Replication of a genetic variant for prostate cancer-specific mortality.
BACKGROUND
Few genetic variants have been confirmed as being associated with prostate cancer-specific mortality (PCSM). A recent study identified 22 candidate single-nucleotide polymorphisms (SNPs) associated with PCSM in a Seattle-based patient cohort. Five of these associations were replicated in an independent Swedish cohort.


METHODS
We genotyped these 22 SNPs in Physicians' Health Study (PHS) participants diagnosed with prostate cancer (PCa). Using the same model that was found to be most significant in the Seattle cohort, we examined the association of these SNPs with lethal disease with Cox proportional hazards models.


RESULTS
One SNP, rs5993891 in the ARVCF gene on chromosome 22q11, which had also replicated in the Swedish cohort, was also significantly associated with PCSM in the PHS cohort (hazard ratio (HR)=0.32; P=0.01). When we tested this SNP in an additional cohort (Health Professionals Follow-up Study, HPFS), the association was null (HR=0.95, P=0.90); however, a meta-analysis across all studies showed a statistically significant association with a HR of 0.52 (0.29-0.93, P=0.03).


CONCLUSIONS
The association of rs5993891 with PCSM was further replicated in PHS and remains significant in a meta-analysis, though there was no association in HPFS. This SNP may contribute to a genetic panel of SNPs to determine at diagnosis whether a patient is more likely to exhibit an indolent or aggressive form of PCa. This study also emphasizes the importance of multiple rounds of replication.
1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA [2] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
K L
KL
Penney
1] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA [2] Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
I M
IM
Shui
Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA.
Z
Z
Feng
1] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA [2] Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
H D
HD
Sesso
1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA [2] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA [3] Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
M J
MJ
Stampfer
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
J L
JL
Stanford
D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000628:therapy
D017430:Prostate-Specific Antigen