Microsatellite instability in multiple colorectal tumors

Pedroni, Monica; Tamassia, Maria Grazia; Percesepe, Antonio; Roncucci, Luca; Benatti, Piero; Lanza, Giovanni; Gafà, Roberta; Gregorio, Carmela Di; Fante, Rossella; Losi, Lorena; Gallinari, L.; Scorcioni, Francesca; Vaccina, F.; Rossi, Giuseppina; Cesinaro, A. M.; Leòn, Maurizio Ponz de

doi:10.1002/(sici)1097-0215(19990331)81:1<1::aid-ijc1>3.0.co;2-k

Cited by 78 publications

(42 citation statements)

References 13 publications

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“…18,22,31,32 We demonstrated MSI for at least 1 of the microsatellite markers in 75% of tumors, a frequency rate in accordance with previous studies of multiple primary tumors but considerably higher compared with the MSI frequency rate in sporadic endometrial and colorectal carcinoma. An MSI-low pattern was detected in 13 tumors from 9 individuals, but whether this finding reflects the same MMR defect that was present in the majority of tumors, which displayed widespread MSI, is unknown.…”

Section: Discussionsupporting

confidence: 89%

“…20 Furthermore, patients with HNPCC are at increased risk of developing multiple primary malignancies, with a high frequency of MSI demonstrated in these tumors. 18,21,22 To assess the contribution of defective MMR to the development of double primary tumors of the endometrium and colorectum at a young age, MSI and immunohistochemical expression of the proteins MLH1, MSH2, and MSH6 were assessed in a population-based cohort of women with these double primary tumors who had their first diagnosis before age 50 years.…”

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confidence: 99%

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High frequency of microsatellite instability and loss of mismatch‐repair protein expression in patients with double primary tumors of the endometrium and colorectum

Planck

Rambech

Möslein

et al. 2002

Cancer

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

High frequency of microsatellite instability and loss of mismatch‐repair protein expression in patients with double primary tumors of the endometrium and colorectum

Planck

Rambech

Möslein

et al. 2002

Cancer

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“…8,11 Results A total of 10 missense changes were observed: eight have been reported by us and/or other groups and two are new (Table 1). Seven variants were identified only once in the patient population, two were found in two independent probands, and one in four probands, for a total of 15 unrelated carriers (Table 1).…”

Section: Molecular Analysismentioning

confidence: 97%

Assessment of pathogenicity criteria for constitutional missense mutations of the hereditary nonpolyposis colorectal cancer genes MLH1 and MSH2

et al. 1999

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To determine the role played by MLH1 and MSH2 missense variants in cancer susceptibility, we have investigated the following genetic and biological characteristics associated with six MLH1 and four MSH2 missense changes identified in Italian hereditary nonpolyposis colorectal cancer (HNPCC) families: co-segregation with disease phenotype and/or bona fide pathogenetic mutations; presence of the variant in healthy control subjects; evolutionary conservation of the involved aminoacid and type of aminoacid change; and presence/absence of microsatellite instability (MSI) in tumour DNA. Overall, nine variants did not fulfil ≥ 2 pathogenicity criteria. MSI was investigated in tumour samples from carriers of nine different missense mutations. Only 3/9 variants were associated with MSI in tumour DNA. In addition, four variants were not present in affected pedigree members, and five variants were observed in the control population. Based upon these results, we conclude that most MLH1 and MSH2 missense changes are unlikely to act as major causative factors in colorectal cancer susceptibility and development.

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“…5,6 The frequency of the MSI is 80 to 95% in HNPCC cancers 6 -8 and 10 to 15% in sporadic colorectal cancers. [7][8][9][10] The fact that a considerable proportion of sporadic colorectal cancers displays MSI makes microsatellite analysis a relatively unspecific marker for HNPCC when applied to malignant tumors. 11 Most colorectal cancers arise within a pre-existing epithelial neoplasm, an adenoma, though only a small proportion of adenomas progresses to malignancy.…”

Section: Hereditary Nonpolyposis Colorectal Cancer (Hnpcc)mentioning

confidence: 99%

Microsatellite Instability in Adenomas as a Marker for Hereditary Nonpolyposis Colorectal Cancer

Loukola¹,

Salovaara²,

Kristo³

et al. 1999

The American Journal of Pathology

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Hereditary nonpolyposis colorectal cancer (HNPCC)is the most common of the well-defined colorectal cancer syndromes , accounting for at least 2% of the total colorectal cancer burden and carrying a greater than 80% lifetime risk of cancer. Significant reduction in cancer morbidity and mortality can be accomplished by appropriate clinical cancer screening of HNPCC patients with mutations in mismatch repair (MMR) genes. Thus , it is desirable to identify individuals who are mutation-positive. In individuals with cancer , mutation detection can be accomplished relatively efficiently by germline mutation analysis of individuals whose cancers show microsatellite instability (MSI). This study was designed to assess the feasibility of screening colorectal adenoma patients for HNPCC in the same manner. Among 378 adenoma patients , six (1.6%) had at least one MSI adenoma. Five out of the six patients (83%) had a germline MMR gene mutation. We conclude that MSI analysis is a useful method of prescreening colorectal adenoma patients for HNPCC. (Am J Pathol 1999, 155:1849 -1853) Germline mutations in DNA mismatch repair genes (MLH1, MSH2, PMS1, PMS2, and MSH6) 1 underlie HNPCC. Deficient DNA mismatch repair results in reduced replication fidelity. Cells deficient for both alleles of a mismatch repair gene acquire a mutator phenotype, leading to accumulation of somatic mutations, which can be demonstrated by analyzing microsatellite sequences in the tumor DNA. These sequences display frequent somatic deletions and insertions, often referred to as microsatellite instability (MSI). HNPCC patients form adenomas at a slightly but not strikingly increased rate as compared with the general population 2 (Jä rvinen HJ, Aarnio M, Mustonen H, Aktan-Collan LA, Peltomäki P, de la Chapelle A, Mecklin J-P, submitted). Adenomas in HNPCC tend to be large and show a villous architecture and high-grade dysplasia. 3 It is possible that the mutator or MSI phenotype characteristic of HNPCC tumors drives the promotion of adenoma to carcinoma.MSI can be seen at an early stage in HNPCC tumors, but usually at later stages in sporadic colorectal tumorigenesis. 4 Adenomas from patients with HNPCC frequently show MSI as opposed to 0 to 3% of apparently sporadic colorectal adenomas. 5,6 The frequency of the MSI is 80 to 95% in HNPCC cancers 6 -8 and 10 to 15% in sporadic colorectal cancers. [7][8][9][10] The fact that a considerable proportion of sporadic colorectal cancers displays MSI makes microsatellite analysis a relatively unspecific marker for HNPCC when applied to malignant tumors.

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Microsatellite instability in multiple colorectal tumors

Cited by 78 publications

References 13 publications

High frequency of microsatellite instability and loss of mismatch‐repair protein expression in patients with double primary tumors of the endometrium and colorectum

High frequency of microsatellite instability and loss of mismatch‐repair protein expression in patients with double primary tumors of the endometrium and colorectum

Assessment of pathogenicity criteria for constitutional missense mutations of the hereditary nonpolyposis colorectal cancer genes MLH1 and MSH2

Microsatellite Instability in Adenomas as a Marker for Hereditary Nonpolyposis Colorectal Cancer

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