All together, co-existence of Aurora-A overexpression and Ha-ras mutation suggests a possible additively effect on the tumorigenesis of bladder cancer.
The c-Ha-ras-1 locus was studied by Southern blotting in white blood cells and tumor samples obtained from 126 patients with bladder cancer (74 Ta-T1 and 52 T2-T4).
The observation that these cell lines have p53 and Ha-ras mutations identical to those in bladder carcinoma cell line T24 prompted us to investigate their possible interrelations.
HRAS1 genotype may be related to the prognosis of bladder cancer, however, because incident cases, i.e., newly diagnosed cases had a higher frequency of rare alleles than did prevalent cases, i.e., cases already existing at the time of recruitment.
DNA sequence analysis of the activated oncogene from the T24 human bladder carcinoma line and two alleles of its normal cellular progenitor (c-Ha-ras-1) indicates that the genes encompass at least four exons, and that only a single point mutation residing within the first exon distinguishes the coding region of both alleles of the normal gene from their activated counterpart.
On the other hand, deletion of one Ha-ras allele was observed in 1 of 5 cases of bladder cancer and in 2 of 3 cases of renal pelvic cancer, suggesting that that deletion may be important in the development of urothelial cancer.
It is evident from our study that HRAST81C SNP moderately increases bladder cancer risk, and rare allele is a predictive marker of advanced bladder tumors.
Analysing only previously reported point mutations, TERT mutations were found in 55% of patients with bladder cancer (independent of stage), FGFR3 mutations in 30% of patients with bladder cancer, PIK3CA in 14% and TP53 mutations in 12% of patients with bladder cancer.
In view of these findings, the authors investigated the incidence of TD mutations in the FGFR3 gene in a large series of bladder carcinomas to clarify their role in the progression of bladder carcinoma.
We carried out a meta-analysis of published findings for FGFR3 and TP53 mutations in bladder cancer (535 tumours, 6 publications) and additional unpublished data for 382 tumours.
In non-invasive BC, these mutations were related to high risk and grade (p<0.0001) as well as progression to muscle-invasive disease (p=0.01), whereas FGFR3 mutations were observed in low-grade BC (p=0.02) and patients with recurrences (p=0.05).
PATIENT SUMMARY: We propose that APOBEC-mediated mutagenesis can generate clinically relevant driver mutations even within suboptimal motifs, such as in the case of FGFR3S249C, one of the most common mutations in bladder cancer.