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Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21


Teerlink, CC and Leongamornlert, D and Dadaev, T and Thomas, A and Farnham, J and Stephenson, RA and Riska, S and McDonnell, SK and Schaid, DJ and Catalona, WJ and Zheng, SL and Cooney, KA and Ray, AM and Zuhlke, KA and Lange, EM and Giles, GG and Southey, MC and Fitzgerald, LM and Rinckleb, A and Luedeke, M and Maier, C and Stanford, JL and Ostrander, EA and Kaikkonen, EM and Sipeky, C and Tammela, T and Schleutker, J and Wiley, KE and Isaacs, SD and Walsh, PC and Isaacs, WB and Xu, J and Cancel-Tassin, G and Cussenot, O and Mandal, D and Laurie, C and Laurie, C and Thibodeau, SN and Eeles, RA and Kote-Jarai, Z and Cannon-Albright, L and The PRACTICAL consortium; International Consortium for Prostate Cancer Genetics, Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21, Human genetics, 135, (8) pp. 923-938. ISSN 0340-6717 (2016) [Refereed Article]

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Copyright 2016 Springer-Verlag Berlin Heidelberg

DOI: doi:10.1007/s00439-016-1690-6


Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.

Item Details

Item Type:Refereed Article
Keywords:prostate cancer
Research Division:Biomedical and Clinical Sciences
Research Group:Oncology and carcinogenesis
Research Field:Cancer genetics
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Fitzgerald, LM (Dr Liesel Fitzgerald)
ID Code:110622
Year Published:2016
Web of Science® Times Cited:27
Deposited By:Menzies Institute for Medical Research
Deposited On:2016-08-05
Last Modified:2017-11-06

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