A rare MSH2 mutation causes defective binding to hMSH6, normal hMSH2 staining, and loss of hMSH6 at advanced cancer stage

Daria Carmela Loconte, Margherita Patruno, Patrizia Lastella, Carmela Di Gregorio, Valentina Grossi, Giovanna Forte, Giuseppe Ingravallo, Dora Varvara, Rosanna Bagnulo, Cristiano Simone, Nicoletta Resta, Alessandro Stella

Research output: Contribution to journalArticle

Abstract

Lynch syndrome is caused by germline mutations in 1 of the 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). Mutations in MSH2 cause concomitant loss of hMSH6, whereas MLH1 mutations lead to concurrent loss of PMS2. Much less frequent mutations in MSH6 or PMS2 are associated with the isolated loss of the corresponding proteins. We here demonstrate the causative role of the first germline mutation of MSH2, c.1249-1251 dupGTT (p.417 V-418I dupV), associated with normal hMSH2 expression and lack of hMSH6 protein despite a normal MSH6 gene sequence. hMSH6 protein was completely lost only in advanced cancer stages due to 2 different "second hits": a whole MSH2 gene deletion and a frame-shifting insertion in the MSH6 (C)8 repeat in the coding sequence.

Original languageEnglish
Pages (from-to)2162-2167
Number of pages6
JournalHuman Pathology
Volume45
Issue number10
DOIs
Publication statusPublished - Oct 1 2014

Keywords

  • Lynch syndrome
  • Mismatch repair
  • MSH2
  • MSH6
  • Second hit
  • Variants of unknown significance

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

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  • Cite this

    Loconte, D. C., Patruno, M., Lastella, P., Di Gregorio, C., Grossi, V., Forte, G., Ingravallo, G., Varvara, D., Bagnulo, R., Simone, C., Resta, N., & Stella, A. (2014). A rare MSH2 mutation causes defective binding to hMSH6, normal hMSH2 staining, and loss of hMSH6 at advanced cancer stage. Human Pathology, 45(10), 2162-2167. https://doi.org/10.1016/j.humpath.2014.05.019