Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer

Department of Laboratory Medicine and Pathobiology, Samuel Lunenfeld Research Institute, University of Toronto, Mount Sinai Hospital, Ontario, Canada.
Human Genetics (Impact Factor: 4.82). 03/1999; 104(2):167-76. DOI: 10.1007/s004390050931
Source: PubMed

ABSTRACT Recent characterization of the molecular genetic basis of hereditary nonpolyposis colorectal cancer provides an important opportunity for identification of individuals and their families with germline mutations in mismatch repair genes. Cancer family history criteria that accurately define hereditary colorectal cancer are necessary for cost-effective testing for germline mutations in mismatch repair genes. The present report describes the results of analysis of 33 colorectal cancer cases/families that satisfy our modified family history criteria (Mount Sinai criteria) for colorectal cancer. Fourteen of these families met the more stringent Amsterdam criteria. Germline MSH2 and MLH1 mutations were identified by the reverse transcription-polymerase chain reaction and the protein truncation test, and confirmed by sequencing. Microsatellite instability analysis was performed on available tumors from affected patients. MSH2 or MLH1 mutations were detected in 8 of 14 Amsterdam criteria families and in 5 of the remaining 19 cases/families that only satisfied the Mount Sinai criteria. Three of the latter families had features of the Muir-Torre syndrome. A high level of microsatellite instability (MSI-H) was detected in almost all (16/18) colorectal cancers from individuals with MSH2 and MLH1 mutations, and infrequently (1/21) in colorectal cancer specimens from cases without detectable mutations. Families with germline MSH2 and MLH1 mutations tended to have individuals affected at younger ages and with multiple tumors. The Amsterdam criteria are useful, but not sufficient, for detecting hereditary colorectal cancer families with germline MSH2 and MLH1 mutations, since a proportion of cases and families with mutations in mismatch repair genes will be missed. Further development of cancer family history criteria are needed, using unbiased prospectively collected cases, to define more accurately those who will benefit from MSH2 and MLH1 mutation analysis.

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    • "MMR (MSH2, MLH1, MSH6) mutational analysis was performed on DNA from peripheral blood lymphocytes or lymphoblastoid cell lines. Large genomic deletions/duplications in MSH2 and MLH1 genes were identified by MLPA [12] and, if absent, underlying germline mutations were further screened by genomic DNA sequencing [9]. Briefly, the entire coding regions of the MSH2 (16 exons) and MLH1 (19 exons) genes were amplified by PCR and screened for mutations using ABI 377 automated sequencer. "
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    ABSTRACT: Several DNA mismatch repair (MMR) genes, responsible for the majority of Lynch Syndrome cancers, have been identified, predominantly MLH1 and MSH2, but the risk associated with these mutations is still not well established. The aim of this study is to provide population-based estimates of the risks of colorectal cancer (CRC) by gender and mutation type from the Ontario population. We analyzed 32 families segregating MMR mutations selected from the Ontario Familial Colorectal Cancer Registry and including 199 first-degree and 421 second-degree relatives. The cumulative risks were estimated using a modified segregation-based approach, which allows correction for the ascertainment of the Lynch Syndrome families and permits account to be taken for missing genotype information. The risks of developing CRC by age 70 were 60% and 47% among men and women carriers of any MMR mutation, respectively. Among MLH1 mutation carriers, males had significantly higher risks than females at all ages (67% vs. 35% by age 70, p-value = 0.02), while the risks were similar in MSH2 carriers (about 54%). The relative risk associated with MLH1 was almost constant with age (hazard ratio (HR) varied between 5.5-5.1 over age 30-70), while the HR for MSH2 decreased with age (from 13.1 at age 30 to 5.4 at age 70). This study provides a unique population-based study of CRC risks among MSH2/MLH1 mutation carriers in a Canadian population and can help to better define and understand the patterns of risks among members of Lynch Syndrome families.
    Hereditary Cancer in Clinical Practice 09/2009; 7(1):14. DOI:10.1186/1897-4287-7-14 · 1.47 Impact Factor
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    • "The same yield of about 50% is found for families with less clinical indications of HNPCC but which, in addition, have MSI-high tumours (Terdiman et al, 2001; Raedle et al, 2001). Among families that only fulfil clinical criteria, usually not as stringent as the Amsterdam criteria, mutations are detected in about 30% of kindreds (Wijnen et al, 1998a; Bapat et al, 1999; Lamberti et al, 1999; Syngal et al, 2000; Wahlberg et al, 2002). Depending on the specific subgroup which "
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    ABSTRACT: Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatch-repair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer. British Journal of Cancer (2002) 87, 892–897. doi:10.1038/sj.bjc.6600565 © 2002 Cancer Research UK
    British Journal of Cancer 11/2002; 87(8):892-7. DOI:10.1038/sj.bjc.6600565 · 4.84 Impact Factor
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    • "For clinical purposes, however, the AC are now recognized to be too restrictive, since other malignancies (e.g., gastric and endometrial) frequently occur in patients with HNPCC and may be the presenting cancers in such families (Beck et al. 1997b; Bapat et al. 1999). As a result, several modifications that include consideration of extracolonic malignancies in the diagnosis have been suggested (Beck et al. 1997b; Bapat et al. 1999; Vasen et al. 1999). In addition to family history, however, there are now laboratory approaches that may aid in establishing this diagnosis in a subset of patients with HNPCC. "
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    ABSTRACT: Familial polyposis (FAP [MIM 175100]) and hereditary nonpolyposis colorectal cancer (HNPCC [MIM 114500]) are two common autosomal dominant disorders predisposing to the development of colorectal cancer (CRC) (Bellacosa et al. 1996; Khine et al. 1996; Fante et al. 1997; Lynch et al. 1997; Soravia et al. 1997). FAP is characterized by the presence of hundreds to thousands of adenomatous polyps. HNPCC, on the other hand, is characterized by the occurrence of colorectal cancer at an early age (fourth to sixth decade), a tendency to develop multiple primary cancers, and an increased risk for the development of certain other cancers, particularly endometrial and stomach cancer (Lynch and Lynch 1995). It is generally easier to ascertain a diagnosis of FAP than HNPCC, because most patients with FAP eventually develop profuse polyposis and, sometimes, other tumor types (e.g., osteomas and periampullary carcinomas) that can aid in the diagnosis. Patients with HNPCC, on the other hand, lack distinctive phenotypic features. Consequently, the diagnosis of HNPCC has historically been based on family history. As a result, the true incidence of this disease and the underlying molecular defects have been difficult to establish. The estimated percentage of CRC cases caused by HNPCC has varied from ∼0.5% to 10% (Aaltonen et al. 1994b; Bellacosa et al. 1996; Brassett et al. 1996; Evans et al. 1997; Peel et al. 2000).
    The American Journal of Human Genetics 11/2001; 69(4):780-90. DOI:10.1086/323658 · 10.93 Impact Factor
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