Germ line mutations of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients with small bowel cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study.
OBJECTIVE
The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC).


METHODS
A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regarding patients with HNPCC-associated SBC and germ line mismatch repair gene mutations.


RESULTS
The study population consisted of 85 HNPCC patients with identified mismatch repair gene mutations and SBCs. SBC was the first HNPCC-associated malignancy in 14 of 41 (34.1%) patients for whom a personal history of HNPCC-associated cancers was available. The study population harbored 69 different germ line mismatch repair gene mutations, including 31 mutations in MLH1, 34 in MSH2, 3 in MSH6, and 1 in PMS2. We compared the distribution of the mismatch repair mutations in our study population with that in a control group, including all pathogenic mismatch repair mutations of the International Society for Gastrointestinal Hereditary Tumours database (excluding those in our study population). In patients with MSH2 mutations, patients with HNPCC-associated SBCs had fewer mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019) but an increased frequency of mutations in codons 626 to 733, a domain that has not previously been associated with a known function, versus the control group (26.5% versus 2.8%, P < 0.001).


CONCLUSIONS
In HNPCC patients, SBC can be the first and only cancer and may develop as soon as the early teens. The distribution of MSH2 mutations found in patients with HNPCC-associated SBCs significantly differed from that found in the control group (P < 0.001).
Park
Jae-Gahb
JG
Korean Hereditary Tumor Registry, Laboratory of Cell Biology, Cancer Research Institute and Cancer Research Center, Seoul National University College of Medicine, Korea. jgpark@plaza.snu.ac.kr
Kim
Duck-Woo
DW
Hong
Chang Won
CW
Nam
Byung-Ho
BH
Shin
Young-Kyoung
YK
Hong
Sung-Hye
SH
Kim
Il-Jin
IJ
Lim
Seok-Byung
SB
Aronson
Melyssa
M
Bisgaard
Marie Luise
ML
Brown
Gregor J
GJ
Burn
John
J
Chow
Elizabeth
E
Conrad
Peggy
P
Douglas
Fiona
F
Dunlop
Malcolm
M
Ford
James
J
Greenblatt
Marc S
MS
Heikki
Jarvinen
J
Heinimann
Karl
K
Lynch
Elly L
EL
Macrae
Finlay
F
McKinnon
Wendy C
WC
Möeslein
Gabriela
G
Rossi
Benedito Mauro
BM
Rozen
Paul
P
Schofield
Lyn
L
Vaccaro
Carlos
C
Vasen
Hans
H
Velthuizen
Mary
M
Viel
Alessandra
A
Wijnen
Juul
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004379:Duodenal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007078:Ileal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D007580:Jejunal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D016609:Neoplasms, Second Primary / Q000175:diagnosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D011237:Predictive Value of Tests; D011795:Surveys and Questionnaires
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes