Prognostic relevance of urinary bladder cancer susceptibility loci


In the last few years, the shift from a candidate-gene to a genome-wide association study (GWAS) approach has led to the identification of several new genetic susceptibility loci for urinary bladder cancer (UBC). However, whether these established bladder cancer risk loci also influence disease prognosis was unknown.

Therefore, the research team of prof. dr. Bart Kiemeney, dr. Sita Vermeulen, and PhD student Anne Grotenhuis (photo) from the department for Health Evidence investigated whether 12 genetic variants with a confirmed role in UBC susceptibility also influence the risk of disease recurrence, progression, and overall survival. The results of this study, which used data of a population-based series of 1,602 UBC patients from the Nijmegen Bladder Cancer Study (NBCS), were published in the journal PLoS One.

The study identified association of the genetic variant rs9642880 at the 8q24 locus with the risk of disease progression in non-muscle invasive bladder cancer patients. Patients carrying two copies of the G allele had significantly shorter progression-free survival compared to patients with the GT or TT genotype. The 8q24 locus, a so-called gene desert, was previously shown to be implicated in the susceptibility to and clinical disease course of various other cancer types. Although the underlying mechanism is yet unknown, it could involve a regulatory effect on the expression of the 30 kb upstream located MYC proto-oncogene.

Furthermore, the study indicated suggestive evidence for an association of several other UBC susceptibility variants with clinical outcome among disease subgroups according to tumor aggressiveness and smoking status. Results require validation in independent patient series. Elucidation of the causal variant(s) and underlying mechanism could further our understanding of urothelial carcinogenesis and progression, could point to new therapeutic targets, and might aid in improvement of prognostic tools.

In the coming years, Anne Grotenhuis and colleagues hope to continue the success of the GWAS approach for the elucidation of genetic variants involved in UBC prognosis and treatment response.

Grotenhuis AJ, Dudek AM, Verhaegh GW, Witjes JA, Aben KK, et al. (2014) Prognostic Relevance of Urinary Bladder Cancer Susceptibility Loci. PLoS ONE 9(2): e89164. doi:10.1371/journal.pone.0089164

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