Genetics and Epigenetics of Bladder Cancer

Bladder cancer(BC) is the fourth most common type of cancer in men. Several types of BCare classified by the type of cancerous cell in the tissue. BC is typicallysporadic, associated with somatic mutations. In rare cases, however, the riskof BC runs in families with autosomal dominant pattern. Genetic causativefactors in BC are categorized in genetic and epigenetic alterations as well aschromosomal aberrations. Firstly, targeted gene panel sequencing have beencomprehensively designed to detect somatic mutations assisting with diagnosisof most cases. TP۵۳, AKT۱, ERBB۲, ERBB۳,KRAS, NRAS, HRAS, BRAF, PIKC۳A, C۳orf۷۰,ERCC۲, RHOB, CDKN۱A, CDKN۲A, FBXW۷, RXRA,CTNNB۱, CREBPP, FGFR۳, SF۳B۱, TERT, KDM۶Aand ELF۳ are considered as the most relevant genes in BC pathogenesis. Some of these genes areinvolved in p۵۳/RB pathway signaling, FGFR۳and RAS-MAPK signaling pathways, and PI۳K/mTOR pathway. Secondly, epigenetic alterations, occurring in variousgrades and stages of BC, are investigated as follows: ۱) DNA methylation is postulated as early-driver events in urothelial tumorigenesis. ۲) DNA hydroxymethylation (۵hmC) is mediatedby Ten-Eleven Translocation (TET)enzymes, presenting low activity in bladder tumors. ۳) Histone modifications play crucial roles in regulating fundamentalbiological processes including gene expression, DNA replication, and DNA damagerepair. Histone H۳K۹ and H۳K۲۷ methylation and histone H۳K۹hypoacetylation is linked to the multiple regional epigenetic silencing (MRES)phenotype in bladder cancer cells. ۴) Nucleosome positioningfunctionsas gene expression repressors by blocking transcription machinery binding topromoter sites. DNA methylation and histone modificationsaffect nucleosome positioning patterns. ۵) MicroRNAs playa key role in regulating gene expression as oncogenes(such as miR-۱۸۳, miR-۹۶, miR۱۷-۵p, and miR-۲۰a) or tumor suppressors (such asmiR-۱۴۵, miR-۱۴۳, and miR۱۲۵b). These molecules also affect otherepigenetic regulators. Finally, leading to oncogene formation, chromosomal rearrangements might initiatetumorigenesis. For instance, patients with tumors harboring deletions of chr۹ havemore rapid recurrence. Chr۹ deletions also affect some tumor suppressor genes.Genome-wide targeting ofgenetic/epigenetic alternations in BC have provided the opportunity to develop novel methods tomonitor early tumors and recurrence, and to achieve personalized therapies. UsingDNMT inhibitors and HDAC inhibitors, BC has been considered for epigenetic therapy. Moreover, clinical trials are being performed to explore the effectiveness ofTGF-β inhibitors combined with NK cell-based therapies.

کلیدواژه ها:

Bladder Cancer ، Chromosomal aberrations ، Epigenetics ، Genetics ، Personalized therapy