title: Tracking sub-clonal TP53 mutated tumor cells in human metastatic renal cell carcinoma.
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.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, Paris, France.|INSERM, Paris, France.|AP-HP-Hôpital Saint-Louis, Service d'Oncologie Médicale, Paris, France.
authors.forename: Guilhem
authors.initials: G
authors.lastname: Bousquet
authors.affiliation: INSERM, Paris, France.|AP-HP-Hôpital Saint-Louis, Service d'Oncologie Médicale, Paris, France.
authors.forename: Morad
authors.initials: M
authors.lastname: El Bouchtaoui
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, Paris, France.|INSERM, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Leboeuf
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, Paris, France.|INSERM, Paris, France.|AP-HP-Hôpital Saint-Louis, Service de Pathologie, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Battistella
authors.affiliation: INSERM, Paris, France.
authors.forename: Mariana
authors.initials: M
authors.lastname: Varna
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, Paris, France.|INSERM, Paris, France.
authors.forename: Irmine
authors.initials: I
authors.lastname: Ferreira
authors.affiliation: INSERM, Paris, France.
authors.forename: Louis-François
authors.initials: LF
authors.lastname: Plassa
authors.affiliation: Centre Hospitalier de Marne-la-Vallée, Service d'Oncologie Médicale, Jossigny, France.
authors.forename: Diaddin
authors.initials: D
authors.lastname: Hamdan
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, Paris, France.|INSERM, Paris, France.|AP-HP-Hôpital Saint-Louis, Service de Pathologie, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertheau
authors.affiliation: INSERM, Paris, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Feugeas
authors.affiliation: AP-HP-Hôtel-Dieu, Service de Pathologie, Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Damotte
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, Paris, France.|INSERM, Paris, France.|AP-HP-Hôpital Saint-Louis, Service de Pathologie, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D016158:Genes, p53; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: TP53 mutation; human RCC; metastases; sub-clonal tumor cells; tumor heterogeneity