Microsatellite instability in colorectal-cancer patients with suspected genetic predisposition

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Abstract
Hereditary non‐polyposis colorectal cancer (HNPCC) is a dominantly inherited syndrome linked to DNA‐mismatch‐repair (MMR) gene defects, which also account for microsatellite instability (MSI) in tumour tissues. Diagnosis is based mainly on family history, according to widely accepted criteria (Amsterdam Criteria: AC). Aim of this work was to assess MSI in colorectal‐cancer patients with suspected genetic predisposition, and to verify whether MSI represents a tool to manage MMR gene (hMSH2 and hMLH1) mutation analysis. We investigated 13 microsatellites (including the 5 NCI/ICG‐HNPCC markers) in 45 patients with suspected hereditary predisposition (including 16 subjects from HNPCC families fulfilling the AC). We found MSI‐H (high frequency of instability, i.e., in ≥30% of the markers) in 85% of the HNPCC patients and in 16% of the non‐HNPCC subjects. The 5 NCI/ICG‐HNPCC microsatellites proved to be the most effective in detecting MSI, being mononucleotide repeats the most unstable markers. We investigated the association between hMSH2‐ and hMLH1 gene mutations and MSI. Our results indicate that AC are highly predictive both of tumour instability and of MMR‐gene mutations. Therefore, as the most likely mutation carriers, HNPCC subjects might be directly analyzed for gene mutations, while to test for MSI in selected non‐HNPCC patients and to further investigate MMR genes in MSI‐H cases, appears to be a cost‐effective way to identify subjects, other than those from kindred fulfilling AC, who might benefit from genetic testing. Int. J. Cancer (Pred. Oncol.) 89:87–91, 2000.