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Tracking sub-clonal TP53 mutated tumor cells in human metastatic renal cell carcinoma

2015; Impact Journals LLC; Volume: 6; Issue: 22 Linguagem: Inglês

10.18632/oncotarget.4220

1949-2553

Guilhem Bousquet, Morad El Bouchtaoui, Christophe Lebœuf, Maxime Battistella, Mariana Varna, Irmine Ferreira, Louis‐François Plassa, Diaddin Hamdan, Philippe Bertheau, Jean‐Paul Feugeas, Diane Damotte, Anne Janin,

Renal and related cancers

// Guilhem Bousquet 1,2,3 , Morad El Bouchtaoui 2,3 , Christophe Leboeuf 1,2 , Maxime Battistella 1,2,4 , Mariana Varna 2 , Irmine Ferreira 1,2 , Louis-François Plassa 2 , Diaddin Hamdan 5 , Philippe Bertheau 1,2,4 , Jean-Paul Feugeas 6 , Diane Damotte 7 and Anne Janin 1,2,4 1 Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, Paris, France 2 INSERM, Paris, France 3 AP-HP-Hôpital Saint-Louis, Service d’Oncologie Médicale, Paris, France 4 AP-HP-Hôpital Saint-Louis, Service de Pathologie, Paris, France 5 Centre Hospitalier de Marne-la-Vallée, Service d’Oncologie Médicale, Jossigny, France 6 INSERM, Paris, France 7 AP-HP-Hôtel-Dieu, Service de Pathologie, Paris, France Correspondence to: Guilhem Bousquet, email: // Anne Janin, email: // Keywords : metastases, human RCC, tumor heterogeneity, sub-clonal tumor cells, TP53 mutation Received : December 21, 2014 Accepted : April 10, 2015 Published : May 20, 2015 Abstract Renal Cell Carcinomas ( RCCs) are heterogeneous tumors with late acquisition of TP53 abnormalities during their evolution. They harbor TP53 abnormalities in their metastases . We aimed to study TP53 gene alterations in tissue samples from primary and metastatic RCCs in 36 patients followed up over a median of 4.2 years, and in xenografted issued from primary RCCs. In 36 primary RCCs systematically xenografted in mice, and in biopsies of metastases performed whenever possible during patient follow-up, we studied p53-expressing tumor cells and TP53 gene abnormalities. We identified TP53 gene alterations in primary tumors, metastases and xenografts. Quantification of tumors cells with TP53 gene alterations showed a significant increase in the metastases compared to the primary RCCs, and, strikingly, the xenografts were similar to the metastases and not to the primary RCCs from which they were derived. Using laser-microdissection of p53-expressing tumor cells, we identified TP53 -mutated tumor cells in the xenografts derived from the primary RCC, and in a lung metastasis later developed in one patient. The mutation enabled us to track back their origin to a minority sub-clone in the primary heterogeneous RCC. Combining in situ and molecular analyses, we demonstrated a clonal expansion in a living patient with metastatic RCC .