Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer

Möslein, Gabriela; Tester, David J.; Lindor, Noralane M.; Honchel, Ronald; Cunningham, Julie M.; French, Amy J.; Halling, Kevin C.; Schwab, Manfred; Goretzki, P. E.; Thibodeau, Stephen N.

doi:10.1093/hmg/5.9.1245

Cited by 199 publications

(126 citation statements)

References 28 publications

Supporting

Mentioning

116

Contrasting

Order By: Relevance

“…No mutations in the hMSH2 gene, and only one somatic mutation in the hMLH1 gene, were found. Our results are in good agreement with previous studies that demonstrated that mismatch repair gene mutations are very rare in the RER+ sporadic forms of colon cancers: the hMSH2 gene was found to be altered in only nine out of 62 colon tumours (Børresen et al, 1995;Liu et al, 1995;Wu et al, 1997); the hMLH1 gene was found to be mutated in only eight out of 50 colon cancers (Liu et al, 1995;Moslein et al, 1996, Wu et al, 1997. Fourteen out of 21 (66.6%) pancreatic tumours were RER+, but 86% (12/14) were altered at a single locus out of the ten analysed; those samples should probably be classified as stable tumours.…”

Section: Discussionsupporting

confidence: 93%

“…With regard to the sporadic forms of the same tumours, alterations of these genes have been shown in only a few cases of colon, endometrial and ovarian tumours with microsatellite instability (Børresen et al, 1995;Fujita et al, 1995;Katabuchi et al, 1995;Liu et al, 1995;Moslein et al, 1996;Wu et al, 1997). Methylation of the hMLH1 promoter region has been suggested to be an alternative mechanism of gene inactivation in sporadic colorectal tumours .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours

et al. 1999

View full text Add to dashboard Cite

Summary Genomic instability has been proposed as a new mechanism of carcinogenesis involved in hereditary non-polyposis colorectal cancer (HNPCC) and in a large number of sporadic cancers like pancreatic and colon tumours. Mutations in human mismatch repair genes have been found in HNPCC patients, but their involvement in sporadic cancer has not been clarified yet. In this study we screened 21 pancreatic and 23 colorectal sporadic cancers for microsatellite instability by ten and six different microsatellite markers respectively. Microsatellite alterations were observed at one or more loci in 66.6% (14/21) of pancreatic cancers and in 26% (6/23) colon tumours, but all the pancreatic and half of the colon samples showed a low rate of microsatellite instability. All the unstable samples were further analysed for mutations in the hMLH1 and hMSH2 genes and for hypermethylation of the hMLH1 promoter region. Alterations in the hMLH1 gene were found only in colorectal tumours with a large presence of microsatellite instability. None of the pancreatic tumours showed any alteration in the two genes analysed. Our results demonstrate that microsatellite instability is unlikely to play a role in the tumorigenesis of sporadic pancreatic cancers and confirm the presence of mismatch repair gene alterations only in sporadic colon tumours with a highly unstable phenotype.

show abstract

Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours

et al. 1999

View full text Add to dashboard Cite

show abstract

“…A MMR gene germline mutation plus a second hit inactivating the wild-type allele in somatic cells (Hemminki et al, 1994) were thus established as the molecular basis fueling the mutator phenotype in HNPCCs; yet, the mechanism leading to sporadic MSI CRCs remained to be understood (Kinzler and Vogelstein, 1996). It turned out that in most sporadic MSI CRCs, mutations could not be identified (Moslein et al, 1996;Wu et al, 1997), leading to the speculation that non-mutational mechanisms were responsible for the defect. Thus, epigenetic changes in DNA were explored as the mechanism leading to gene silencing in cancer cells, alternate to mutational events.…”

Section: The Discovery Of Msimentioning

confidence: 99%

Differences and evolution of the methods for the assessment of microsatellite instability

2008

View full text Add to dashboard Cite

Microsatellite instability (MSI) originates from the systematic accumulation of uncorrected deletion/insertion in repetitive DNA tracts in cancer cells with a deficient mismatch repair system. Among colorectal cancers, the MSI signature identifies hereditary cases arising in patients with germline mutations in hMLH1, hMSH2, PMS2 and a fraction of those with hMSH6 mutations, as well as sporadic cancers with epigenetic hMLH1 promoter hypermethylation. Considering the specific pathogenesis, pathological features, natural history and response to 5-fluoro-uracil-based chemotherapy of the MSI cancers, confusion about the genetic markers for MSI recognition seems surprising. In this clinically relevant field, an agreement has not been reached concerning the use of di-or mononucleotide markers for MSI assessment. The Revised Bethesda Guidelines still recommend a panel of markers consisting of mono-and dinucleotides, despite being questioned whether it is congruous to continue to use dinucleotide markers for MSI identification. In any event, no single marker is accurate enough for MSI testing, and an awareness of their pros and cons is required for proper interpretation of results. In recent years, several papers have reported different prevalence of MSI in unrelated series, largely depending on the detection and classification method, suggesting that MSI test interpretation also requires the understanding of the phenomenon rather than simply the crude satisfaction of panel recommendations. Inaccuracies can otherwise lead to under-or overdiagnosis and inaccurate disease classification, which always have a negative impact on the clinical practice of medicine.

