Genome-wide association study of prostate cancer mortality.
BACKGROUND
A pressing clinical issue in prostate cancer is to distinguish which men will have an indolent or aggressive course of disease. Clinical variables such as Gleason grade and stage are useful predictors of lethal cancer; however, the low predictive values of the common Gleason scores, changes in grading over time, and earlier diagnosis of patients due to screening limits their clinical utility. Identifying genetic variants associated with lethal prostate cancer could inform clinical decision making.


METHODS
We conducted a genome-wide association study, comparing lethal prostate cancer cases to cases surviving at least 10 years beyond their initial diagnosis. Genotyping was done with the Affymetrix 5.0 chip [∼500,000 single nucleotide polymorphisms (SNP) and 1,483 copy number variants (CNV)] on DNA from participants in the Physicians' Health Study and Health Professionals Follow-up Study (196 lethal cases, 368 long-term survivors). After excluding SNPs and individuals based on quality control criteria, logistic regression assuming an additive model was done using the PLINK software.


RESULTS
No SNP reached genome-wide significance (P ≤ 1 × 10(-7)); however, three independent SNPs had P < 1 × 10(-5). One top-ranked SNP replicated (P = 0.05) in an independent follow-up study. Although no CNV had genome-wide significance, 14 CNVs showed nominal association with prostate cancer mortality (P < 0.05).


CONCLUSIONS
No variants were significantly associated at a genome-wide level with prostate cancer mortality. Common genetic determinants of lethal prostate cancer are likely to have odds ratios <2.0.


CONCLUSIONS
Genetic markers identified could provide biological insight to improve therapy for men with potentially fatal cancer. Larger studies are necessary to detect the genetic causes of prostate cancer mortality.
Penney
Kathryn L
KL
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
Pyne
Saumyadipta
S
Schumacher
Fredrick R
FR
Sinnott
Jennifer A
JA
Mucci
Lorelei A
LA
Kraft
Peter L
PL
Ma
Jing
J
Oh
William K
WK
Kurth
Tobias
T
Kantoff
Philip W
PW
Giovannucci
Edward L
EL
Stampfer
Meir J
MJ
Hunter
David J
DJ
Freedman
Matthew L
ML
D018628:Gene Dosage; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality*
D005819:Genetic Markers