Originally published as JCO Early Release 10.1200/JCO.2005.02.7227 on December 5 2005

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Multipopulation Analysis of Polymorphisms in Five Mononucleotide Repeats Used to Determine the Microsatellite Instability Status of Human Tumors

From the Institut National de la Santé et de la Recherche Médicale (INSERM) U434, Centre d'Etude du Polymorphisme Humain (CEPH); Service d'Anatomo-Pathologie, Hôpital Saint-Antoine, Paris, France; Dipartimento di Genetica e Microbiologica, University of Pavia, Pavia, Italy; Department of Obstetrics & Gynaecology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; and the Institute of Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel

Address reprint requests to Richard Hamelin, INSERM U434-CEPH, 27 rue Juliette Dodu, 75010 Paris, France; e-mail: richard.hamelin{at}cephb.fr

PURPOSE: Human gastrointestinal tumors with inactivated DNA mismatch repair system (microsatellite instability [MSI] tumors) have distinct molecular and clinicopathologic profiles, and are associated with favorable prognosis. There is evidence suggesting that colorectal cancer patients with MSI tumors respond differently to adjuvant chemotherapy as compared with patients with non-MSI tumors. Finally, determination of the MSI status has clinical application for assisting in the diagnosis of suspected hereditary cases. It is thus becoming increasingly recognized that testing for MSI should be conducted systematically in all human cancers potentially of this type. We recently described a pentaplex polymerase chain reaction of five mononucleotide repeats to establish the MSI status of human tumors, and showed that this assay was 100% sensitive and specific. Moreover, these markers are quasimonomorphic in germline DNA of the white population (ie, individuals of Eurasian origin), and could be used for tumor MSI determination without the requirement for matching normal DNA in this group.

PATIENTS AND METHODS: In this study, we analyzed a comparable panel of five mononucleotide markers in germline DNA from 1,206 individuals encompassing 55 different populations worldwide.

RESULTS: With the exception of two Biaka Pygmies and one San individual for whom three markers showed variant alleles (three cases [0.2%]), the remaining 1,203 individuals showed no alleles of variant size (1,055 cases [87.5%]), or only one (122 cases [10.1%]) or two (26 cases [2.2%]) markers with variant alleles. All 60 MSI tumors investigated display instability in at least four of the five markers.

CONCLUSION: We demonstrated that tumor MSI status can be determined using the pentaplex reaction for all human populations without the need for matching normal DNA.

Supported in part by Association de la Recherche Contre le Cancer, and an Interface grant from INSERM/Assistance Publique-Hôpitaux de Paris. Exchange agreements were obtained from INSERM–Consiglio Nazionale delle Ricerche and Procore-France/Hong-Kong Joint Research Scheme grants for Italy and Hong-Kong, respectively.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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• Microsatellite Instability Testing in Genetically Heterogeneous Populations
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