show abstract

“…MSI is reported in 85 to 92% of CRC associated with HNPCC and in 10 to 15% of sporadic CRC. 17,[21][22][23] In 1996 Leach and colleagues 24 and Thibodeau and colleagues 25 reported the use of monoclonal antibodies directed against MSH2 and MLH1 in the immunohistochemical analysis of CRCs. Subsequent reports described immunohistochemistry (IHC) of MLH1, MSH2, and MSH6 in sporadic and HNPCC tumors with varying results.…”

Section: Immunohistochemistry (Ihc) Of Mismatch Repair (Mmr) Proteinsmentioning

confidence: 99%

Conventional and Tissue Microarray Immunohistochemical Expression Analysis of Mismatch Repair in Hereditary Colorectal Tumors

Hendriks

Franken

Dierssen

et al. 2003

The American Journal of Pathology

154

174

View full text Add to dashboard Cite

Immunohistochemistry (IHC) of mismatch repair (MMR) proteins in colorectal tumors together with microsatellite analysis (MSI) can be helpful in identi-fying families eligible for mutation analysis. The aims were to determine sensitivity of IHC for MLH1, MSH2, and MSH6 and MSI analysis in tumors from known MMR gene mutation carriers; and to evaluate the use of tissue microarrays for IHC (IHC-TMA) of colon tumors in its ability to identify potential carriers of MMR gene mutations, and compare it with IHC on whole slides. IHC on whole slides was performed in colorectal tumors from 45 carriers of a germline mutation in one of the MMR genes. The TMA cohort consisted of 129 colon tumors from (suspected) hereditary nonpolyposis colorectal cancer (HNPCC) patients. Whole slide IHC analysis had a sensitivity of 89% in detecting MMR deficiency in carriers of a pathogenic MMR mutation. Sensitivity by MSI analysis was 93%. IHC can also be used to predict which gene is expected to harbor the mutation: for MLH1, MSH2, and MSH6, IHC on whole slides would have correctly predicted the mutation in 48%, 92%, and 75% of the cases, respectively. We propose a scheme for the diagnostic approach of families with (suspected) HNPCC. Comparison of the IHC results based on whole slides versus TMA, showed a concordance of 85%, 95%, and 75% for MLH, MSH2, and MSH6, respectively. This study therefore shows that IHC-TMA can be reliably used to simultaneously screen a large number of tumors from (suspected) HNPCC patients, at first in a research setting. Colorectal cancer (CRC) is the second most common cause of death because of malignancy in the Western world. The cause of CRC is multifactorial, involving hereditary and environmental factors and somatic genetic changes during tumor progression. 1 A family history of CRC is a clinically significant risk factor and may be found in up to 15% of all patients with CRC. 2 The most common hereditary CRC syndromes are familial adenomatous polyposis coli (FAP), accounting for Ͻ1% of CRC cases and HNPCC (hereditary nonpolyposis colorectal cancer), accounting for 1 to 6% of the cases. 3 HNPCC is an autosomal dominantly inherited disorder that is clinically defined by the Amsterdam Criteria. 4,5 In HNPCC, germline mutations have been identified in four DNA mismatch repair (MMR) genes, MSH2, 6 MLH1, 7 PMS2, 8 and MSH6. 9 -14 In 50 to 70% of the families fulfilling the Amsterdam criteria a germline mutation is detected in MLH1 or MSH2. 15,16 Germline mutations have been found in MSH6 in families with atypical HNPCC, ie, not entirely fulfilling the Amsterdam criteria. [11][12][13][14] Microsatellite instability (MSI) in colorectal tumors, first reported in 1993, [17][18][19] is caused by a failure of the DNA MMR machinery to repair errors occurring during DNA replication and leading to length alterations in simple, repetitive microsatellite sequences distributed throughout the genome. 20 According to international guidelines, a panel of five specific microsatellite markers has been recommended for MSI evalua...

show abstract

Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer

Cited by 199 publications

References 28 publications

Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours

Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours

Differences and evolution of the methods for the assessment of microsatellite instability

Conventional and Tissue Microarray Immunohistochemical Expression Analysis of Mismatch Repair in Hereditary Colorectal Tumors

Contact Info

Product

Resources

About