TY - JOUR

T1 - Functional characterization of rare missense mutations in MLH1 and MSH2 identified in Danish colorectal cancer patients

AU - Christensen, Lise Lotte

AU - Kariola, Reetta

AU - Korhonen, Mari K

AU - Wikman, Friedrik P

AU - Sunde, Lone

AU - Gerdes, Anne-Marie

AU - Okkels, Henrik

AU - Brandt, Carsten A

AU - Bernstein, Inge

AU - Hansen, Thomas V O

AU - Hagemann-Madsen, Rikke

AU - Andersen, Claus L

AU - Nyström, Minna

AU - Ørntoft, Torben F

AU - Christensen, Lise

AU - Kariola, Reetta

AU - Korhonen, Mari

AU - Wikman, Friedrik

AU - Sunde, Lone

AU - Gerdes, Anne-Marie

AU - Okkels, Henrik

AU - Brandt, Carsten

AU - Bernstein, Inge

AU - Hansen, Thomas

AU - Hagemann-Madsen, Rikke

AU - Andersen, Claus

AU - Nyström, Minna

AU - Orntoft, Torben

N1 - Keywords: Adaptor Proteins, Signal Transducing; Adult; Blotting, Western; Colorectal Neoplasms; Denmark; Female; Humans; Male; Middle Aged; MutS Homolog 2 Protein; Mutagenesis, Site-Directed; Mutation, Missense; Nuclear Proteins; Pedigree

PY - 2009

Y1 - 2009

N2 - Recently, we have performed a population based study to analyse the frequency of colorectal cancer related MLH1 and MSH2 missense mutations in the Danish population. Half of the analyzed mutations were rare and most likely only present in the families where they were identified originally. Some of the missense mutations were located in conserved regions in the MLH1 and MSH2 proteins indicating a relation to disease development. In the present study, we functionally characterized 10 rare missense mutations in MLH1 and MSH2 identified in 13 Danish CRC families. To elucidate the pathogenicity of the missense mutations, we carried out in vitro functional analyses. The missense mutations were analyzed for their effect on protein expression and repair efficiency. The results of the functional analysis were correlated with clinical data on the families carrying these mutations. Eight missense mutations resulted in proteins with expression and repair efficiency similar to the wild type. One missense mutation (MSH2 p.Met688Val) caused reduced protein expression and one (MSH2 p.Leu187Arg) caused both reduced protein expression and repair deficiency. The MSH2 p.Leu187Arg mutation was found in an Amsterdam II family presenting with high microsatellite instability and loss of MSH2 and MSH6 proteins in tumours. In conclusion, only 1/10 missense mutations displayed repair deficiency and could be classified as pathogenic. No final conclusion can be drawn on the MSH2 p.Met688Val mutation, which caused reduced protein expression. Although, no deficiencies have been identified in the proteins harbouring the other missense mutations, pathogenicity of these variants cannot be unambiguously excluded.

AB - Recently, we have performed a population based study to analyse the frequency of colorectal cancer related MLH1 and MSH2 missense mutations in the Danish population. Half of the analyzed mutations were rare and most likely only present in the families where they were identified originally. Some of the missense mutations were located in conserved regions in the MLH1 and MSH2 proteins indicating a relation to disease development. In the present study, we functionally characterized 10 rare missense mutations in MLH1 and MSH2 identified in 13 Danish CRC families. To elucidate the pathogenicity of the missense mutations, we carried out in vitro functional analyses. The missense mutations were analyzed for their effect on protein expression and repair efficiency. The results of the functional analysis were correlated with clinical data on the families carrying these mutations. Eight missense mutations resulted in proteins with expression and repair efficiency similar to the wild type. One missense mutation (MSH2 p.Met688Val) caused reduced protein expression and one (MSH2 p.Leu187Arg) caused both reduced protein expression and repair deficiency. The MSH2 p.Leu187Arg mutation was found in an Amsterdam II family presenting with high microsatellite instability and loss of MSH2 and MSH6 proteins in tumours. In conclusion, only 1/10 missense mutations displayed repair deficiency and could be classified as pathogenic. No final conclusion can be drawn on the MSH2 p.Met688Val mutation, which caused reduced protein expression. Although, no deficiencies have been identified in the proteins harbouring the other missense mutations, pathogenicity of these variants cannot be unambiguously excluded.

U2 - 10.1007/s10689-009-9274-4

DO - 10.1007/s10689-009-9274-4

M3 - Journal article

C2 - 19697156

VL - 8

SP - 489

EP - 500

JO - Familial Cancer

JF - Familial Cancer

SN - 1389-9600

IS - 4

ER -