Hereditary Nonpolyposis Colorectal Cancer: the Syndrome, the Genes, and Historical Perspectives

Marra, Giancarlo; Boland, C. Richard

doi:10.1093/jnci/87.15.1114

Cited by 458 publications

(243 citation statements)

References 0 publications

Supporting

Mentioning

234

Contrasting

Unclassified

Order By: Relevance

“…MLH1 or MSH2 are the most commonly mutated MMR genes in LS, whereas mutations in MSH6 or PMS2 are significantly less common. 3,4 Occasionally, the presence of constitutional epimutations in MSH2 and MLH1 has been reported (reviewed in Hitchins and Ward 5 and Kuiper et al 6 ).…”

Section: Introductionmentioning

confidence: 99%

MLH1 methylation screening is effective in identifying epimutation carriers

et al. 2012

View full text Add to dashboard Cite

Recently, constitutional MLH1 epimutations have been identified in a subset of Lynch syndrome (LS) cases. The aim of this study was the identification of patients harboring constitutional MLH1 epimutations in a set of 34 patients with a clinical suspicion of LS, MLH1-methylated tumors and non-detected germline mutations in mismatch repair (MMR) genes. MLH1 promoter methylation was analyzed in lymphocyte DNA samples by MS-MLPA (Methylation-specific multiplex ligation-dependent probe amplification). Confirmation of MLH1 constitutional methylation was performed by MS-MCA (Methylation-specific melting curve analysis), bisulfite sequencing and pyrosequencing in different biological samples. Allelic expression was determined using heterozygous polymorphisms. Vertical transmission was evaluated by MS-MLPA and haplotype analyses. MS-MLPA analysis detected constitutional MLH1 methylation in 2 of the 34 individuals whose colorectal cancers showed MLH1 methylation (5.9%). These results were confirmed by bisulfite-based methods. Both epimutation carriers had developed metachronous early-onset LS tumors, with no family history of LS-associated cancers in their first-degree relatives. In one of the cases, the identified MLH1 constitutional methylation was monoallelic and results in MLH1 and EPM2AIP1 allele-specific transcriptional silencing. It was present in normal somatic tissues and absent in spermatozoa. The methylated MLH1 allele was maternally transmitted and methylation was reversed in a daughter who inherited the same allele. MLH1 methylation screening in lymphocyte DNA from patients with early-onset MLH1-methylated LS-associated tumors allows the identification of epimutation carriers. The present study adds further evidence to the emerging entity of soma-wide MLH1 epimutation and its heritability.

show abstract

Section: Introductionmentioning

confidence: 99%

MLH1 methylation screening is effective in identifying epimutation carriers

et al. 2012

View full text Add to dashboard Cite

show abstract

“…The human mismatch repair system plays an important role in maintaining genomic integrity by removing replication errors from DNA in a strand-speci®c manner (Eshleman and Markowitz, 1996;Kolodner, 1996;Marra and Boland, 1995;Modrich, 1997). Inactivation of this DNA repair system raises mutation rate by two to three orders of magnitude (Bhattacharyya et al, 1994;Eshleman et al, 1995), and leads to the development of human cancers with microsatellite instability (Eshleman and Markowitz, 1996;Fishel and Kolodner, 1995;Kinzler and Vogelstein, 1996;Marra and Boland, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…Inactivation of this DNA repair system raises mutation rate by two to three orders of magnitude (Bhattacharyya et al, 1994;Eshleman et al, 1995), and leads to the development of human cancers with microsatellite instability (Eshleman and Markowitz, 1996;Fishel and Kolodner, 1995;Kinzler and Vogelstein, 1996;Marra and Boland, 1995). In particular, inactivation of DNA mismatch repair has been associated with human colon cancers displaying microsatellite instability [MSI] that arises in kindreds with the hereditary nonpolyposis colon cancer syndrome and additionally in 13% of sporadic nonfamilial colon cancers (Kinzler and Vogelstein, 1996).…”

