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SAN FRANCISCO, CA USA (UroToday.com) - Identification of new therapeutic targets in patients with metastatic bladder cancer is badly needed.

gucancerssympalt thumbToward that aim, Dr. Jonathan Rosenberg (MSKCC) and colleagues have attempted to provide a comprehensive landscape of molecular alterations in patients with bladder cancer. Using tissue from 131 patients with chemotherapy-naïve MIBC, whole exome sequencing and SNP arrays were performed. In total, 32 genes demonstrated significant levels of recurrent somatic mutations. Combined analysis of significantly mutated genes (SMGs) and genes with somatic copy number alterations (SCNA) revealed three groups with distinct differences in the pattern of genomic alteration.

  • Genes regulating epigenetic machinery are more involved in urothelial cancer than any other tumor type identified to date
  • At least three separate and distinct molecular pathways of bladder cancer pathogenesis have been identified
  • A number of distinct therapeutic targets within the PI3K/AKT/mTOR and RTK/MAPK pathways have been identified via molecular analysis and profiling

Group A is highly enriched in focal SCNAs in several genes, as well as mutations in MLL2. Group B is enriched in papillary histology, loss of CDKN2A, and alterations in FGFR3. Group C has TP53 mutations, enrichment with RB1 mutations, and amplifications of E2F3 and CCNE1. Interestingly, there was no association between smoking and any specific SMG’s or SCNA’s. Combined analysis identified unique therapeutic targets in 69% of specimens examined, mainly in the PI3K/AKT/mTOR and RTK/MAPK pathways. Seventy-six percent of tumors had at least one inactivating mutation in epigenetic regulatory genes, and 41% had two mutations. Genes regulating epigenetic machinery were frequently mutated, and the distinct “groupings” observed may indicate three separate pathways of bladder cancer pathogenesis. Urothelial carcinoma has a high mutation rate, and genomic clustering suggests the existence of several different oncogenic mechanisms. Exploration of epigenetic-modifying therapy is warranted.

Targeting epigenetic regulatory pathways may hold promise for future therapies. Further, many of the mutated pathways identified are treatable with either currently approved drugs or others in clinical development.

Highlights of a presentation by Jonathan E. Rosenberg, MD at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA

Memorial Sloan Kettering Cancer Center, New York, NY USA

Click HERE to listen to an exclusive interview with one of the authors of this study

Click HERE to view the poster from this session

Written by Jeffrey J. Tomaszewski, MD, medical writer for UroToday.com

View Full 2014 GU Cancers Symposium Coverage

 

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