Chemotherapeutic implications in microsatellite unstable colorectal cancer¹

Issue title: Lynch Syndrome (HNPCC) and Microsatellite Instability Guidelines – Part 2

Guest editors: Asad Umar

Article type: Research Article

Authors: Jo, Won-Seok^a | Carethers, John M.^{a; b; c; *}

Affiliations: [a] Department of Medicine, University of California, San Diego, CA, USA | [b] Rebecca and John Moores Comprehensive Cancer Center, University of California, San Diego, CA, USA | [c] VA San Diego Healthcare System, San Diego, CA, USA | Gastrointestinal & Other Cancers Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, 6130 Executive Blvd, Rockville, MD 20852, USA

Correspondence: [*] Corresponding author: John M. Carethers, M.D., GI Section [111D], VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. Tel.: +1 858 642 1109; Fax: +1 858 552 4327; E-mail: [email protected].

Note: [1] Supported by the US Public Health Service [CA90231 and DK067287], the California Department of Health Services Cancer Research Program, and the University of California Cancer Research Coordinating Committee.

Abstract: Chemotherapy for colorectal cancer is currently offered to patients based on the stage of their cancer, and there is evidence to show an overall survival benefit with 5-fluorouracil-based (5-FU) therapy for patients with lymph node metastasis who receive it. The pathogenesis of colorectal cancer involves genomic instability, with about 15% of tumors demonstrating a form of genomic instability called high-frequency microsatellite instability (MSI-H) and due to loss of DNA mismatch repair function, and the remainder of colorectal tumors lacking MSI-H with retained DNA mismatch repair function and called microsatellite stable (MSS), with a large proportion of these tumors demonstrating another form of genomic instability called chromosomal instability. There is now evidence to show that the form of genomic instability that is present in a patient's colorectal cancer may predict a survival benefit from 5-FU. In particular, patients whose colorectal tumors have MSI-H do not gain a survival benefit with 5-FU as compared to patients with MSS tumors. In vitro evidence supports these findings, as MSI-H colon cancer cell lines are more resistant to 5-FU compared to MSS cell lines. More specifically, components of the DNA mismatch repair system have been shown to recognize and bind to 5-FU that becomes incorporated into DNA and which could be a trigger to induce cell death. The binding and subsequent cell death events would be absent in colorectal tumors with MSI-H, which have lost intact DNA mismatch repair function. These findings suggest that: (a) tumor cytotoxicity of 5-FU is mediated by DNA mechanisms in addition to well-known RNA mechanisms, and (b) patients whose tumors demonstrate MSI-H may not benefit from 5-FU therapy. Future studies should include a better understanding of the cellular mechanisms of the DNA recognition of 5-FU, multi-centered prospective trials investigating the survival benefit of 5-FU based on genomic instability, and the investigation of alternative chemotherapeutic regimens for patients with MSI-H tumors to improve survival.

Keywords: DNA mismatch repair, microsatellite instability, colorectal cancer, chemotherapy, treatment

DOI: 10.3233/CBM-2006-21-206

Journal: Cancer Biomarkers, vol. 2, no. 1-2, pp. 51-60, 2006