Retention of CD44 introns in bladder cancer: Understanding the alternative splicing of pre‐mRNA opens new insights into the pathogenesis of human cancers

It is well accepted that dysregulation of gene expression plays a pivotal role in the tumourigenesis of human malignancy. Defects at a number of steps in the assembly and expression of a gene product from the complex transcriptional unit of higher eukaryotes may be involved in the production of malignancy or a metastatic phenotype. These include transcript initiation, transcriptional fidelity, pre-mRNA splicing, transcript termination, and transport. Overexpression of a normal or an activated gene product such as ras;'.* functional loss of expression of a gene product by inactivation, deletion, or sequestration such as RB-l;3 and the untimely expression of a gene product such as A F P have been in the first two examples directly linked to causal roles in the pathogenesis of cancer, and in the third case have become useful diagnostic markers of disease. Greater diagnostic emphasis has been placed on the strictly structural genetic changes associated with the origins of cancer such as nucleotide mutations (p53, k -r ~s -2 ) ~~~ and genetic recombination (t 9:22),' to name classical examples. This may be because rapid molecular analysis lends itself to technologies that are qualitative rather than quantitative and favour analysis of protein or DNA over RNA, due to its instability in a environment full of RNase. Thus, for a number of years, we have been aware of a role for RNA processing in the development of cancer but have seen few assays developed. A notable exception is the detection of chimeric RT-PCR products from haematolymphoid and solid tumour malignancies, for direct detection and measurement of these events involved in RNA metabolism.