Molecular & Cancer Biomarkers

Biography

Biography: Mohammad O Hoque

Abstract

Over 90% of bladder cancer in the western world present as urothelial carcinoma (UC), from which non-muscle invasive urothelial cancers (NMIBC) is the most common histology at presentation (around 75%). NMIBC is usually treated by trans-urethral resection of bladder tumor (TURBT) where 20% of patients will be cured, 70% will recur at least once every 5 years, and the remaining will progress to muscle-invasive disease with poor prognosis. Currently there are no well validated markers that can discern the tumors at the time of diagnosis that will recur/progress from those that will not. Moreover, conventional approaches are not ideal to predict risk of recurrence/progression. Hence, it is crucial to develop molecular markers that can predict recurrence/progression at the time of diagnosis and such markers will allow a more individualized therapy based on a patient’s risk. Furthermore, it would also be important to develop a test that could provide cost-effective, non-invasive monitoring for low-risk patients, while using a more active approach to identify high-risk cancers before they progress. By a candidate gene approach, we analyzed the promoter methylation (PM) of 8 genes genes (ARF, TIMP3, RAR-β2, NID2, CCNA1, AIM1, CALCA and CCND2) by quantitative methylation specific PCR (QMSP) in DNA of 17 non-recurrent and 19 recurrent noninvasive low grade papillary urothelial carcinoma (LGPUC) archival tissues. Among the genes tested, by establishing an empiric cutoff value, CCND2, CCNA1, NID2, and CALCA showed higher frequency of methylation in recurrent than in non-recurrent LGPUCC: CCND2 10/19 (53%) vs. 2/17 (12%) (p=0.014); CCNA1 11/19 (58%) vs. 4/17 (23.5%) (p=0.048); NID2 13/19 (68%) vs. 3/17 (18%) (p=0.003) and CALCA 10/19 (53%) vs. 4/17 (23.5%) (p=0.097), respectively. We further analyzed PM of CCND2, CCNA1, and CALCA in urine DNA from UC patients including LGPUC and controls. The frequency of CCND2, CCNA1 and CALCA was significantly higher (p<0.0001) in urine of UC cases [38/148 (26%), 50/73 (68%) and 94/148 (63.5%) respectively] than controls [0/56 (0%), 10/60 (17%) and 16/56 (28.5%), respectively)]. Most importantly we found any one of the 3 markers methylation positive in 25 out of 30 (83%) cytology negative LGPUC cases. We also explored the biological function of CCNA1 in UC. Prospective confirmatory studies are needed to develop a reliable tool for prediction of recurrence using primary LGUC tissues and/or urine.