Immunohistochemical staining for mismatch repair proteins, and its relevance in the diagnosis of hereditary non-polyposis colorectal cancer

Ewald, Jacques; Rodrigue, Christelle M; Mourra, Najat; Lefèvre, Jérémie H.; Fléjou, Jean‐François; Tiret, Emmanuel; Gespach, Christian; Parc, Yann

doi:10.1002/bjs.5704

Cited by 17 publications

(9 citation statements)

References 29 publications

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“…This mutation was previously described as deleterious in the Europe and the USA population [34][35][36][37]. According to our data, there is no evidence that such mutation is associated to related families, therefore, it was considered a hot spot.…”

Section: Spectrum Of Non-pathogenic Mutationsmentioning

confidence: 65%

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals

et al. 2011

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Lynch syndrome (LS) is an autosomal dominant syndrome that predisposes individuals to development of cancers early in life. These cancers are mainly the following: colorectal, endometrial, ovarian, small intestine, stomach and urinary tract cancers. LS is caused by germline mutations in DNA mismatch repair genes (MMR), mostly MLH1 and MSH2, which are responsible for more than 85% of known germline mutations. To search for germline mutations in MLH1 and MSH2 genes in 123 unrelated South American suspected LS patients (Bethesda or Amsterdam Criteria) DNA was obtained from peripheral blood, and PCR was performed followed by direct sequencing in both directions of all exons and intron-exon junctions regions of the MLH1 and MSH2 genes. MLH1 or MSH2 pathogenic mutations were found in 28.45% (34/123) of the individuals, where 25/57 (43.85%) fulfilled Amsterdam I, II and 9/66 (13.63%) the Bethesda criteria. The mutations found in both genes were as follows: nonsense (35.3%), frameshift (26.47%), splicing (23.52%), and missense (9%). Thirteen alterations (35.14%) were described for the first time. The data reported in this study add new information about MLH1 and MSH2 gene mutations and contribute to better characterize LS in Brazil, Uruguay and Argentina. The high rate of novel mutations demonstrates the importance of defining MLH1 and MSH2 mutations in distinct LS populations.

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Section: Spectrum Of Non-pathogenic Mutationsmentioning

confidence: 65%

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals

et al. 2011

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“…This mutation causes deletion of two bases, with the resultant change in reading frame. Note that a 4-base deletion in this same region has been reported [20].…”

Section: Discussionmentioning

confidence: 82%

A study on MSH2 and MLH1 mutations in hereditary nonpolyposis colorectal cancer families from the Basque Country, describing four new germline mutations

et al. 2009

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Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome underlies between 2 and 5% of all colorectal cancer. It is inherited as an autosomal dominant condition due to mutations in the mismatch repair genes. Fifty-four non-related index cases, 21 of them fulfilling Amsterdam criteria I or II, were studied. Ten (10/21 = 47.6%) different pathological mutations were found in this group, two of which had not previously been reported--one in MLH1 and the other in MSH2-. In the remaining patients, we also found another family with one of these new mutations, and four additional changes, two of which were also new--a pathological change in MSH2 and a second change of uncertain significance in MLH1-, while the other two changes had already been reported. Of all mutations, eight were found in MSH2 (8/15 = 53.3%) and seven in MLH1 (7/15 = 46.6%), suggesting a slightly greater involvement of MSH2 in HNPCC than MLH1 in our population, in contrast to the results reported by other authors.

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“…In our diagnostic algorithm, we classified two patterns of abnormalities to be virtually diagnostic of LS: (1) absent MLH1 staining and non-methylated MLH1 gene promoter and (2) absent MSH2 and/or MSH6 staining [35, 36]. Three of the nine patients classified as LS based on these patterns of molecular abnormalities underwent commercial genetic testing and all three (100%) were confirmed to carry a deleterious mutation.…”

Section: Discussionmentioning

confidence: 99%

Lynch syndrome among gynecologic oncology patients meeting Bethesda guidelines for screening

Walsh¹,

Blum²,

Walts³

et al. 2010

Gynecologic Oncology

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Objective Lynch Syndrome (LS) is characterized by a high lifetime incidence of colorectal cancer and gynecologic malignancies such as endometrial and ovarian cancer. Identification of LS families is important as it allows for heightened cancer screening which decreases colorectal cancer mortality. The original 1996 Bethesda guidelines included two gynecologic populations that should be further evaluated for LS: those with endometrial cancer before the age of 45 and those with two LS-related cancers (i.e. synchronous endometrial and ovarian cancer). Our study aims to estimate the prevalence of LS in these two populations. Methods We utilized a diagnostic algorithm that included immunohistochemistry for mismatch repair protein expression followed by selective evaluation for microsatellite instability and MLH1 gene promoter methylation. Results Among 72 eligible patients, 9 (12%) had molecular findings consistent with LS: 6/50 (12%) in the early-onset endometrial cancer group and 3/22 (14%) in the synchronous primary cancer group. In an additional 3 cases, MLH1 silencing was due to promoter methylation: 1/50 (2%) in the early-onset endometrial cancer group and 2/22 (9%) in the synchronous primary cancer group. Of the 9 women with molecular criteria suggesting LS, only three had pedigrees meeting the Amsterdam criteria. Conclusions A diagnostic algorithm can identify patients with LS and those who warrant further genetic testing. Our findings reinforce the recommendation that women diagnosed with endometrial cancer before age 45 and women with synchronous endometrial and ovarian cancer be screened for LS, irrespective of family history.

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Immunohistochemical staining for mismatch repair proteins, and its relevance in the diagnosis of hereditary non-polyposis colorectal cancer

Abstract: MLH1-deficient patients who are young or have a positive family history of cancer should be referred for genetic testing and counselling, whereas MSH2-deficient patients should be counselled in the same way as patients with HNPCC.

Cited by 17 publications

References 29 publications

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals

A study on MSH2 and MLH1 mutations in hereditary nonpolyposis colorectal cancer families from the Basque Country, describing four new germline mutations

Lynch syndrome among gynecologic oncology patients meeting Bethesda guidelines for screening

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