Recurrent Novel and Potentially Targetable Genetic Alterations in High Grade, Invasive Urothelial Carcinoma of the Bladder
Hikmat A Al-Ahmadie, Gopa Iyer, Philip H Kim, John P Sfakianos, Ying-Bei Chen, Anuradha Gopalan, Samson W Fine, Satish K Tickoo, Bernard H Bochner, Dean F Bajorin, Victor E Reuter, Michael F Berger, David B Solit. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: A significant proportion of urothelial carcinoma (UC) will present at an advanced stage or will develop into advanced or metastatic disease after repeated recurrences. By then, such patients will have limited therapeutic options. This underscores the importance of identifying novel therapeutic approaches to managing these patients. With the advent of new small molecules targeting specific molecular aberrations, we sought to characterize a cohort of high grade UC using targeted genetic analysis to define the prevalence of known cancer genes and identify potential targets for therapy.
Design: We analyzed tumor and matched normal samples from 50 radical cystectomies resected for high grade, invasive UC. All samples were analyzed using a targeted, deep-sequencing assay designed to identify point mutations, indels, and copy number alterations in 275 cancer-associated genes.
Results: Somatic mutations in TP53 were the most common alteration, present in 29 (58%) samples. Nine samples contained mutations in RB (18%). Alterations in the PI3K/AKT/mTOR pathway were also observed (9 PIK3CA mutations, 3 MTOR, 3 PTEN, 2 AKT). These mutations were mostly non-overlapping. Non-overlapping mutations were present in FGFR3 (8 tumors), ERBB2 (6 tumors) and BRAF (3 tumors). Mutations in chromatin remodeling genes were also common including 18 (36%) tumors with mutations in KDM6A, 16 (32%) with mutations in ARID1A, and 11 (22%) with mutations in MLL2. Overall, 36% of all analyzed tumors harbored potentially targetable alterations in genes such as ERBB2, BRAF, and FGFR3.
Conclusions: High grade, invasive urothelial carcinoma is a genetically heterogeneous disease. In addition to common alterations in TP53, mutations in the genes involved in chromatin remodelling are relatively common, particularly KDM6A, ARID1A and MLL2. Some of the identified alterations have been successfully targeted in other solid tumors and may offer a novel therapeutic option for patients with advanced bladder cancer. Further clinical correlation is needed to determine the prognostic significance of these genetic events.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 2:00 PM
Proffered Papers: Section A, Tuesday Afternoon