A rareMSH2mutation causes defective binding to hMSH6, normal hMSH2 staining, and loss of hMSH6 at advanced cancer stage

Lynch syndrome is caused by germline mutations in 1 of the 4 DNA mismatch repair genes (MLH1,MSH2,MSH6, andPMS2). Mutations inMSH2cause concomitant loss of hMSH6, whereasMLH1mutations lead to concurrent loss of PMS2. Much less frequent mutations inMSH6orPMS2are associated with the isolated loss of t...

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Bibliographic Details
Published in:Human pathology 2014-10, Vol.45 (10), p.2162
Main Authors: Loconte, Daria Carmela, Patruno, Margherita, Lastella, Patrizia, Di Gregorio, Carmela, Grossi, Valentina, te, Giovan na, Ingravallo, Giuseppe, Varvara, Dora, Bagnulo, Rosanna, Simone, Cristiano, Resta, Nicoletta, Stella, Alessandro
Format: Article
Language:English
Subjects:
Colorectal cancer
Genes
Mutation
Tumors
Online Access:Get full text
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Summary:Lynch syndrome is caused by germline mutations in 1 of the 4 DNA mismatch repair genes (MLH1,MSH2,MSH6, andPMS2). Mutations inMSH2cause concomitant loss of hMSH6, whereasMLH1mutations lead to concurrent loss of PMS2. Much less frequent mutations inMSH6orPMS2are associated with the isolated loss of the corresponding proteins. We here demonstrate the causative role of the first germline mutation ofMSH2, c.1249-1251 dupGTT (p.417V-418I dupV), associated with normal hMSH2 expression and lack of hMSH6 protein despite a normalMSH6 gene sequence. hMSH6 protein was completely lost only in advanced cancer stages due to 2 different "second hits": a wholeMSH2gene deletion and a frame-shifting insertion in theMSH6(C)8repeat in the coding sequence.
ISSN:0046-8177
1532-8392
DOI:10.1016/j.humpath.2014.05.019