title: Evidence of heterogeneity within colorectal liver metastases for allelic losses, mRNA level expression and in vitro response to chemotherapeutic agents.
abstract: A goal of oncology is to predict chemosensitivity of tumors. This approach assumes that in a patient all tumor deposits are homogeneous. We have tested the heterogeneity between several samples of the same liver metastasis (LM; intrametastatic heterogeneity) or between multiple LM (intermetastatic heterogeneity) from colorectal cancer in a single patient. In 16 untreated patients, several fragments of LM and nontumorous liver were collected. Heterogeneity to anticancer drug treatment was assessed in vitro on primary tissue cultures on poly-HEMA-coated surface with or without the topoisomerase-I inhibitor metabolite SN-38. Heterogeneity of response to SN-38 was observed in 55% of cases from one fragment to another in the same LM and in 64% of cases from one LM to another in the same patient. Allelic losses were characterized on 5q, 8p, 17p, 18q, 22q using 29 microsatellites markers. Seven patients (58%) had a perfect homogeneity for allelic losses in their LM whereas 3 (21%) had intrametastatic and 2 (18%) had intermetastatic heterogeneity. The analysis of gene expression was carried out by real time RT-PCR quantification using specific probes for TS, TOPO1, ERCC1, and CES2. Level expression of genes tested appeared heterogeneous with average variations of 57(+ or - 23)%, 52(+ or - 18)%, 53(+ or - 18)%, 56(+ or - 16)% for TS, TOPO1, ERCC1, and CES2 respectively for intermetastatic variability and 47(+ or - 26)%, 36(+ or - 14)%, 38(+ or - 19)%, and 56(+ or - 29)%, respectively for intrametastatic variability. Our results demonstrate intermetastatic and intrametastatic heterogeneity suggesting that pretherapeutic analysis of a single tumor biopsy is likely to lead to a misinterpretation of sensitivity to anticancer treatment.
authors.affiliation: Department of Gastroenterology, Université Paris V, Laboratoire de Toxicologie Moléculaire, Inserm UMR-S775 and AP-HP, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goasguen
authors.forename: Cecile
authors.initials: C
authors.lastname: de Chaisemartin
authors.forename: Antoine
authors.initials: A
authors.lastname: Brouquet
authors.forename: Catherine
authors.initials: C
authors.lastname: Julié
authors.forename: Gregoire P
authors.initials: GP
authors.lastname: Prevost
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Christophe
authors.initials: C
authors.lastname: Penna
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014644:Genetic Variation; D006801:Humans; D066298:In Vitro Techniques; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D019656:Loss of Heterozygosity / Q000235:genetics*; D011102:Polyhydroxyethyl Methacrylate / Q000737:chemistry / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D011102:Polyhydroxyethyl Methacrylate; D000077146:Irinotecan; D002166:Camptothecin