Mapping of the 7q31 subregion common to the small chromosome 7 derivatives from two sporadic papillary renal cell carcinomas: increased copy number and overexpression of the MET proto-oncogene

Glukhova, Liubov; Lavialle, Christian; Fauvet, Didier; Chudoba, Ilse; Danglot, Gisèle; Angevin, Eric; Bernheim, Alain; Goguel, A

doi:10.1038/sj.onc.1203397

Cited by 35 publications

(18 citation statements)

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“…The evaluation and development of novel therapeutics is further hampered by the lack of suitable in vitro and in vivo model systems. Here we describe the use of two PRCC PDX models, RCC-43b and RCC-47 (13,26). Detailed aCGH and FISH analysis confirmed that both PRCC PDX models are wild-type for MET and have increased MET copy number.…”

Section: Discussionmentioning

confidence: 99%

The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models

Schuller

Barry

Jones

et al. 2015

Clinical Cancer Research

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Purpose: Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occurring in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and antitumor response of the selective MET inhibitor AZD6094 in two PRCC patient-derived xenograft (PDX) models.Experimental Design: Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and antitumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared with the activity of the RCC standard-of-care sunitinib (in RCC43b) or the multikinase inhibitor crizotinib (in RCC47).Results: AZD6094 treatment resulted in tumor regressions, whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes, including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a doseand time-dependent induction of cleaved PARP, a marker of cell death.Conclusions: Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication.

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Section: Discussionmentioning

confidence: 99%

The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models

Schuller

Barry

Jones

et al. 2015

Clinical Cancer Research

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“…La trisomía 7 es característica pero no específica, pudiendo encontrarse también en tumores de vejiga, próstata y de cabeza y cuello, en la hiperplasia benigna de próstata y en otras enfermedades benignas. Sin embargo, es una alteración muy constante y frecuente en las fases tempranas de la enfermedad, lo que sugiere que los genes situados en él juegan un papel crítico en la patogenia de estos tumores 39 . La trisomía 17 es mucho más específica y valorable desde el punto de vista diagnóstico, pudiendo encontrarse trisomías completas, isocromosomas 17q, o duplicaciones de 17q21.…”

Section: Carcinoma Renal Papilar Esporádicounclassified

El espectro del carcinoma renal papilar

Ugalde

López²

2008

Actas Urológicas Españolas

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Objetivos: Los últimos años están asistiendo a la gran expansión conceptual del cáncer renal. La conjunción entre los hallazgos histológicos y los datos moleculares ha sido un punto clave en este fenómeno, y resultado de ello ha sido la clasificación de los tumores renales del adulto de la OMS de 2004. En ella se han unido viejos y nuevos tumores renales. Lejos de estar cerrada, esta clasificación se actualiza gracias a nuevos puntos de vista surgidos a la luz de los nuevos hallazgos que se obtienen fundamentalmente en el campo de la genética.Material y Métodos: El carcinoma papilar renal en el sentido más amplio del término es el objeto de revisión en este trabajo. Este fenotipo histológico en el cáncer renal es un buen ejemplo de evolución incesante de la anatomía patológica como disciplina clínica, con un crecimiento importante en los últimos tiempos.Resultados: El conjunto de neoplasias renales que muestran una histología papilar o túbulo-papilar, o que tienen su sustrato genético, algunas de las cuales son entidades muy recientes y están aún hoy en día en discusión, es amplio y variado: carcinoma papilar esporádico convencional, carcinomas papilares ligados a síndromes genéticos (carcinoma papilar hereditario, carcinoma papilar asociado a leiomiomatosis hereditaria, carcinoma papilar asociado a carcinoma papilar hereditario de tiroides, síndrome de Birt-Hogg-Dubé) o a alteraciones genéticas específicas (carcinomas papilares con translocación Xp11.2), carcinomas papilares con morfología peculiar (carcinoma micropapilar, carcinoma papilar invertido, carcinoma papilar con células fusiformes y túbulos angulados) y carcinomas renales de nuevo cuño englobados dentro del grupo del carcinoma papilar (carcinoma tubulo-quístico y carcinoma mucinoso, tubular y fusocelular).Conclusión: Además de las variedades clásicamente reconocidas, nuevas entidades, algunas no bien definidas aún, están engrosando de forma progresiva el grupo de carcinomas renales con morfología papilar. Lejos de agotarse, este crecimiento continuará en los próximos años a la luz de los nuevos hallazgos, y en éstos los patólogos tendrán mucho que decir.Palabras clave: Tumor renal. Clasificación de la OMS. Carcinoma papilar. Alteración genética. Histología. Diagnóstico diferencial. ABSTRACTPAPILLARY RENAL CELL CARCINOMA SPECTRUM Objectives: Significant conceptual expansion of renal cancer continues to increase. The key point to this phenomenon is based on the combination of morphology and molecular data. The result is the new 2004 WHO classification of renal tumors in adults. The apparently never ending advance in molecular genetics is constantly pushing to update recently proposed listings.Material and Methods: Papillary renal cell carcinoma, considered the term in the broader sense, is the subject of this study. This histological phenotype in renal cancer, with an accelerated growth in the last times, is a good example of the never ending evolution of pathology as a clinical discipline.Results: The genetic background and the phenotype of all renal ...

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“…58,108 Changes that were mostly found in sporadic papillary tumours were 2-or 3-fold gains of wildtype chromosome 7. 109 It is postulated that these gains may be sufficient to result in tumour formation without an activating mutation in the MET gene. 109 These gains are found in up to 80% of sporadic papillary forms of RCC, along with duplications of chromosome 17 or loss of the Y chromosome.…”

Section: Papillary Rccmentioning

confidence: 99%

“…109 It is postulated that these gains may be sufficient to result in tumour formation without an activating mutation in the MET gene. 109 These gains are found in up to 80% of sporadic papillary forms of RCC, along with duplications of chromosome 17 or loss of the Y chromosome. 110 A few cases of sporadic forms of papillary RCC have been associated with translocations involving chromosome X, in which it has been fused to the TFE3 transcription gene.…”

Section: Papillary Rccmentioning

confidence: 99%

Current understanding of the molecular mechanisms of kidney cancer: a primer for urologists

Lim

Pautler

2012

CUAJ

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Renal cell carcinoma (RCC), the fifth leading malignant condition for menand tenth for women, accounts for 3% of all malignancies in Canada. It is aheterogeneous epithelial malignancy with different subtypes and varied tumourbiology. Although most cases of RCC are sporadic, up to 4% of patients havean inherited predisposition for the disease. In this article, we review the currentmolecular genetics of the different subtypes in hereditary and sporadic RCC. Significant developments in understanding the underlying genetic basis of RCC over the last 2 decades are attributed to intensive research about rareinherited renal cancer syndromes and the identification of the genes responsiblefor them. Many of these genes are also found in sporadic RCC. Understanding the molecular mechanisms involved in the pathogenesis of RCC has aided the development of molecular-targeted drugs for this disease.

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Mapping of the 7q31 subregion common to the small chromosome 7 derivatives from two sporadic papillary renal cell carcinomas: increased copy number and overexpression of the MET proto-oncogene

Cited by 35 publications

References 31 publications

The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models

The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models

El espectro del carcinoma renal papilar

Current understanding of the molecular mechanisms of kidney cancer: a primer for urologists

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