093282
references: Cancer Discov. 2012 Jan;2(1):41-6
references: 22585167
references: Science. 1992 Nov 13;258(5085):1148-52
references: 1439824
references: J Natl Cancer Inst. 1994 Nov 2;86(21):1600-8
references: 7932824
references: Am J Hum Genet. 2005 Aug;77(2):219-29
references: 15988677
references: Prostate. 2007 May 1;67(6):605-13
references: 17299800
references: Am J Hum Genet. 1999 Jul;65(1):134-40
references: 10364525