Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis.
One of the central goals of human genetics is to discover the genes and pathways driving human traits. To date, most of the common risk alleles discovered through genome-wide association studies (GWAS) map to nonprotein-coding regions. Because of our relatively poorer understanding of this part of the genome, the functional consequences of trait-associated variants pose a considerable challenge. To identify the genes through which risk loci act, we hypothesized that the risk variants are regulatory elements. For each of 12 known risk polymorphisms, we evaluated the correlation between risk allele status and transcript abundance for all annotated protein-coding transcripts within a 1-Mb interval. A total of 103 transcripts were evaluated in 662 prostate tissue samples [normal (n = 407) and tumor (n = 255)] from 483 individuals [European Americans (n = 233), Japanese (n = 127), and African Americans (n = 123)]. In a pooled analysis, 4 of the 12 risk variants were strongly associated with five transcripts (NUDT11, MSMB, NCOA4, SLC22A3, and HNF1B) in histologically normal tissue (P ≤ 0.001). Although associations were also observed in tumor tissue, they tended to be more attenuated. Previously, we showed that MSMB and NCOA4 participate in prostate cancer pathogenesis. Suppressing the expression of NUDT11, SLC22A3, and HNF1B influences cellular phenotypes associated with tumor-related properties in prostate cancer cells. Taken together, the data suggest that these transcripts contribute to prostate cancer pathogenesis.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Chiara
C
Grisanzio
Lillian
L
Werner
David
D
Takeda
Bisola C
BC
Awoyemi
Mark M
MM
Pomerantz
Hiroki
H
Yamada
Prasanna
P
Sooriakumaran
Brian D
BD
Robinson
Robert
R
Leung
Anna C
AC
Schinzel
Ian
I
Mills
Helen
H
Ross-Adams
David E
DE
Neal
Masahito
M
Kido
Toshihiro
T
Yamamoto
Gillian
G
Petrozziello
Edward C
EC
Stack
Rosina
R
Lis
Philip W
PW
Kantoff
Massimo
M
Loda
Oliver
O
Sartor
Shin
S
Egawa
Ashutosh K
AK
Tewari
William C
WC
Hahn
Matthew L
ML
Freedman
D000483:Alleles; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D051539:Hepatocyte Nuclear Factor 1-beta / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008957:Models, Genetic; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis*; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011755:Pyrophosphatases / Q000096:biosynthesis*; D040641:Quantitative Trait Loci; D012306:Risk; D000099254:Organic Cation Transporter 3; D000096964:Nudix Hydrolases
D051539:Hepatocyte Nuclear Factor 1-beta; D027701:Organic Cation Transport Proteins; D011755:Pyrophosphatases; D000099254:Organic Cation Transporter 3; C496495:HNF1B protein, human; C469382:NUDT11 protein, human; D000096964:Nudix Hydrolases