High frequency of hereditary colorectal cancer in Newfoundland likely involves novel susceptibility genes.
OBJECTIVE
Newfoundland has one of the highest rates of colorectal cancer in North America. The most common hereditary form of colorectal cancer is hereditary nonpolyposis colorectal cancer caused by mutations in genes involved in mismatch repair. Our purpose was to determine the proportion of hereditary colorectal cancer and to determine the genetic basis of disease in both population and clinically referred cohorts from Newfoundland.


METHODS
Seventy-eight colorectal cancer patients were accrued over a 2-year period from the Avalon Peninsula of Newfoundland. We also examined 31 hereditary nonpolyposis colorectal cancer-like families, which had been referred to the Provincial Medical Genetics Program. Tumors from probands were tested by immunohistochemistry for deficiencies in MLH1, MSH2, and MSH6 proteins and tested for DNA microsatellite instability. Mutation analyses of MLH1, MSH2, and MSH6 were undertaken by direct sequencing and an assay to detect deletions, amplifications, and rearrangements in MSH2 and MLH1.


RESULTS
We identified eight population-based families that fulfill the Amsterdam I or II criteria, 4 (50%) of which seem to have hereditary cancer not attributable to the most commonly mutated mismatch repair genes. In addition, in 16 of 21 (76%) referred families fulfilling Amsterdam I or II criteria, no mutations were found in the three most commonly altered mismatch repair genes, and tumor analyses corroborated these findings.


CONCLUSIONS
It seems that strong and novel genetic causes of hereditary colorectal cancer are responsible for a high proportion of colorectal cancer in this population. Conditions are suitable for the identification of these genes by linkage studies of large Newfoundland cancer families.
Woods
Michael O
MO
Discipline of Genetics, Department of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada. mwoods@mun.ca
Hyde
Angela J
AJ
Curtis
Fiona K
FK
Stuckless
Susan
S
Green
Jane S
JS
Pollett
Aaron F
AF
Robb
J Desmond
JD
Green
Roger C
RC
Croitoru
Marina E
ME
Careen
Amanda
A
Chaulk
Jason A W
JA
Jegathesan
Jegan
J
McLaughlin
John R
JR
Gallinger
Steven S
SS
Younghusband
H Banfield
HB
Bapat
Bharati V
BV
Parfrey
Patrick S
PS
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000367:Age Factors; D000368:Aged; D020137:Base Pair Mismatch; D002352:Carrier Proteins / Q000235:genetics; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D019175:DNA Methylation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008957:Models, Genetic; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D009523:Newfoundland and Labrador; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein