Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance.
OBJECTIVE
Hereditary nonpolyposis colorectal carcinoma (HNPCC) is caused by a mutated mismatch repair (MMR) gene. The aim of our study was to determine the cumulative risk of developing cancer in a large series of MSH6 mutation carriers.


METHODS
Mutation analysis was performed in 20 families with a germline mutation in MSH6. We compared the cancer risks between MSH6 and MLH1/MSH2 mutation carriers. Microsatellite instability (MSI) analysis and immunohistochemistry (IHC) were performed in the available tumors.


RESULTS
A total of 146 MSH6 mutation carriers were identified. In these carriers, the cumulative risk for colorectal carcinoma was 69% for men, 30% for women, and 71% for endometrial carcinoma at 70 years of age. The risk for all HNPCC-related tumors was significantly lower in MSH6 than in MLH1 or MSH2 mutation carriers (P = 0.002). In female MSH6 mutation carriers, the risk for colorectal cancer was significantly lower (P = 0.0049) and the risk for endometrial cancer significantly higher (P = 0.02) than in MLH1 and MSH2 mutation carriers. In male carriers, the risk for colorectal cancer was lower in MSH6 mutation carriers, but the difference was not significant (P = 0.0854). MSI analysis in colorectal tumors had a sensitivity of 86% in predicting a MMR defect. IHC in all tumors had a sensitivity of 90% in predicting a mutation in MSH6.


CONCLUSIONS
We recommend starting colonoscopic surveillance in female MSH6 mutation carriers from age 30 years. Prophylactic hysterectomy might be considered in carriers older than 50 years. MSI and IHC analysis are sensitive tools to identify families eligible for MSH6 mutation analysis.
Hendriks
Yvonne M C
YM
Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. y.m.c.hendriks@lumc.nl
Wagner
Anja
A
Morreau
Hans
H
Menko
Fred
F
Stormorken
Astrid
A
Quehenberger
Franz
F
Sandkuijl
Lodewijk
L
Møller
Pal
P
Genuardi
Maurizio
M
Van Houwelingen
Hans
H
Tops
Carli
C
Van Puijenbroek
Marjo
M
Verkuijlen
Paul
P
Kenter
Gemma
G
Van Mil
Anneke
A
Meijers-Heijboer
Hanne
H
Tan
Gita B
GB
Breuning
Martijn H
MH
Fodde
Riccardo
R
Wijnen
Juul Th
JT
Bröcker-Vriends
Annette H J T
AH
Vasen
Hans
H
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D002352:Carrier Proteins; D043171:Chromosomal Instability / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D033142:Genetic Services; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000209:etiology / Q000235:genetics; D009687:Nuclear Proteins; D012306:Risk
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; D000070957:MutL Protein Homolog 1