Project description:Therapy-related acute myeloid leukemia (t-AML) is a severe complication of the cytotoxic therapy used for primary cancer treatment. The outcome of these patients is poor compared to people who develop de novo acute myeloid leukemia (p-AML). Chromosome abnormalities in t-AML are partly dependent on the induction agent. Partial or total losses of chromosome 5 and/or 7 are observed after therapy with alkylating agents. Balanced translocations, most of which involve 11q23 with MLL rearrangement, are found after treatment with the topoisomerase II inhibitor. Complex cases are also more frequent. The aim of this study was to compare t-AML to p-AML using high-resolution array CGH in order to identify gene-specific copy number abnormalities (CNA). Thirty t-AML versus thirty-six p-AML patient samples were studied. In t-AML, 99 CNAs were observed with 63 losses and 36 gains while the mean number was 3,3 per case. In p-AML, 64 CNAs were observed with 30 losses and 34 gains with a mean number of 1.78 per case. A few very complex cases (>8 chromosomal abnormalities) contributed considerably to the chromosomal burden in p-AML. Several minimal critical regions (MCR) that contain proteins and microRNA genes implicated in leukemogenesis were found in t-AML. On 7p15.2, a HOXA gene cluster involved in the processes of hematopoietic progenitor cell development and leukemogenesis was recurrently gained. Loss of a 5 Mb MCR located on 5q31.3q32 (142,91-148,19 Mb) was found distal to a previously described MCR; it harbored 29 genes. A 40kb deleted MCR pointed to RUNX1 on 21q22, a gene coding for a transcription factor implicated in frequent rearrangements in leukemia and in familial thrombocytopenia with susceptibility to AML. The sequence revealed no abnormality in 3 patients and a mutation in one patient, resulting in complete deficiency of RUNX1. In de novo AML a gain of 21q22<38,41-39,36> harboring ERG and ETS2 was observed in two patients with very complex rearrangements.

Project description:Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and might be more relevant preclinical models to evaluate effective therapeutic agents. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer models. From 86 unsupervised surgical colon sample collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinosis and 14 metastases. Our histological and molecular characterization of patient tumors, first passage on mice and later passages includes the sequence of key genes involved in CRC (ie APC, KRAS, TP53), CGH array and transcriptomic analysis. This comprehensive characterization demonstrates that our collection recapitulates the clinical situation regarding the histopathological and molecular diversity of colorectal cancers. Moreover, patient tumors and corresponding models are clustering together which gives the opportunity to look for relevant signatures and comparison studies between clinical and preclinical data. Hence, we performed pharmacological monotherapy studies with standard of care for colon cancer (5-FU, oxaliplatin, irinotecan, cetuximab). Through this extensive in vivo analysis, we have compared the molecular profile with the drug sensitivity of each tumor models, and run an equivalent of a cetuximab phase II clinical trial in a preclinical setting. Our results confirm the key role of KRAS mutation in the cetuximab resistance and demonstrate that such collection could bring benefit to evaluate novel targeted therapeutic strategies and potentially help the stratification strategy for cancer patients according to molecular marker. This set correspond to 82 CGH profiles, with 7 samples from patient tumor and 75 samples from mouse xenograft at different passages P0 to P9. All hybridizations are performed with Human CGH 244K Agilent arrays (amadid 014693) in dual color with Human DNA Promega (sex matched) as reference. ID for biosources without an -Px suffix correspond to tumor patients. ID with a suffix correspond to xenograft with 0 for the first passage.

Dataset Information

Comparative genomic hybridization of a mother and daughter with a familial translocation t(2;6)(p25;p21) balanced in the mother and unbalanced in the daughter to determine breakpoint location and contribute to a map of haplotolerant genes

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