Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability

Francesca Duraturo, Raffaella Liccardo, Angela Cavallo, Marina De Rosa, Giovanni Battista Rossi, Paola Izzo

Research output: Contribution to journalArticlepeer-review

Abstract

Loss of function of mismatch repair (MMR) genes, mainly MLH1 and MSH2, manifests as high levels of microsatellite instability (MSI) that occurs in >90% of carcinomas in patients with Lynch syndrome (LS). The MSI-high status has also been described in sporadic colorectal cancer (CRC) associated with BRAF gene mutation (V600E); this mutation was not present in LS-associated cancers. The present study performed MSI analysis on 39 CRC patients selected according to Bethesda guidelines, and BRAF V600E genotyping was performed in 26 cases classified as MSI-high or MSI-low (15 MSI-H and 11 MSI-L). These 26 patients were then screened for MLH1 and MSH2 germ-line mutations. Germ-line mutations in these genes were detected in 11/15 patients with MSI-H tumors (73%) and in 1/11 patients with MSI-L tumors (9%). Overall, 11 germ-line mutations in 12/26 analyzed patients (46%) in these genes were identified. Two of these mutations are novel genetic MLH1 variants not previously described in the literature, c.438A>G and c.1844T>C. A combination of computational approaches, co-segregation analysis and RNA assay suggested that these novel mutations, silent and missense, respectively, were probably pathogenic. The findings of the present study further emphasized the requirement for genetic testing in patients with a risk for hereditary CRC and has broadened the spectrum of known mutations of the MLH1 gene.

Original languageEnglish
Pages (from-to)511-517
Number of pages7
JournalInternational Journal of Molecular Medicine
Volume36
Issue number2
DOIs
Publication statusPublished - Aug 1 2015

Keywords

  • Colorectal cancer
  • Computational analysis
  • Lynch syndrome
  • Microsatellite instability
  • MLH1 gene
  • Novel mutations
  • RNA assay
  • Segregation analysis

ASJC Scopus subject areas

  • Genetics

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