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

Fingerprint

Germ-Line Mutation
Staining and Labeling
Mutation
Hereditary Nonpolyposis Colorectal Neoplasms
Neoplasms
Proteins
DNA Mismatch Repair
Gene Deletion
Genes

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Cite this

A rare MSH2 mutation causes defective binding to hMSH6, normal hMSH2 staining, and loss of hMSH6 at advanced cancer stage. / Loconte, Daria Carmela; Patruno, Margherita; Lastella, Patrizia; Di Gregorio, Carmela; Grossi, Valentina; Forte, Giovanna; Ingravallo, Giuseppe; Varvara, Dora; Bagnulo, Rosanna; Simone, Cristiano; Resta, Nicoletta; Stella, Alessandro.

In: Human Pathology, Vol. 45, No. 10, 01.10.2014, p. 2162-2167.

Research output: Contribution to journalArticle

Loconte, DC, 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, vol. 45, no. 10, pp. 2162-2167. https://doi.org/10.1016/j.humpath.2014.05.019
Loconte, Daria Carmela ; Patruno, Margherita ; Lastella, Patrizia ; Di Gregorio, Carmela ; Grossi, Valentina ; Forte, Giovanna ; Ingravallo, Giuseppe ; Varvara, Dora ; Bagnulo, Rosanna ; Simone, Cristiano ; Resta, Nicoletta ; Stella, Alessandro. / A rare MSH2 mutation causes defective binding to hMSH6, normal hMSH2 staining, and loss of hMSH6 at advanced cancer stage. In: Human Pathology. 2014 ; Vol. 45, No. 10. pp. 2162-2167.
@article{05f0298af34e4f6c9df9dc9debafa60d,
title = "A rare MSH2 mutation causes defective binding to hMSH6, normal hMSH2 staining, and loss of hMSH6 at advanced cancer stage",
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.",
keywords = "Lynch syndrome, Mismatch repair, MSH2, MSH6, Second hit, Variants of unknown significance",
author = "Loconte, {Daria Carmela} and Margherita Patruno and Patrizia Lastella and {Di Gregorio}, Carmela and Valentina Grossi and Giovanna Forte and Giuseppe Ingravallo and Dora Varvara and Rosanna Bagnulo and Cristiano Simone and Nicoletta Resta and Alessandro Stella",
year = "2014",
month = "10",
day = "1",
doi = "10.1016/j.humpath.2014.05.019",
language = "English",
volume = "45",
pages = "2162--2167",
journal = "Human Pathology",
issn = "0046-8177",
publisher = "W.B. Saunders Ltd",
number = "10",

}

TY - JOUR

T1 - A rare MSH2 mutation causes defective binding to hMSH6, normal hMSH2 staining, and loss of hMSH6 at advanced cancer stage

AU - Loconte, Daria Carmela

AU - Patruno, Margherita

AU - Lastella, Patrizia

AU - Di Gregorio, Carmela

AU - Grossi, Valentina

AU - Forte, Giovanna

AU - Ingravallo, Giuseppe

AU - Varvara, Dora

AU - Bagnulo, Rosanna

AU - Simone, Cristiano

AU - Resta, Nicoletta

AU - Stella, Alessandro

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.

AB - 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.

KW - Lynch syndrome

KW - Mismatch repair

KW - MSH2

KW - MSH6

KW - Second hit

KW - Variants of unknown significance

UR - http://www.scopus.com/inward/record.url?scp=84908210130&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908210130&partnerID=8YFLogxK

U2 - 10.1016/j.humpath.2014.05.019

DO - 10.1016/j.humpath.2014.05.019

M3 - Article

C2 - 25106712

AN - SCOPUS:84908210130

VL - 45

SP - 2162

EP - 2167

JO - Human Pathology

JF - Human Pathology

SN - 0046-8177

IS - 10

ER -