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a Dipartimento di
Medicina Interna, Università di Modena, Italy, b Dipartimento di Scienze
Morfologiche e Medico-Legali, Università di Modena, c Divisione di Anatomia Patologica, Ospedale di
Carpi, Modena, d Istituto
di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy, e Divisione di Oncologia Sperimentale A, Centro di
Riferimento Oncologico, Aviano, Pordenone, Italy
Correspondence to: Dr M Ponz de Leon, Dipartimento di Medicina Interna, Medicina III, Policlinico, Via del Pozzo 71, 41100 Modena, Italy.
Accepted for publication 2 February 1999
BACKGROUND
Hereditary
non-polyposis colorectal cancer (HNPCC) is one of the most common
inherited disorders predisposing to cancer. The genes responsible for
the disease have recently been cloned and characterised; their
mutations induce a generalised genomic instability which is
particularly evident at microsatellite loci (replication error (RER)+ phenotype).
AIMS
To investigate
how to select individuals and families in the general population who
should be screened for constitutional mutations predisposing to
colorectal cancer.
PATIENTS/METHODS
Between
1984 and 1995, 1899 colorectal malignancies in 1831 patients were
registered, and in 1721 of these (94%), family trees could be
obtained. Patients and families were classified into five categories
according to a more or less likely genetic basis: HNPCC;
"suspected" HNPCC; juvenile cases; aspecific cancer aggregation; sporadic cases. In 18 families with HNPCC as well as in 18 with suspected HNPCC, microsatellite instability in tumour tissues and
constitutional mutations of two DNA mismatch repair genes (MSH2 and MLH1)
could be evaluated. RER status was studied with five markers
(BAT40, D2S123,
D18S57, D17S787,
and BAT26) in paraffin embedded tissues.
Germline mutations of MSH2 or
MLH1 genes were assessed on DNA and RNA
extracted from lymphomonocytic cells, using reverse transcription
polymerase chain reaction, single strand conformation polymorphism
analysis, and direct DNA sequencing.
RESULTS
HNPCC
represented 2.6% and suspected HNPCC 4.6% of all registered
colorectal neoplasms. Eleven out of 18 HNPCC families (61%) showed
microsatellite instability as opposed to four (of 18) suspected HNPCC
(22%; p<0.02). Three germline mutations (two in
MSH2 and one in
MLH1 gene) were found in three different
large HNPCC families, whereas no mutations were detected in suspected HNPCC.
CONCLUSIONS
In this
study of cancer genetic epidemiology, data from a tumour registry were
analysed and this ultimately led to the identification and selection of
families that should be tested for mutator gene mutations. With the use
of a population based approach, the incidence of mutations was
appreciably lower than previously reported and limited to families with
full blown HNPCC. It is possible that in most families with a clinical
spectrum of HNPCC (or suspected HNPCC) other DNA mismatch repair genes
are involved in the pathogenesis of the disease.
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