Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study.
OBJECTIVE
Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer.


METHODS
Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1.


RESULTS
Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P <.01), high mucinous component (P <.01), and poor differentiation (P =.002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations.


CONCLUSIONS
We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.
Percesepe
A
A
Department of Internal Medicine, University of Modena, Modena, Italy. percesepe.antonio@unimo.it
Borghi
F
F
Menigatti
M
M
Losi
L
L
Foroni
M
M
Di Gregorio
C
C
Rossi
G
G
Pedroni
M
M
Sala
E
E
Vaccina
F
F
Roncucci
L
L
Benatti
P
P
Viel
A
A
Genuardi
M
M
Marra
G
G
Kristo
P
P
Peltomäki
P
P
Ponz de Leon
M
M
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D012042:Registries
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; 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