Genetic and functional analyses implicate the NUDT11 , HNF1B , and SLC22A3 genes in prostate cancer pathogenesis

Abstract

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.expression quantitative trait loci | prostate cancer risk SNPs | multi-ethnic

Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer

“…Two of the top four genes overexpressed in CC are bona fide tumor suppressor genes-GALNT12 and HPGDwhereas the role of the other two-UBD and NUDT11-in CRC is uncertain (42)(43)(44). Because we previously showed EGFRinduced COX-2 expression and basolateral release of one of the COX-2 products, PGE 2 in HCA-7 cells, we decided to focus on HPGD because HPGD metabolizes PGE 2 to 13,14-dihydro-15-keto-PGE 2 (16,45,46).…”

Variants at IRX4 as prostate cancer expression quantitative trait loci

“…16,17 However, the acquisition of the appropriate tissue type is logistically challenging and the majority of eQTL studies were based on lymphoblastoid cell lines (LCLs). Recently, Grisanzio et al 18 reported five cis-eQTLs in prostate tissue (both normal and tumor) that alter expression of nearby genes. 18 Here, we present an unbiased cis-eQTL analysis of PrCa GWAS variants in prostate tumor tissue.…”

“…Recently, Grisanzio et al 18 reported five cis-eQTLs in prostate tissue (both normal and tumor) that alter expression of nearby genes. 18 Here, we present an unbiased cis-eQTL analysis of PrCa GWAS variants in prostate tumor tissue.…”

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

“…However, another study indicated that HNF1B may function as a tumor suppressor gene in chromophobe renal cell carcinogenesis through control of PKHD1 expression (15). It has been proven that HNF1B is downregulated in ovarian, gastric, pancreatic and colorectal cells (16,17), and its suppression influences cellular phenotypes associated with tumor-related properties in prostate cancer cells (18). The associations of HNF1B with cancer focus mainly on the single nucleotide polymorphisms (SNPs).…”