A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting

Ramsoekh, Dewkoemar; Wagner, Anja; Leerdam, Monique E. van; Dinjens, Winand N.M.; Steyerberg, Ewout W.; Halley, Dicky; Kuipers, Ernst J.; Dooijes, Dennis

doi:10.1136/gut.2008.156695

Cited by 32 publications

(31 citation statements)

References 27 publications

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“…This increased the sensitivity of the detection of Lynch syndrome to 78% [7]. However, a recent study showed that only 39% of patients with Lynch syndrome fulfilled the Amsterdam II criteria, and only 25% of patients with MSH6 mutations meet Amsterdam II criteria [8].…”

Section: Introductionmentioning

confidence: 97%

Are prediction models for Lynch syndrome valid for probands with endometrial cancer?

et al. 2009

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Currently, three prediction models are used to predict a patient's risk of having Lynch syndrome (LS). These models have been validated in probands with colorectal cancer (CRC), but not in probands presenting with endometrial cancer (EMC). Thus, the aim was to determine the performance of these prediction models in women with LS presenting with EMC. Probands with EMC and LS were identified. Personal and family history was entered into three prediction models, PREMM(1,2), MMRpro, and MMRpredict. Probabilities of mutations in the mismatch repair genes were recorded. Accurate prediction was defined as a model predicting at least a 5% chance of a proband carrying a mutation. From 562 patients prospectively enrolled in a clinical trial of patients with EMC, 13 (2.2%) were shown to have LS. Nine patients had a mutation in MSH6, three in MSH2, and one in MLH1. MMRpro predicted that 3 of 9 patients with an MSH6, 3 of 3 with an MSH2, and 1 of 1 patient with an MLH1 mutation could have LS. For MMRpredict, EMC coded as "proximal CRC" predicted 5 of 5, and as "distal CRC" three of five. PREMM(1,2) predicted that 4 of 4 with an MLH1 or MSH2 could have LS. Prediction of LS in probands presenting with EMC using current models for probands with CRC works reasonably well. Further studies are needed to develop models that include questions specific to patients with EMC with a greater age range, as well as placing increased emphasis on prediction of LS in probands with MSH6 mutations.

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Section: Introductionmentioning

confidence: 97%

Are prediction models for Lynch syndrome valid for probands with endometrial cancer?

et al. 2009

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“…The complete coding sequence of the MSH6 gene, including intron/exon boundaries up to 25 bases in the intron, was amplified by standard PCR. Amplified fragments were subsequently analyzed for genetic alterations by denaturing gradient gel electrophoresis (DGGE) or by direct sequencing as described [17][18][19]. Unique sequence alterations were confirmed at least once by sequence analysis of an independently generated PCR product.…”

Section: Msh6 Mutation Analysismentioning

confidence: 99%

Association of rare MSH6 variants with familial breast cancer

Wasielewski

Riaz

Vermeulen

et al. 2009

Breast Cancer Res Treat

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Germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 predispose to Lynch syndrome (also known as hereditary non-polyposis colorectal cancer). Recently, we have shown that the CHEK2 1100delC mutation also is associated with Lynch syndrome/Lynch syndrome-associated families albeit in a polygenic setting. Two of the ten CHEK2 1100delC positive Lynch syndrome families additionally carried a pathogenic MLH1 or MSH6 mutation, suggesting that mutations in mismatch repair genes may be involved in CHEK2 1100delC-associated cancer phenotypes. A phenotype of importance is hereditary breast and colorectal cancer (HBCC), with the CHEK2 1100delC mutation present in almost one-fifth of the families-again in a polygenic setting. In order to evaluate the involvement of MSH6 in polygenic CHEK2 cancer susceptibility, we, here, have analyzed the entire MSH6 coding sequence for genetic alterations in 68 HBCC breast cancer families. Rare MSH6 variants, with population frequencies below 1%, were identified in 11.8% of HBCC breast cancer families, whereas the same variants were identified in only 1.5% of population controls, suggesting that rare MSH6 variants are associated with HBCC breast cancer (P B 0.00001). However, screening of the entire MSH6 coding sequence in 68 non-HBCC breast cancer families showed a similar association (8.8 vs. *1.4% in controls, P B 0.001), suggesting that rare MSH6 variants are not confined to HBCC breast cancer. Together, our data suggest that rare MSH6 variants may predispose to familial breast cancer. However, none of the rare MSH6 variants are obviously pathogenic, suggesting that a more subtle disease mechanism may operate in breast carcinogenesis.

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“…Specifically, MSH6 mutations have been associated with a higher cumulative risk for endometrial cancer with a later age of onset as compared to other mismatch repair gene mutations [1][2][3][4][5], and cancers other than colon and endometrial may account for as much as 50% of cancer reported with MSH6 mutations [6]. Clarifying the efficacy of MSI/IHC in other extra-colonic cancers associated with LS is important, since certain cases of LS are likely to present in a clinically atypical manner.…”

Section: Resultsmentioning

confidence: 99%

Atypical identification of Lynch syndrome by immunohistochemistry and microsatellite instability analysis on jejunal adenocarcinoma

McIlvried

Birhiray²,

Lu³

2010

Familial Cancer

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A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting

Cited by 32 publications

References 27 publications

Are prediction models for Lynch syndrome valid for probands with endometrial cancer?

Are prediction models for Lynch syndrome valid for probands with endometrial cancer?

Association of rare MSH6 variants with familial breast cancer

Atypical identification of Lynch syndrome by immunohistochemistry and microsatellite instability analysis on jejunal adenocarcinoma

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