Download Translocation renal cell carcinoma

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
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
Histology of Translocation RCC
Translocation RCC with TFE3. Mixed histology ( papillary and clear-cell)
French Juvenile RCC Network
Distribution of Cases According to Age (n=54)
Malouf GG et al. Journal of Urology, 2011
Overall Survival According to Metastatic Status (A) and Age (B)
Malouf GG et al. Journal of Urology, 2011
Outcomes with targeted therapies
A
B
C
Median PFS=7.1 months
Median OS=14.3 months
A : Malouf GG et al. Annals of Oncology, 2010
B & C: Choueiri TK et al. Cancer, 2010
Genomics of Translocation RCC Have Been Until Recently Poorly Understood
Cc-RCC
TRCC
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
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.
Malouf GG et al. Clinical Cancer Research, 2013
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
Workflow process of the fusion detection algorithm
implemented and applied to data from TCGA.
TCGA
dataset
(n=460)
No Translocation*
(n=379)
MITF
family
RCC
(n=7)
PRCC/TFE3 (n=5)
KHSRP/TFE3 (n=1)
KHDRBS2/TFEB (n=1)
Translocation
(n=81)
Previously
known
gene
fusions
(n=12)
Novel
fusions
(n=62)
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
The Two Tumors with KHSRP-TFE3 and TFEB-KHDBRS2
Bear the Highest Number of Translocations
DOCK8-JAK2
TFEB-KHDRBS2
KHSRP-TFE3
Malouf GG et al. Clinical Cancer Research, 2014
Identification of 2 Novel TFE3 and TFEB Partners, both
Involved in RNA splicing
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
Malouf GG et al. Clinical Cancer Research, 2014
Identification of Frequent Mutations in Chromatin Remodelers
in Translocation RCC
Malouf GG et al, Clinical Cancer Research , 2014
Activation of CTLA4 signaling in Xp11.2 cases with 17q gain
Malouf GG et al, Clinical Cancer Research , 2013
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
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
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