Section: Introductionmentioning

confidence: 99%

Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability

Xia

Littman

et al. 2000

Oncogene

View full text Add to dashboard Cite

Inactivation of DNA-mismatch repair underlies the genesis of microsatellite unstable (MSI) colon cancers. hPMS2 is one of several genes encoding components of the DNA-mismatch repair complex, and germline hPMS2 mutations have been found in a few kindreds with hereditary nonpolyposis colorectal carcinoma (HNPCC), in whom hereditary MSI colon cancers develop. However, mice bearing null hPMS2 genes do not develop colon cancers and hPMS2 mutations in sporadic human colon cancers have not been described. Here we report that in Vaco481 colon cancer the hPMS2 gene is inactivated by somatic mutations of both hPMS2 alleles. The cell line derived from this tumor is functionally de®cient in DNA mismatch repair. This de®ciency can be biochemically complemented by addition of a puri®ed hMLH1-hPMS2 (hMutLa) complex. The hPMS2 de®cient Vaco481 cancer cell line demonstrates microsatellite instability, an elevated HPRT gene mutation rate, and resistance to the cytotoxicity of the alkylator MNNG. We conclude that somatic inactivation of hPMS2 can play a role in development of sporadic MSI colon cancer expressing the full range of cancer phenotypes associated with inactivation of the mismatch repair system. Oncogene (2000) 19, 2249 ± 2256.

show abstract

“…7,8 Germline mutation of a MMR gene has been shown to be the autosomal dominant genetic defect in most hereditary nonpolyposis colon cancer (HNPCC) kindreds. 9,10 A second hit incurred by tumor cells in HNPCC individuals results in biallelic inactivation of the specific MMR gene, causing loss of faithful replication of microsatellite DNA in tumor. 11 MSI is thus a marker of an underlying DNA mismatch repair defect and, additionally, is associated with enhanced mutation rates in coding DNA.…”

mentioning

confidence: 99%

Detection of Microsatellite Instability by Fluorescence Multiplex Polymerase Chain Reaction

Berg

Glaser

Thompson

et al. 2000

The Journal of Molecular Diagnostics

136

116

View full text Add to dashboard Cite

We have created a clinical molecular diagnostic assay to test for microsatellite instability (MSI) at multiple loci simultaneously in paraffin-embedded surgical pathology colon resection specimens. This fluorescent multiplex polymerase chain reaction (PCR) assay analyzes the five primary microsatellite loci recommended at the 1997 National Cancer Institute-sponsored conference on MSI for the identification of MSI or replication errors in colorectal cancer: Bat-25, Bat-26, D2S123, D5S346, and D17S250. Amplicon detection is accomplished by capillary electrophoresis using the ABI 310 Genetic Analyzer. Assay validation compared 18 specimens previously assessed by radioactive PCR and polyacrylamide gel electrophoresis detection to results generated by the reported assay. Germline and tumor DNA samples were amplified in separate multiplex PCR reactions, sized in separate capillary electrophoresis runs, and compared directly to identify novel length alleles in tumor tissue. A concordance of 100% between the two modalities was achieved. The multiplex assay routinely detected a subpopulation of 10% tumor alleles in the presence of 90% normal alleles. A novel statistical model was generated that corroborates the validity of using results generated by analysis of five independent microsatellites to achieve a single overall MSI diagnosis. The assay presented is superior to standard radioactive monoplex PCR, polyacrylamide gel electrophoretic analysis, primarily due to the multiplex PCR format. (J Mol Diag 2000, 2:20 -28)Microsatellite instability (MSI), or replication error, is a manifestation of genomic instability arising in a variety of human neoplasms where tumor cells have a decreased overall ability to faithfully replicate DNA. This phenomenon has been shown to be a frequent, if not obligatory, surrogate marker of underlying functional inactivation of one of the human DNA mismatch repair (MMR) genes. [1][2][3][4][5][6]

show abstract

Hereditary Nonpolyposis Colorectal Cancer: the Syndrome, the Genes, and Historical Perspectives

Cited by 458 publications

References 0 publications

MLH1 methylation screening is effective in identifying epimutation carriers

MLH1 methylation screening is effective in identifying epimutation carriers

Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability

Detection of Microsatellite Instability by Fluorescence Multiplex Polymerase Chain Reaction

Contact Info

Product

Resources

About