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More than 50% of transitional cell carcinomas of the bladder show loss of heterozygosity of a region spanning theTSC1locus at 9q34 and mutations ofTSC1have been identified in 14.5% of tumours. These comprise nonsense mutations, splicing mutations, small deletions and missense mutations. Missense mutations are only rarely found in the germline in TSC disease. Therefore, we have examined six somatic missense mutations found in bladder cancer to determine whether these result in loss of function. We describe loss of function via distinct mechanisms. Five mutations caused mutually exclusive defects at mRNA and protein levels. Of these, two mutations caused pre-mRNA splicing errors that were predicted to result in premature protein truncation and three resulted in markedly reduced stability of exogenous TSC1 protein. Primary tumours with aberrantTSC1pre-mRNA splicing were confirmed as negative for TSC1 expression by immunohistochemistry. Expression was also significantly reduced in a tumour with aTSC1missense mutation resulting in diminished protein half-life. A singleTSC1missense mutation identified in a tumour with retained heterozygosity of theTSC1region on chromosome 9 caused an apparently TSC2- and mTOR-independent localization defect of the mutant protein. We conclude that althoughTSC1missense mutations do not play a major role in causation of TSC disease, they represent a significant proportion of somatic loss of function mutations in bladder cancer.

Bladder tumour-derived somatic TSC1 missense mutations cause loss of function via distinct mechanisms