Papillary type 2 renal cell carcinoma: Characterization and observation of genetic changes during therapy with target agents and correlation to real patient's clinical course
Final Report Abstract
The project was modified before the start of the research fellowship, because of the development of incoming results on papillary renal cell carcinoma by a large cooperative study group. The focus of my research work was therefore set on chromophobe renal cell carcinoma. The resulting project was termed “Metastatic chromophobe renal cell carcinoma: genomic landscape and evolution of a rare disease”. Here we defined the molecular characteristics of the third most common subtype of renal cell carcinoma, chromophobe renal cell carcinoma. This subtype very rarely leads to metastatic disease, but for the affected patients there is no standard of care due to lack of knowledge of the underlying molecular pathogenesis. A recently published characterization of chromophobe RCC has unraveled the genomic underpinnings of this disease, however, the rare metastatic chromophobe RCC was not separately defined. We collected the to-date largest cohort of samples from patients with metastatic chromophobe renal cell carcinoma and studied primary tumors, but also metastatic tumors from a subset of selected patients, with multi-platform analysis (whole genome DNA sequencing, custom-target sequencing, DNA copy number analysis) and generated a model for the development of metastatic disease in chromophobe RCC. Our results improved the understanding of this rare and lethal disease and the knowledge of the existence of TP53 and PTEN mutations or imbalanced chromosomal duplication can potentially serve as prognostic biomarker and as target for future treatment options. Further the genomic database initiated with chromophobe RCC patients, was expanded to all patients with renal cell carcinoma treated at Memorial Sloan Kettering Cancer Center. By addition of publically available datasets on clear cell renal cell carcinoma, we were able to perform several analyses to define predictive genomic biomarkers. For instance, SETD2 mutations in clear cell renal cell carcinoma are associated with reduced progression free survival. Since the created database is constantly being updated, we are expecting more results in the near future that will lead to a more personalized follow-up for patients with localized disease and allow a novel molecular stratification of patients with metastatic disease based on the correlation of mutation status and response to systemic target treatment. Treatment response in metastatic patients was also recapitulated in preclinical mouse xenografts models generated with tissue from primary and metastatic tumors. The study of xenografts highlights the development of drug resistance mechanisms and will potentially promote the advancement of personalized medicine.
Publications
- Integration of Recurrent Somatic Mutations with Clinical Outcomes: A Pooled Analysis of 1049 Patients with Clear Cell Renal Cell Carcinoma. European Urology Focus, Published online: October 17, 2016
Brandon John Manley, Emily C. Zabor, Jozefina Casuscelli, Daniel M. Tennenbaum, Almedina Redzematovic, Maria F. Becerra, Nicole Benfante, Yusuke Sato,Teppei Morikaa, Haruki Kume, Masashi Fukuyama, Yukio Homma, Seishi Ogawa, Maria E. Arcila, Martin H. Voss, Darren R. Feldman, Jonathan A. Coleman, Victor E. Reuter, Robert J. Motzer, Paul Russo, James J. Hsieh, A. Ari Hakimi
(See online at https://doi.org/10.1016/j.euf.2016.06.015) - The difficulty in selecting patients for cytoreductive nephrectomy: An evaluation of previously described predictive models. Urol Oncol. 2017 Jan;35(1):35.e1-35.e5
Manley BJ, Tennenbaum DM, Vertosick EA, Hsieh JJ, Sjoberg DD, Assel M, Benfante NE, Strope SA, Kim E, Casuscelli J, Becerra MF, Coleman JA, Hakimi AA, Russo P
(See online at https://doi.org/10.1016/j.urolonc.2016.07.010) - Tumor Xenografts of Human Clear Cell Renal Cell Carcinoma But Not Corresponding Cell Lines Recapitulate Clinical Response to Sunitinib: Feasibility of Using Biopsy Samples. European Urology Focus, Published online: October 17, 2016
Yiyu Dong, Brandon J. Manley, Maria F. Becerra, Almedina Redzematovic, Jozefina Casuscelli, Daniel M. Tennenbaum, Ed Reznik, Song Han, Nicole Benfante, Ying-Bei Chen, Maria E. Arcila, Omer Aras, Martin H. Voss, Darren R. Feldman, Robert J. Motzer, Nicola Fabbri, John H Healey, Patrick J. Boland, Mohit Chawla, Jeremy C. Durack, Chung-Han Lee, Jonathan A. Coleman, Paul Russo, A. Ari Hakimi, Emily H. Cheng, James J. Hsieh
(See online at https://doi.org/10.1016/j.euf.2016.08.005) - Genomic alterations as predictors of survival among patients within a combined cohort with clear cell renal cell carcinoma undergoing cytoreductive nephrectomy. Urol Oncol. 2017 Apr 10. pii: S1078-1439(17)30116-3
Tennenbaum DM, Manley BJ, Zabor E, Becerra MF, Carlo MI, Casuscelli J, Redzematovic A, Khan N, Arcila ME, Voss MH, Feldman DR, Motzer RJ, Benfante Nicole E, Coleman JA, Russo P, Hsieh JJ, Hakimi AA
(See online at https://doi.org/10.1016/j.urolonc.2017.03.015)
