Evidence of heterogeneity within colorectal liver metastases for allelic losses, mRNA level expression and in vitro response to chemotherapeutic agents
✍ Scribed by Nicolas Goasguen; Cecile de Chaisemartin; Antoine Brouquet; Catherine Julié; Gregoire P. Prevost; Pierre Laurent-Puig; Christophe Penna
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- French
- Weight
- 619 KB
- Volume
- 127
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
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(±23)%, 52(±18)%, 53(±18)%, 56(±16)% for TS, TOPO1, ERCC1, and CES2 respectively for intermetastatic variability and 47(±26)%, 36(±14)%, 38(±19)%, and 56(±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.