Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium.
OBJECTIVE
The aim of the study was the analysis of the involvement and phenotypic manifestations of MSH6 germline mutations in families suspected of hereditary nonpolyposis colorectal cancer (HNPCC).


METHODS
Patients were preselected among 706 families by microsatellite instability, immunohistochemistry, and/or exclusion of MLH1 or MSH2 mutations and were subjected to MSH6 mutation analysis. Clinical and molecular data of MSH6 mutation families were compared with data from families with MLH1 and MSH2 mutations.


RESULTS
We identified 27 families with 24 different pathogenic MSH6 germline mutations, representing 3.8% of the total of the families, and 14.7% of all families with DNA mismatch repair (MMR) gene mutations (n = 183). The median age of onset of colorectal cancer in putative mutation carriers was 10 years higher for MSH6 (54 years; 95% CI, 51 to 56) compared with MLH1 and MSH2 (44 years; 95% CI, 43 to 45; log-rank test, P = .0038). Relative to other malignant tumors, colorectal cancer was less frequent in MSH6 families compared with MLH1 and MSH2 families (Fisher's exact test, P < .001). In contrast, the frequency of non-HNPCC-associated tumors was increased (Fisher's exact test, P < .001).


CONCLUSIONS
Later age of disease onset and lower incidence of colorectal cancer may contribute to a lower proportion of identified MSH6 mutations in families suspected of HNPCC. However, in approximately half of these families, at least one patient developed colorectal or endometrial cancer in the fourth decade of life. Therefore, a surveillance program as stringent as that for families with MLH1 or MSH2 mutations is recommended.
Department of Surgical Research, Dresden University of Technology, Dresden, Germany. plaschke@rcs.urz.tu-dresden.de
Jens
J
Plaschke
Christoph
C
Engel
Stefan
S
Krüger
Elke
E
Holinski-Feder
Constanze
C
Pagenstecher
Elisabeth
E
Mangold
Gabriela
G
Moeslein
Karsten
K
Schulmann
Johannes
J
Gebert
Magnus
M
von Knebel Doeberitz
Josef
J
Rüschoff
Markus
M
Loeffler
Hans K
HK
Schackert
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D017668:Age of Onset; D000368:Aged; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology* / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012307:Risk Factors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein