Hereditary colorectal cancer in the general population: from cancer registration to molecular diagnosis

Leòn, Maurizio Ponz de; Pedroni, Monica; Benatti, Piero; Percesepe, Antonio; Gregorio, Carmela Di; Foroni, Moira; Rossi, Giuseppina; Genuardi, Maurizio; Neri, Giovanni; Leonardi, Francesca; Viel, Alessandra; Capozzi, E; Boiocchi, Mauro; Roncucci, Luca

doi:10.1136/gut.45.1.32

Cited by 53 publications

(30 citation statements)

References 44 publications

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“…To reconfirm the MSS status or to reveal putative instabilities in other than the recommended markers, we performed an extended microsatellite analysis with 1 mononucleotide (BAT40), 3 dinucleotide (D10S197, D13S153, D18S58), and 1 tetranucleotide (MYCL1) repeats. These 5 microsatellites were chosen since they had been shown to also be useful in HNPCC screening [27, 28, 29]. Among them, especially MYCL1 has been shown to have a relatively high instability rate [22].…”

Section: Discussionmentioning

confidence: 99%

Extended Microsatellite Analysis in Microsatellite Stable, MSH2 and MLH1 Mutation-Negative HNPCC Patients: Genetic Reclassification and Correlation with Clinical Features

Schiemann¹,

Müller-Koch

Gross³

et al. 2004

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Background: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder predisposing to predominantly colorectal cancer (CRC) and endometrial cancer frequently due to germline mutations in DNA mismatch repair (MMR) genes, mainly MLH1, MSH2 and also MSH6 in families seen to demonstrate an excess of endometrial cancer. As a consequence, tumors in HNPCC reveal alterations in the length of simple repetitive genomic sequences like poly-A, poly-T, CA or GT repeats (microsatellites) in at least 90% of the cases. Aim of the Study: The study cohort consisted of 25 HNPCC index patients (19 Amsterdam positive, 6 Bethesda positive) who revealed a microsatellite stable (MSS) – or low instable (MSI-L) – tumor phenotype with negative mutation analysis for the MMR genes MLH1 and MSH2. An extended marker panel (BAT40, D10S197, D13S153, D18S58, MYCL1) was analyzed for the tumors of these patients with regard to three aspects. First, to reconfirm the MSI-L phenotype found by the standard panel; second, to find minor MSIs which might point towards an MSH6 mutation, and third, to reconfirm the MSS status of hereditary tumors. The reconfirmation of the MSS status of tumors not caused by mutations in the MMR genes should allow one to define another entity of hereditary CRC. Their clinical features were compared with those of 150 patients with sporadic CRCs. Results: In this way, 17 MSS and 8 MSI-L tumors were reclassified as 5 MSS, 18 MSI-L and even 2 MSI-H (high instability) tumors, the last being seen to demonstrate at least 4 instable markers out of 10. Among all family members, 87 malignancies were documented. The mean age of onset for CRCs was the lowest in the MSI-H-phenotyped patients with 40.5 ± 4.9 years (vs. 47.0 ± 14.6 and 49.8 ± 11.9 years in MSI-L- and MSS-phenotyped patients, respectively). The percentage of CRC was the highest in families with MSS-phenotyped tumors (88%), followed by MSI-L-phenotyped (78%) and then by MSI-H-phenotyped (67%) tumors. MSS tumors were preferentially localized in the distal colon supposing a similar biologic behavior like sporadic CRC. MSH6 mutation analysis for the MSI-L and MSI-H patients revealed one truncating mutation for a patient initially with an MSS tumor, which was reclassified as MSI-L by analyzing the extended marker panel. Conclusion: Extended microsatellite analysis serves to evaluate the sensitivity of the reference panel for HNPCC detection and permits phenotype confirmation or upgrading. Additionally, it confirms the MSS status of hereditary CRCs not caused by the common mutations in the MMR genes and provides hints to another entity of hereditary CRC.

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Section: Discussionmentioning

confidence: 99%

Extended Microsatellite Analysis in Microsatellite Stable, MSH2 and MLH1 Mutation-Negative HNPCC Patients: Genetic Reclassification and Correlation with Clinical Features

Schiemann¹,

Müller-Koch

Gross³

et al. 2004

Digestion

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“…In Modena, the families were identified through a multistep approach based on a colorectal cancer registry instituted in 1984 (Ponz de Leon et al, 1987;Ponz de Leon et al, 1999). All tumours of the large bowel diagnosed in the population (265 227 residents at the 1991 census) were registered.…”

Section: Selection Of Familiesmentioning

confidence: 99%

“…Details of the procedure have already been given (Pedroni et al, 1999). Briefly, formalin-fixed and paraffin-embedded tumour samples from the affected subjects in each family were sectioned at 6 mm, deparaffined and rehydrated.…”

Section: Msh2 Mlh1 and Msh6 Protein Expressionmentioning

confidence: 99%

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Genetic testing among high-risk individuals in families with hereditary nonpolyposis colorectal cancer

et al. 2004

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Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected -that is, with HNPCC-related cancer diagnosis -and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or 'fatalistic' attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (Po0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we are unable to provide adequate protection against cancer development in these families.

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“…According to the Amsterdam I criteria, 3 the incidence of HNPCC is 2 to 3 percent of all CRC. [4][5][6] The HNPCC phenotype depends on germline mutations of DNA mismatch repair (MMR) genes (MSH2, MLH1, PMS1, PMS2, MSH6, and MLH3); the mutations induce a generalized genomic instability, with variations in the length of the short repeat DNA sequences, referred to as microsatellite instability (MSI). [7][8][9] Family history ascertainment is the most effective available tool for identifying HNPCC families.…”

mentioning

confidence: 99%

Early-Age-at-Onset Colorectal Cancer and Microsatellite Instability as Markers of Hereditary Nonpolyposis Colorectal Cancer

Pucciarelli¹,

Agostini²,

Viel³

et al. 2003

Diseases of the Colon &Amp; Rectum

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Hereditary colorectal cancer in the general population: from cancer registration to molecular diagnosis

Cited by 53 publications

References 44 publications

Extended Microsatellite Analysis in Microsatellite Stable, MSH2 and MLH1 Mutation-Negative HNPCC Patients: Genetic Reclassification and Correlation with Clinical Features

Extended Microsatellite Analysis in Microsatellite Stable, MSH2 and MLH1 Mutation-Negative HNPCC Patients: Genetic Reclassification and Correlation with Clinical Features

Genetic testing among high-risk individuals in families with hereditary nonpolyposis colorectal cancer

Early-Age-at-Onset Colorectal Cancer and Microsatellite Instability as Markers of Hereditary Nonpolyposis Colorectal Cancer

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