Editors' ChoiceHuman Genetics

Bladder Relief?

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Science Translational Medicine  07 Apr 2010:
Vol. 2, Issue 26, pp. 26ec55
DOI: 10.1126/scitranslmed.3001123

Bladder cancer is frequently underappreciated as a substantial source of cancer-related morbidity and mortality. However, in 2009 the National Cancer Institute estimated that of the 70,000 individuals who will be newly diagnosed with carcinomas of the bladder, over 14,000 individuals will die from this disorder. Further, the clinical course of bladder cancer is highly heterogeneous, with recurrence being very common even in minimally invasive disease. This underscores a substantial need for better surveillance and predictive models for individuals with low pathologic grade disease.

Now, Kiemeney et al. have identified a single nucleotide polymorphism (SNP) that may serve as a valuable genomic biomarker for bladder cancer. The investigators performed a genome-wide association study (GWAS) on over 2000 Dutch and Icelandic cases and close to 40,000 controls and validated top SNPs in a replication cohort from nine independent study populations. One marker on chromosome 4p16.3 reached genome-wide significance in the replication cohort and overall analysis (P = 9.9 × 10–12) and conferred a 24% increase in risk for disease. This SNP is located in a noncoding portion of the gene TACC3, which encodes a protein that regulates microtubule dynamics. Interestingly, the TACC3 susceptibility allele was more strongly linked to low-grade recurrent noninvasive carcinomas than high-grade disease. This association to low-grade bladder carcinoma is very similar to the association of a neighboring gene that is strongly linked to low-grade bladder cancer, FGFR3. Whether these two genes cooperate to malignantly transform bladder tumors is unclear; however, Kiemeney et al. observed that the TACC3 susceptibility allele was significantly more common in individuals with existing somatic mutations (odds ratio 2.81, P = 0.016) and with higher tumor levels of FGFR3. Going forward, further delineating the functional genomics and the potential shared effects of these variants on low-grade bladder cancers will hopefully allow for more precise risk stratification and surveillance strategies for individuals at high risk for recurrent disease.

L. A. Kiemeney et al., A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nat. Gen. 28 March 2010 (10.1038/ng.558). [Full Text]

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