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a Division of
Gastroenterology, Dana-Farber Cancer Institute, and Harvard Medical
School, 44 Binney Street, Boston, Massachusetts 02115, USA, b Brigham and Women's Hospital, Population
Sciences, Boston, Massachusetts, USA, c Charles A Dana Human Cancer Genetics
Unit, Dana-Farber Cancer Institute, and Harvard Medical School, Boston,
Massachusetts, USA, d Ludwig
Institute of Cancer Research, La Jolla, California, USA
Correspondence to: Dr Syngal, sapna_syngal@dfci.harvard,edu
Revised version received 20 April 2000;
Accepted for publication 3 May 2000
BACKGROUND AND AIMS
There are
multiple criteria for the clinical diagnosis of hereditary
non-polyposis colorectal cancer (HNPCC). The value of several of the
newer proposed diagnostic criteria in identifying subjects with
mutations in HNPCC associated mismatch repair genes has not been
evaluated, and the performance of the different criteria have not been
formally compared with one another.
METHODSWe classified 70 families
with suspected hereditary colorectal cancer (excluding familial
adenomatous polyposis) by several existing clinical criteria for HNPCC,
including the Amsterdam criteria, the Modified Amsterdam criteria, the
Amsterdam II criteria, and the Bethesda criteria. The results of
analysis of the mismatch repair genes MSH2
and MLH1 by full gene sequencing were
available for a proband with colorectal neoplasia in each family. The
sensitivity and specificity of each of the clinical criteria for the
presence of MSH2 and
MLH1 mutations were calculated.
RESULTSOf the 70 families, 28 families fulfilled the Amsterdam criteria, 39 fulfilled the Modified
Amsterdam Criteria, 34 fulfilled the Amsterdam II criteria, and 56 fulfilled at least one of the seven Bethesda Guidelines for the
identification of HNPCC patients. The sensitivity and specificity of
the Amsterdam criteria were 61% (95% CI 43-79) and 67% (95% CI
50-85). The sensitivity of the Modified Amsterdam and Amsterdam II
criteria were 72% (95% CI 58-86) and 78% (95% CI 64-92),
respectively. Overall, the most sensitive criteria for identifying
families with pathogenic mutations were the Bethesda criteria, with a
sensitivity of 94% (95% CI 88-100); the specificity of these criteria
was 25% (95% CI 14-36). Use of the first three criteria of the
Bethesda guidelines only was associated with a sensitivity of 94% and
a specificity of 49% (95% CI 34-64).
CONCLUSIONSThe Amsterdam criteria
for HNPCC are neither sufficiently sensitive nor specific for use as a
sole criterion for determining which families should undergo testing
for MSH2 and MLH1
mutations. The Modified Amsterdam and the Amsterdam II criteria
increase sensitivity, but still miss many families with mutations. The most sensitive clinical criteria for identifying subjects with pathogenic MSH2 and
MLH1 mutations were the Bethesda Guidelines; a streamlined version of the Bethesda Guidelines may be more specific and easier to use in clinical practice.
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