Molecular Characterization and Therapeutic Targeting of TFE Fusion - - PDF document

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Molecular Characterization and Therapeutic Targeting of TFE Fusion Kidney Cancers

Srinivas R. Viswanathan, MD, PhD Dana-Farber Cancer Institute 10-22-2020

Translocation renal cell carcinoma (tRCC)

Overview

• Aggressive type of non-clear cell renal

cell carcinoma.

• Distinct subtype of RCC (WHO, 2016)
• Characterized by in-frame gene fusions

involving a member of the MIT/TFE transcription factor family (TFEB, TFEC, TFE3, MiTF)

Moch et al., Eur Urol, 2016

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Translocation renal cell carcinoma (tRCC)

Epidemiological/Clinical Features

• 30-40% of pediatric RCC; 1-5% of adult RCC
• Incidence in adults may be underestimated due

to morphological

• verlap

with

• ther

RCC subtypes

• Median age ~ 40 (for both TFE3 and TFEB tRCC)
• Female to male predominance
• Associated with prior exposure to chemotherapy

(secondary malignancy)

• Lymph node metastases predominate

Caliò et al., Cancers, 2019

Translocation renal cell carcinoma (tRCC)

Pathological Features

• Can mimic other common subtypes of RCC
• Many different architectural and cytologic

features possible

• Papillary architecture with epithelioid clear

cells and abundant psammoma bodies most distinctive

Caliò et al., Cancers, 2019; Crumley et al., WJCC, 2013 Clear cell pattern Papillary pattern Cystic pattern

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Translocation renal cell carcinoma (tRCC)

Diagnosis

• PAX2/8+CK7-
• Melanocyte markers may be positive (Melan-A;

HMB45)

• Cathepsin K positive in ~50%
• IHC for TFE3 protein can detect overexpressed

nuclear TFE3 due to translocation but poor PPV.

• Caveats: false positives from detection of native TFE3;

detection is highly fixation-dependent

• Break-apart FISH highly sensitive and specific
• Caveat: split signals can be very close in cases of

fusions arising via intrachromosomal inversion

Green et al., AJSP, 2013; Crumley et al., WJCC, 2013

Structure of TFE Fusions

TFE3 fusions

• In-frame fusions that produce a chimeric

protein product

• C-terminal exons of TFE3 (bHLH-LZ +/- AD) and

N-terminal exons from one of several fusion partners

TFEB fusions

• Typically MALAT1-TFEB gene fusions with

breakpoints before the start codon in TFEB

• Retention of complete TFEB coding sequence

Fusion partner TFE3 TFE3 fusion Shatha AbuHammad; Kauffman et al., Nat Rev Urol., 2014 TFE3 Fusion Structure

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TFE3 fusion partners

• > 15 different TFE3 fusion

partners have been described

• Most common:
• PRCC-TFE3:

t(X;1)(p11.2;q21)

• ASPL-TFE3:

t(X;17)(11.2;q25)

• SFPQ-TFE3:

t(X;1)(p11.2;p34)

• Many partners are RNA

binding proteins or nuclear proteins

ASPL DVL2 FUBP1 FUBP2 EWSR1 GRIPAP1 CLTC MATR3 MED15 NONO PRCC RBM10 SFPQ U2FA2 SETD1B RBMX LUC7L3 PARP14

RRM PLD KH RGG Domains Shatha AbuHammad

TFE3 fusion partners and the mechanisms that produce fusions

• TFE3 fusions usually arise via

balanced (reciprocal) translocation

• Both intra- and inter-

chromomal rearrangement partners

• Some chromosomal locations

harbor multiple TFE3 partners

chrX chr17 Argani et al., Am. J. Path., 2001; Cheng-Zhong Zhang

chr1 chrX 150 155 160 165 40 45 50 55 1 2 3

Genome Coordinate (Mb)

PRCC-TFE3 fusion in a male

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The molecular landscape of tRCC

• tRCC cohorts have been profiled by

targeted panel/WES

• MIT/TFE fusions are universal
• Few other recurrent alterations
• Mutations in chromatin remodeling

genes

• TERT promoter mutations
• Arm-level copy number events relatively

common and may be associated with disease aggressiveness.

Malouf et al., CCR, 2013/14; Marcon et al., CCR, 2020 From Marcon et al., CCR, 2020

Prior RCC sequencing studies contain tRCC samples

• Several prior large-scale ccRCC,

pRCC, chRCC sequencing efforts each contain a small number of “mis-classified” tRCCs

• Pooling tRCC data across these

large datasets may provide increased power to more precisely define the molecular landscape of tRCC

Ziad Bakouny; Nebiyou Metaferia; Toni Choueiri

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Prior RCC sequencing studies contain tRCC samples

• The transcriptional

program in tRCC is quite distinct from that of other RCC subtypes

Ziad Bakouny; Nebiyou Metaferia; Toni Choueiri

tRCC has distinct clinical features from other RCC subtypes

Variable N (%) Sex Male Female 24 (36) 42 (64) Age at diagnosis, median (range) 48 (15-89) Initial disease extent Localized Subsequent relapse Metastatic (de novo) 42 (64) 14 (33) 24 (36) History of childhood cancer 1 (2) Prior chemotherapy 4 (6)

Praful Ravi; Ziad Bakouny; Toni Choueiri; IMDC

Variable N (%) Sex Male Female De novo metastatic disease Male Female 29 (51) 28 (49) 18 (45) 22 (55) Age at diagnosis, median (range) 42 (15-78) Prior chemotherapy 4 (7) IMDC risk at 1st line therapy Good Intermediate/Poor 4 (7) 53 (93)

Institutional Cohort (localized & metastatic) IMDC (metastatic) OS Time

• Female predominance (localized dz)
• Subset have exposure to prior to

chemotherapy

• OS poor compared with ccRCC and

chRCC

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Selectively targeting tRCC

• TFE3 fusions are a selective

vulnerability of tRCC cells

ccRCC tRCC

Potential therapeutic targets in tRCC

Theraputic Target Reference RET Baba, M. et al. Mol Cancer Res, 201 MET Tsuda, M. et al. Cancer research, 2007 Kobos, R. et al. The Journal of pathology, 2013 NAMPT nicotinamide phosphoribosyltransferase Kobos, R. et al. The Journal of pathology, 2013 WNT Calcagni, A. et al. Elife, 2016 mTORC1/2 Kauffman, E. C. et al. BMC Cancer, 2019 IRS-1/PI3K/AKT/mTOR Damayanti et al. CCR, 2018

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Conclusions

• tRCC is clinically aggressive compared with other RCC subtypes and

further research into this subtype of RCC remains an unmet need

• Molecular landscape of tRCC is emerging
• Several molecular pathways downstream of MIT/TFE fusions have

been nominated as therapeutic targets

Acknowledgements

Viswanathan Lab

• Shatha AbuHammad
• Jiao Li
• Vidya Sethunath
• Emma Garner
• Nebiyou Metaferia
• Stephen Tang
• Ziad Bakouny
• Praful Ravi
• Thomas Denize
• Jack Steinharter
• Gabrielle Bouchard
• Catherine Curran
• Jinyu Wang
• Richard Tourdot
• Gregory Brunette
• Tarek Bismar
• Shaan Dudani
• Daniel Heng
• Sabina Signoretti
• Cheng-Zhong Zhang
• Toni Choueiri
• IMDC

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