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(623)%, 52(618)%, 53(618)%, 56(616)% for TS, TOPO1, ERCC1, and CES2 respectively for intermetastatic variability and 47(626)%, 36(614)%, 38(619)%, and 56(629)%, 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.Colorectal carcinoma is one of the most prevalent cancer in western countries.1,2 Nearly 50% of patients suffering from colorectal cancer develop distant metastases at some point during the course of their disease, which represents the main cause of cancer related death. In case of liver metastases, treatment is based upon surgical resection but only 10-20% of metastases are amenable to resection.3 Patients with multiple liver metastases receive systemic chemotherapy.The increasing number of active cytotoxic drugs and targeted therapies has placed clinicians in front of a broad spectrum of therapeutic options. [4][5][6][7][8] Predictive factors for the response to chemotherapy are currently extensively studied in order to identify markers of chemosensitivity or chemoresistance which could guide oncologists for the choice of the most effective drug for a given patient. [9][10][11][12][13][14][15] To date, most of these studies aiming to determine a molecular signature of the tumor are conducted from DNA or RNA extracted from a single tumor biopsy either on primary tumor or metastases.Validity of such an approach predicting chemosensitivity is based on the clonality of molecular alterations within the tumor and metastases, in other word considering that all part of the tumor and all tumor deposits (i.e., primary and metastases) have the same m...

Primary Colorectal Cancers and Their Subsequent Hepatic Metastases Are Genetically Different: Implications for Selection of Patients for Targeted Treatment

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Impact of Systemic Therapy and Recurrence Pattern on Survival Outcome after Radiofrequency Ablation for Colorectal Liver Metastases

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Regional differences in prostaglandin E2 metabolism in human colorectal cancer liver metastases

“…Moreover, there are conflicting data on 15-PGDH expression in gastric cancer [12]. Heterogeneity of 15-PGDH expression in human cancers may reflect tissue-specific differences in regulatory pathways upstream of 15-PGDH [12], but may also be related to sampling variation secondary to intra-tumoral genetic and micro-environmental influences on 15-PGDH expression [13,14]. …”