Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1

Division of Gastroenterology, Dana-Farber Cancer Institute, and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA. sapna_syngal@dfci.harvard,edu
Journal of Medical Genetics (Impact Factor: 6.34). 10/2000; 37(9):641-5.
Source: PubMed


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.
We 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.
Of 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).
The 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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    • "Studies of families meeting the Amsterdam criteria have identified germline MSH2 and MLH1 mutations with a relatively high sensitivity (~60 %) and specificity (~70 %). In contrast, germline MSH2 and MLH1 mutations were found with a higher sensitivity (~94 %) and a lower specificity (~30 %) when families meeting the Bethesda criteria were studied [12]. Compared with these two criteria, one of the differences is extracolonic cancers types. "
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    ABSTRACT: The aim of this study was to investigate the clinical value of different criteria and to understand the relationship between genotype and phenotype in Chinese hereditary nonpolyposis colorectal cancer (HNPCC). A total of 116 unrelated probands of suspected HNPCC families from the Fudan Colorectal Registry were studied. A total of 32, 28, and 56 families fulfilled the Amsterdam criteria, the Fudan criteria and the revised Bethesda guideline, respectively. Direct DNA sequencing of all exons of hMSH2 and hMLH1 genes were performed on all 116 samples. Mutations and clinicopathological features were compared between the groups. Thirty-two pathological germline mutations were identified. Out of 32 mutations, 16 were located at hMLH1 and 16 at hMSH2. The sensitivity of Amsterdam criteria was 50 %, specificity was 81 %, and Youden's index was 31 %. The sensitivity of Fudan criteria was 75 %, specificity was 58 %, and Youden's index was 33 %. Among all the 32 families with mutations, families with hMSH2 mutation had a higher ratio of synchronous and metachronous colon cancers than families with hMLH1 mutation (33 vs. 6 %, P = 0.04). Patients with hMSH2 mutation more frequently harbour synchronous and metachronous colon cancers. Fudan criteria had a little higher sensitivity and accuracy than Amsterdam criteria for identification of Chinese HNPCC.
    Medical Oncology 10/2014; 31(10):223. DOI:10.1007/s12032-014-0223-1 · 2.63 Impact Factor
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    • "Current laboratory algorithms detecting Lynch syndrome include MSI testing, immunochemistry (IHC) of MMR proteins, and germ line testing for mutations in MMR genes [7]. The sensitivity and specificity of BGs have been reported to be 94% and 25%, respectively [8]. As a result, a number of published studies [7,9] have approached colorectal carcinomas in terms of molecular biology and an effective strategy to detect Lynch syndrome. "
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    ABSTRACT: Purpose Sporadic colorectal cancers with high-frequency microsatellite instability (MSI-H) are related to hypermethylation of mismatch repair (MMR) genes and a higher frequency of BRAF mutations than Lynch syndrome. We estimated the feasibility of hereditary colorectal cancer based on hMLH1 methylation and BRAF mutations. Methods Between May 2005 and June 2011, we enrolled all 33 analyzed patients with MSI-H cancer (male:female, 23:10; mean age, 65.5 ± 9.4 years) from a prospectively maintained database that didn't match Bethesda guidelines and who had results of hMLH1 methylation and BRAF mutations. Results Among the 33 patients, hMLH1 promoter methylation was observed in 36.4% (n = 12), and was not significantly related with clinicopathologic variables, including MLH1 expression. BRAF mutations were observed in 33.3% of the patients (n = 11). Four of 11 and five of 22 patients with MSI-H colon cancers were BRAF mutation (+)/hMLH1 promoter methylation (-) or BRAF mutation (-)/hMLH1 promoter methylation (+). Of the 33 patients, 21.2% were BRAF mutation (+)/hMLH1 promoter methylation (+), indicating sporadic cancers. Seventeen patients (51.5%) were BRAF mutation (-)/hMLH1 promoter methylation (-), and suggested Lynch syndrome. Conclusion Patients with MSI-H colorectal cancers not fulfilling the Bethesda guidelines possibly have hereditary colorectal cancers. Adding tests of hMLH1 promoter methylation and BRAF mutations can be useful to distinguish them from sporadic colorectal cancers.
    Annals of Surgical Treatment and Research 09/2014; 87(3):123-30. DOI:10.4174/astr.2014.87.3.123
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    • "Fifteen patients had a normal expression of MLH1, MSH2 and MLH6, 8 patients had a doubtful expression (25.8%), and 8 patients showed markedly deficient expression of at least one MMR protein (25.8%). The clinical features of the 16 patients considered as having altered immunohistochemical expression of MMR protein(s) are as follows: 5/16 patients (31.2%) belonged to Amsterdam and 16/16 patients belonged to Bethesda criteria (due to the inclusion in group A of only younger than 50 year old cases) [15,16]; 8/16 patients (50%) had an association with other synchronous or metachronous extracolonic tumors; in 11/16 cases (68.7%) another colorectal cancer developed in the 4 generations analyzed for each patient; finally, 6/16 patients (37.5%) developed another subsequent colonic neoplasm (Table 2). A total of 37 cases of cancer were diagnosed, including colorectal (19), endometrium (6), breast (2), kidney (2), Vateri papilla (1), prostate (3), skin cancers (3) and lung (1). "
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    ABSTRACT: In clinical practice, unexpected diagnosis of colorectal cancer in young patients requires prompt surgery, thus genetic testing for Lynch Syndrome is frequently missed, and clinical management may result incorrect. Patients younger than 50 years old undergoing colorectal resection for cancer in the period 1994-2007 were identified (Group A, 49 cases), and compared to a group of randomly selected patients more than 50 (Group B, 85 cases). In 31 group A patients, immunohistochemical expression analysis of MLH1, MSH2 and MSH6 was performed; personal and familial history of patients with defective MMR proteins expression was further investigated, searching for synchronous and metachronous tumors in probands and their families. Fifty-one percent of patients did not express one or more MMR proteins (MMR-) and should be considered Lynch Syndrome carriers (16 patients, group A1); while only 31.2% of them were positive for Amsterdam criteria, 50% had almost another tumor, 37.5% had another colorectal tumor and 68% had relatives with colorectal tumor. This group of patients, compared with A2 group (< 50 years old, MMR+) and B group, showed typical characteristics of HNPCC, such as proximal location, mucinous histotype, poor differentiation, high stage and shorter survival. The present study confirms that preoperative knowledge of MMR proteins expression in colorectal cancer patients would allow correct staging, more extended colonic resection, specific follow-up and familial screening.
    BMC Surgery 02/2014; 14(1):9. DOI:10.1186/1471-2482-14-9 · 1.40 Impact Factor
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