Introduction
Prostate cancer is the fifth most common cancer in Korean men. Additionally, its incidence has doubled and prevalence has tripled in the Korean population in the last decade. Prostate cancer is highly heritable, thus it is imperative to study germline variants. Common variants associated with prostate cancer have been studied in various populations including those in Korea. However, less is known about rare variants (minor allele frequency<5%), they may have greater phenotypic effects and can help us better comprehend genetic etiology of prostate cancer. Rare variants have not been widely studied in Korean populations. Therefore we investigated prostate cancer related rare variants among 985 prostate cancer patients and 6,273 normal populations.
Material and methods
We prospectively recruited 985 prostate cancer patients from single tertiary hospital and conducted a case-control study including 6,273 controls from the Korean Association Resource (KARE) study as part of the Korean Genome and Epidemiology study (KoGES). All included subjects were analyzed using the HumanExome BeadChip 12v1-1 system (Illumina, Inc.; San Diego, CA), which included 213,099 probes focused on protein-altering variants (nonsynonymous, stop and splice) selected from exome and whole-genome sequences. The rare variants analysis using variants with low minor allele frequency (<5%) was conducted to find prostate cancer association.
Results
The rare variants were fist collapsed into gene bins and intergenic region bins and applied a dispersion test using SKAT to identify rare variants on 34 genes associated with prostate cancer in the Korean population (Table 1). Finally, in a separate analysis, rare variants were binned into their respective pathways. Many significant genes and marginally significant pathways were identified, some of which have been already implicated in Prostate cancer.
Conclusions
Taken together, our findings suggest that identified rare variants may play a crucial role as prostate cancer susceptibility genes in the Korean population.
Table 1. Gene-based rare variant analysis among prostate cancer patients and normal control
Gene
|
Num_Loci
|
SKAT_logistic
|
FDR
|
TC2N
|
1
|
1.40E-07
|
0.001945491
|
NMRK1
|
1
|
7.93E-07
|
0.002199497
|
SYT10
|
1
|
7.25E-07
|
0.002199497
|
RAPGEFL1
|
1
|
3.70E-07
|
0.002199497
|
GGT5
|
2
|
4.81E-07
|
0.002199497
|
JAM2
|
1
|
1.37E-06
|
0.003170887
|
MED25
|
1
|
1.88E-06
|
0.003267297
|
DDTL
|
1
|
1.85E-06
|
0.003267297
|
CDYL2
|
2
|
2.55E-06
|
0.00353096
|
USP18
|
1
|
2.35E-06
|
0.00353096
|
MDM4
|
1
|
3.93E-06
|
0.004955617
|
PLCB1
|
2
|
6.62E-06
|
0.007060574
|
NAGA
|
1
|
6.21E-06
|
0.007060574
|
RXFP4
|
3
|
8.81E-06
|
0.008144126
|
ENO4
|
1
|
1.80E-05
|
0.014668583
|
SHTN1
|
1
|
1.80E-05
|
0.014668583
|
ADRB2
|
1
|
2.26E-05
|
0.017424981
|
SPATA3
|
2
|
2.63E-05
|
0.019184615
|
CORT
|
1
|
3.03E-05
|
0.020022921
|
LOC102724438
|
4
|
2.99E-05
|
0.020022921
|
CHST10
|
1
|
3.79E-05
|
0.0224277
|
PARD3B
|
9
|
4.20E-05
|
0.0224277
|
MST1R
|
6
|
3.60E-05
|
0.0224277
|
LOC105376844
|
2
|
4.20E-05
|
0.0224277
|
LRRC37A3
|
2
|
4.20E-05
|
0.0224277
|
SLC36A2
|
5
|
4.67E-05
|
0.023996059
|
IDO1
|
1
|
5.25E-05
|
0.025999802
|
ZBTB46
|
2
|
6.64E-05
|
0.031752919
|
FBXO34
|
2
|
7.46E-05
|
0.034503188
|
NAA11
|
2
|
8.15E-05
|
0.036480864
|
IL27
|
1
|
8.86E-05
|
0.037781662
|
ZFPM1
|
1
|
8.99E-05
|
0.037781662
|
SLC5A11
|
6
|
0.000106098
|
0.042779749
|
ROMO1
|
1
|
0.000107944
|
0.042779749
|