Wilms tumor is the most common pediatric kidney cancer and is closely connected to kidney development. Mutafions in two genes, WT1 and beta-catenin, and epigenefic changes in the insulin-like growth factor 2 (IGF2) locus have been described but the genetic basis of the majority of cases remains unknown. Given that current treatment protocols for Wilms tumor achieve high success rates (85%), there is a pressing need for prognosfic markers that can guide clinical management but these have been difficult to define. We have recently identified a novel tumor suppressor located on the X chromosome, WTX, which is inactivated in 30% of Wilms tumor cases. We now propose to build on our initial findings to establish clinical correlates of WTX inacfivafion and to test the potenfial applicafion of WTX mutafions as markers of prognosis. We wil also define additional markers by identifying molecular pathways that are affected by WTX inactivation Together, these studies will achieve immediate translational goals by defining novel biomarkers in Wilms tumor and will further our understanding of this disease to allow the future development of biologically based therapies.
Specific aims : 1) To define clinical correlafions of WTX inactivation in Wilms tumor. We will analyze 200 Wilms tumors for WTX mutations and correlate our findings with disease outcomes and other clinical parameters such as age at presentation, stage at diagnosis, bilaterality and associated developmental malformafions. We will also develop a WTX polyclonal antibody and a Wilms tumor fissue microarray to test WTX protein levels. 2) Modeling WTX funcfion to identify pathways of potential clinical significance. We will use immunoprecipitation of tagged WTX followed by mass spectrometry to define interactions between WTX and other cellular components. The funcfional consequences of these interactions will be validated in vitro using kidney derived cell lines and in vivo using a WTX conditional knockout mouse. 3) Clinical validation of novel Wilms tumor markers. Genes involved in WTX related pathways will be tested for potenfial clinical applicafions as biomarkers by correlafing expression levels with clinical parameters. We will also test selected genes for mutafions in primary Wilms tumors. We anticipated that, by defining prognostic markers and furthering our knowledge of WTX related pathways in Wilms tumor, this project will have public health applications in the treatment of pediatric kidney cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
De Velasco, Guillermo; Je, Youjin; Bossé, Dominick et al. (2017) Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients. Cancer Immunol Res 5:312-318
Carey, Christopher D; Gusenleitner, Daniel; Lipschitz, Mikel et al. (2017) Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood 130:2420-2430
Kansy, Benjamin A; Concha-Benavente, Fernando; Srivastava, Raghvendra M et al. (2017) PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer. Cancer Res 77:6353-6364
Juneja, Vikram R; McGuire, Kathleen A; Manguso, Robert T et al. (2017) PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 214:895-904
Ott, Patrick A; Hu, Zhuting; Keskin, Derin B et al. (2017) An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547:217-221
Zhang, Ying; Kurupati, Raj; Liu, Ling et al. (2017) Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. Cancer Cell 32:377-391.e9
Abelin, Jennifer G; Keskin, Derin B; Sarkizova, Siranush et al. (2017) Mass Spectrometry Profiling of HLA-Associated Peptidomes in Mono-allelic Cells Enables More Accurate Epitope Prediction. Immunity 46:315-326
Zhang, Yiqun; Kwok-Shing Ng, Patrick; Kucherlapati, Melanie et al. (2017) A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. Cancer Cell 31:820-832.e3
Zhou, Jun; Mahoney, Kathleen M; Giobbie-Hurder, Anita et al. (2017) Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade. Cancer Immunol Res 5:480-492
Akbay, Esra A; Koyama, Shohei; Liu, Yan et al. (2017) Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade. J Thorac Oncol 12:1268-1279

Showing the most recent 10 out of 137 publications