Translocation Renal Cell Carcinomas: Molecular insights and Future Directions

Transcription

1 Translocation Renal Cell Carcinomas: Molecular insights and Future Directions Gabriel G. Malouf, MD, PhD Assistant professor Department of medical oncology Pitié-Salpêtrière Hospital, Paris, France

2 Background Rare subtype of RCC introduced in 2004 as a genetically distinct entity in the WHO classification of renal tumors Incidence: one-third of pediatric RCC and ~15% of RCC in patients <45 years Translocations involving Xp11.2 (TFE3) and 6p21.1 (TFEB) Several fusion partners of TFE3 identified including PRCC, SFPQ, ASPSCR1, NONO, CLTC, LUC7L3 and KHSRP genes Two fusion partners of TFEB identified including KHDRBS2 and Alpha genes

3 Histology of Translocation RCC Translocation RCC with TFE3. Mixed histology ( papillary and clear-cell)

4 French Juvenile RCC Network Distribution of Cases According to Age (n=54) Malouf GG et al. Journal of Urology, 2011

5 Overall Survival According to Metastatic Status (A) and Age (B) Malouf GG et al. Journal of Urology, 2011

6 Outcomes with targeted therapies A B Median PFS=7.1 months C Median OS=14.3 months A : Malouf GG et al. Annals of Oncology, 2010 B & C: Choueiri TK et al. Cancer, 2010

7 Genomics of Translocation RCC Have Been Until Recently Poorly Understood TRCC Cc-RCC CGH-array? CGH-array 3p loss, 9p loss Transcriptome: Pathway enrichment? Comparison with cc-rcc? Comparison with papillary RCC? Novel partners? Transcriptome: cc-rcc: hypoxia pathway Mutations? Methylations? Mutations: VHL, PBRM1, SETD2, UTX, JARID1C Methylations VHL, KLHL35,QPCT, SCUBE3, ZSCAN18, CCDC8, FBN2, ATP5G2, PCDH8, CORO6

8 Malouf GG et al. Clinical Cancer Research, 2013 Tumors from Patients <18 years Harbor Fewer Genetic Abnormalities Compared with Tumors from Patients 18 years Age <18 years Age 18 years Cumulative frequency of chromosomal lesions in translocation RCC (n=16) subdivided by age less than 18 (n=5) and more than 18 years (n=11). Gains are indicated as positive values and losses as negative.

9 17q Gain Is the Most Frequent Abnormality in Adults with Translocation RCC and Is Associated with Poor Outcome Malouf GG et al. Clinical Cancer Research, 2013

10 Workflow process of the fusion detection algorithm implemented and applied to data from TCGA. TCGA dataset (n=460) No Translocation* (n=379) Translocation (n=81) MITF family RCC (n=7) Previously known gene fusions (n=12) Novel fusions (n=62) PRCC/TFE3 (n=5) KHSRP/TFE3 (n=1) KHDRBS2/TFEB (n=1) FHIT (n=2), SLC9A9 (n=2), AFF1 (n=1), MKL1 (n=1), LHFP (n=1), JAK2 (n=1), ELL (n=1), DCX (n=1), EP300 (n=1) & LNP1 (n=1) Malouf GG et al. Clinical Cancer Research, 2014

11 Malouf GG et al. Clinical Cancer Research, 2014 The Two Tumors with KHSRP-TFE3 and TFEB-KHDBRS2 Bear the Highest Number of Translocations DOCK8-JAK2 TFEB-KHDRBS2 KHSRP-TFE3

12 Identification of 2 Novel TFE3 and TFEB Partners, both Involved in RNA splicing Malouf GG et al. Clinical Cancer Research, 2014

13 Malouf GG et al. Clinical Cancer Research, 2014 Unsupervised clustering of the TCGA Reveals that Translocation RCC Display a Unique Gene Expression Signature No mutations in VHL PBRM1 BAP1

14 Identification of Frequent Mutations in Chromatin Remodelers in Translocation RCC Malouf GG et al, Clinical Cancer Research, 2014

15 Activation of CTLA4 signaling in Xp11.2 cases with 17q gain Malouf GG et al, Clinical Cancer Research, 2013

16 Translocation RCC Might be Derived from the Distal Nephron Long-non coding RNA classification of clear-cell RCC reveals four subtypes Cluster C4 is associated with CDH1 and CDH16 overexpression Malouf GG et al. Molecular Oncology, 2014

17 Future Directions Define the epigenetic alterations in adults versus pediatric cases in large dataset of patients Establish the first transcriptomic classification of translocation RCC Define the genetic alterations of aggressive cases as compared to cases with no recurrence Establish Xenografts to model disease Testing in vitro and in vivo novel agents targeting chromatin remodeling genes and/or immune checkpoints. Launch the first clinical trial in this setting

18 Acknowledgments MD Anderson Cancer Center, Houston, USA Nizar M. Tannir (medical oncology) Christopher G. Wood (Urology) Xiaoping Su (Bionformatics) Hui Yao (Bionformatics) Pitié-Salpêtrière Hospital, Paris, France: David Khayat Eva Compérat Olivier Cussenot Morgan Rouprêt Institut Gustave Roussy, Villejuif, France: Bernard Escudier Trousseau Hospital, Paris, France: Aurore Coulomb-L hermine CHU Lille, France: Xavier Leroy Necker Hospital, Paris, France: Virginie Verkarre