Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer

Abstract

Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 × 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.

NOTCH pathway inactivation promotes bladder cancer progression

“…In particular, a high fraction of bladder carcinomas present deletion of the long arm of chromosome 9q, where NOTCH1 is located (39), and low levels of NOTCH1 and JAGGED1 are associated with short survival in bladder cancer patients (40). Even more, a genome-wide association study in patients with bladder cancer found a significant association with a SNP in a region near to JAGGED1, and carriers of this SNP showed a trend to have lower JAGGED1 expression, again suggesting a tumor-suppressive role for the NOTCH pathway (41). Following on these observations, our analyses of NOTCH mutations from bladder cancer patients, mouse genetic models, cellbased assays, and human cancer samples provide solid evidence that the canonical NOTCH pathway plays a relevant tumor-suppressive role in bladder cancer.…”

Genome-Wide Association Study of Bladder Cancer in a Chinese Cohort Reveals a New Susceptibility Locus at 5q12.3

“…Furthermore, genome-wide association studies (GWAS) have identified a subset of common variants associated with bladder cancer risk (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). However, these studies have primarily been conducted in individuals of European descent, and only one GWAS reported by Matsuda and colleagues had been performed in Japanese (14).…”

Genetic Variants in the Wnt/β-Catenin Signaling Pathway as Indicators of Bladder Cancer Risk

“…It has also been established that genetics play an important role in risk of developing bladder cancer 3 . Recent genome-wide association studies have identified a total of at least 14 unique genetic loci that have a significant effect on bladder cancer risk in European-descent populations 4–15 . However, these risk factors only represent a small portion of the genetic basis of this disease suggesting that the full spectrum of genetic factors influencing risk of bladder cancer remains undetermined.…”