Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21.
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.
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA. craig.teerlink@utah.edu.
Craig C
CC
Teerlink
Division of Genetics and Epidemiology, Institute of Cancer Research, London, SW7 3RP, UK.
Daniel
D
Leongamornlert
Division of Genetics and Epidemiology, Institute of Cancer Research, London, SW7 3RP, UK.
Tokhir
T
Dadaev
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA.
Alun
A
Thomas
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA.
James
J
Farnham
Department of Urology, University of Utah School of Medicine, Salt Lake City, UT, 84132, USA.|Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, 84132, USA.|Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
Robert A
RA
Stephenson
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
Shaun
S
Riska
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
Shannon K
SK
McDonnell
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
Daniel J
DJ
Schaid
Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
William J
WJ
Catalona
Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
S Lilly
SL
Zheng
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.|Department of Urology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Kathleen A
KA
Cooney
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.|Department of Urology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Anna M
AM
Ray
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.|Department of Urology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Kimberly A
KA
Zuhlke
Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.|Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA.
Ethan M
EM
Lange
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, 3004, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, 3010, Australia.|Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia.
Graham G
GG
Giles
Department of Pathology, University of Melbourne, Melbourne, 3010, Australia.
Melissa C
MC
Southey
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, 3004, Australia.
Liesel M
LM
Fitzgerald
Department of Urology, University Hospital Ulm, 53179, Ulm, Germany.
Antje
A
Rinckleb
Department of Urology, University Hospital Ulm, 53179, Ulm, Germany.
Manuel
M
Luedeke
Institute for Human Genetics, University of Ulm, 89081, Ulm, Germany.
Christiane
C
Maier
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, 98109, USA.
Janet L
JL
Stanford
Cancer Genetics Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA.
Elaine A
EA
Ostrander
Department of Medical Biochemistry and Genetics, University of Turku, 20520, Turku, Finland.
Elina M
EM
Kaikkonen
Department of Medical Biochemistry and Genetics, University of Turku, 20520, Turku, Finland.
Csilla
C
Sipeky
Department of Urology, University of Tampere and Tampere University Hospital, 33520, Tampere, Finland.
Teuvo
T
Tammela
Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, 20520, Turku, Finland.
Johanna
J
Schleutker
Brady Urological Institute, Johns Hopkins University, Baltimore, MD, 21287, USA.
Kathleen E
KE
Wiley
Brady Urological Institute, Johns Hopkins University, Baltimore, MD, 21287, USA.
Sarah D
SD
Isaacs
Brady Urological Institute, Johns Hopkins University, Baltimore, MD, 21287, USA.
Patrick C
PC
Walsh
Brady Urological Institute, Johns Hopkins University, Baltimore, MD, 21287, USA.
William B
WB
Isaacs
Program for Personalized Cancer Care, NorthShore University Health System, Evanston, IL, 60201, USA.
Jianfeng
J
Xu
CeRePP, Hopital Tenon, Assistance Publique-Hopitaux de Paris, 75020, Paris, France.
Geraldine
G
Cancel-Tassin
CeRePP, Hopital Tenon, Assistance Publique-Hopitaux de Paris, 75020, Paris, France.
Olivier
O
Cussenot
Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA.
Diptasri
D
Mandal
Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA.
Cecelia
C
Laurie
Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA.
Cathy
C
Laurie
Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
Stephen N
SN
Thibodeau
Division of Genetics and Epidemiology, Institute of Cancer Research, London, SW7 3RP, UK.
Rosalind A
RA
Eeles
Division of Genetics and Epidemiology, Institute of Cancer Research, London, SW7 3RP, UK.
Zsofia
Z
Kote-Jarai
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA.|George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, 84148, USA.
Lisa
L
Cannon-Albright
D000368:Aged; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D062085:RNA, Long Noncoding / Q000235:genetics*; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C000611466:PRNCR1 long non-coding RNA, human; D062085:RNA, Long Noncoding; D025521:Tumor Suppressor Proteins; C484713:long non-coding RNA CASC2, human