Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP.
BACKGROUND
The consistent finding of a genetic susceptibility to prostate cancer suggests that there are germline sequence variants predisposing individuals to this disease. These variants could be useful in screening and treatment.


METHODS
We performed an exploratory genome-wide association scan in 498 men with aggressive prostate cancer and 494 control subjects selected from a population-based case-control study in Sweden. We combined the results of this scan with those for aggressive prostate cancer from the publicly available Cancer Genetic Markers of Susceptibility (CGEMS) Study. Single-nucleotide polymorphisms (SNPs) that showed statistically significant associations with the risk of aggressive prostate cancer based on two-sided allele tests were tested for their association with aggressive prostate cancer in two independent study populations composed of individuals of European or African American descent using one-sided tests and the genetic model (dominant or additive) associated with the lowest value in the exploratory study.


RESULTS
Among the approximately 60,000 SNPs that were common to our study and CGEMS, we identified seven that had a similar (positive or negative) and statistically significant (P<.01) association with the risk of aggressive prostate cancer in both studies. Analysis of the distribution of these SNPs among 1032 prostate cancer patients and 571 control subjects of European descent indicated that one, rs1571801, located in the DAB2IP gene, which encodes a novel Ras GTPase-activating protein and putative prostate tumor suppressor, was associated with aggressive prostate cancer (one-sided P value = .004). The association was also statistically significant in an African American study population that included 210 prostate cancer patients and 346 control subjects (one-sided P value = .02).


CONCLUSIONS
A genetic variant in DAB2IP may be associated with the risk of aggressive prostate cancer and should be evaluated further.
Duggan
David
D
Division of Genetic Basis of Human Disease, Translational Genomics Research Institute, Phoenix, AZ, USA.
Zheng
Siqun L
SL
Knowlton
Michele
M
Benitez
Debbie
D
Dimitrov
Latchezar
L
Wiklund
Fredrik
F
Robbins
Christiane
C
Isaacs
Sarah D
SD
Cheng
Yu
Y
Li
Ge
G
Sun
Jielin
J
Chang
Bao-Li
BL
Marovich
Leslie
L
Wiley
Kathleen E
KE
Bälter
Katarina
K
Stattin
Pär
P
Adami
Hans-Olov
HO
Gielzak
Marta
M
Yan
Guifang
G
Sauvageot
Jurga
J
Liu
Wennuan
W
Kim
Jin Woo
JW
Bleecker
Eugene R
ER
Meyers
Deborah A
DA
Trock
Bruce J
BJ
Partin
Alan W
AW
Walsh
Patrick C
PC
Isaacs
William B
WB
Grönberg
Henrik
H
Xu
Jianfeng
J
Carpten
John D
JD
D001741:Black or African American / Q000235:genetics; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D013548:Sweden; D044465:White People / Q000235:genetics*; D020703:ras GTPase-Activating Proteins / Q000235:genetics*
D014408:Biomarkers, Tumor; C462952:DAB2IP protein, human; D020703:ras GTPase-Activating Proteins