A large MSH2 Alu insertion mutation causes HNPCC in a German kindred

Kloor, Matthias; Sutter, Christian; Wentzensen, Nicolas; Cremer, Friedrich W.; Buckowitz, Annick; Keller, Monika; Doeberitz, Magnus von Knebel; Gebert, Johannes

doi:10.1007/s00439-004-1176-9

Cited by 31 publications

(23 citation statements)

References 25 publications

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“…Southern blot analysis consistently showed an aberrant fragment of 4 -4.2 kb, and sequencing across the breakpoints permitted determination of the exact size of the duplication: 4219 bp. Duplication breakpoints are lying in long T stretches, a (T) 21 located 8 bp upstream of exon 12 and a (T) 19 in intron 13 starting 896 bp downstream of exon 13 (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

“…3. A, Duplication breakpoints lie in long T stretches, a (T) 21 lying 8 bp upstream of exon 12 and a (T) 19 in intron 13 starting 896 bp downstream of exon 13. B, Primers 12aR and 13F were used to screen for the MLH1 duplication in other Colombian CRC families by a rapid specific PCR amplification that resulted in a fragment of 1289 bp in duplication carriers as depicted in lanes 2 and 3.…”

Section: Resultsmentioning

confidence: 99%

“…Duplication breakpoints lie in long T stretches, a (T) 21 located 8 bp upstream of exon 12 and a (T) 19 in intron 13 starting 896 bp downstream of exon 13 (Fig. 3A).…”

Section: Discussionmentioning

confidence: 99%

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Novel MLH1 duplication identified in Colombian families with Lynch syndrome

Alonso-Espinaco

Giraldez

Trujillo³

et al. 2011

Genetics in Medicine

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Purpose: Lynch syndrome accounts for 2-4% of all colorectal cancer, and is mainly caused by germline mutations in the DNA mismatch repair genes. Our aim was to characterize the genetic mutation responsible for Lynch syndrome in an extensive Colombian family and to study its prevalence in Antioquia. Methods: A Lynch syndrome family fulfilling Amsterdam criteria II was studied by immunohistochemistry and by multiplex ligation-dependent probe amplification (MLPA). Results were confirmed by additional independent MLPA, Southern blotting, and sequencing. Results: Index case tumor immunohistochemistry results were MLH1Ϫ, MSH2ϩ, MSH6ϩ, and PMS2Ϫ. MLPA analysis detected a duplication of exons 12 and 13 of MLH1. This mutation was confirmed and characterized precisely to span 4219 base pairs. Duplication screening in this family led to the identification of six additional carriers and 13 noncarriers. We also screened 123 early-onset independent colorectal cancer cases from the same area and identified an additional unrelated carrier. Conclusion: A novel duplication of exons 12 and 13 of the MLH1 gene was detected in two independent Lynch syndrome families from Colombia. A putative founder effect and prescreening Lynch syndrome Antioquia families for this specific mutation before thorough mismatch repair mutational screening could be suggested. Genet Med 2011:13(2):155-160.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Novel MLH1 duplication identified in Colombian families with Lynch syndrome

Alonso-Espinaco

Giraldez

Trujillo³

et al. 2011

Genetics in Medicine

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“…Immunohistochemistry was performed as described, 25 using the following mouse monoclonal antibodies: MSH2 (clone FE11, Calbiochem, San Diego, CA), MLH1 (clone G168-15, BD Pharmingen, San Diego, CA), MSH6 (clone 44, Cell Marque, Rocklin, CA) and PMS2 (clone A16-4, BD Pharmingen).…”

Section: Immunohistochemistrymentioning

confidence: 99%

BRAF V600E‐specific immunohistochemistry for the exclusion of Lynch syndrome in MSI‐H colorectal cancer

Capper

Voigt

Bozukova

et al. 2013

Intl Journal of Cancer

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101

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The differentiation between hereditary and sporadic microsatellite-unstable (MSI-H) colorectal cancer is a crucial step in Lynch syndrome diagnostics. Within MSI-H colorectal cancers, the BRAF V600E mutation is strongly associated with sporadic origin. Here, we asked whether BRAF V600E-specific immunohistochemistry (clone VE1) is helpful in separating sporadic from Lynch syndrome-associated MSI-H colorectal cancers. To that end, we performed VE1 immunohistochemistry and BRAF sequencing in a series of 91 MSI-H colorectal cancer specimens from patients tested for Lynch syndrome. Concordance of VE1 immunohistochemistry and molecular BRAF mutation status was observed in 90 of 91 (98.9%) MSI-H samples. All 11 tumors classified as BRAF V600E mutation-positive by Sanger sequencing were immunopositive, and 79 (98.8%) of 80 tumors classified as BRAF wild type showed negative staining. All VE1-positive tumors were MLH1-and PMS2-negative by immunohistochemistry. None of the tumors from mismatch repair (MMR) gene germline mutation carriers (n 5 28) displayed positive VE1 staining, indicating that BRAF V600E mutation-specific immunostaining has a low risk of excluding Lynch syndrome patients from germline mutation analysis. In conclusion, implementation of VE1 immunohistochemistry was able to detect BRAF-mutated MSI-H colorectal cancers with a sensitivity of 100% and a specificity of 98.8%. Among MLH1-negative colorectal cancers, the rate of VE1-positive lesions was 21%, offering the exclusion of these patients from MMR germline testing. Therefore, we suggest the integration of VE1 immunohistochemistry into the diagnostic panel of Lynch syndrome.Lynch syndrome, which represents one of the most frequent autosomal dominantly inherited cancer syndromes, is caused by germline mutations affecting DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2, followed by MSH6 and PMS2.

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“…These structural rearrangements largely comprise intragenic deletions encompassing at least one exon, accounting for as many as one third to half of the mutations affecting these 2 genes in certain populations (2)(3)(4)(5)(6)(7)(8). MLH1 and MSH2 duplications, insertions, and inversions have also been reported (9)(10)(11). In the case of MSH2, deletions frequently encompass the first exon and, in some cases, extend upstream into the adjacent epithelial cell adhesion molecule (EPCAM) gene as well (3,5).…”

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confidence: 99%

Alu in Lynch Syndrome: A Danger SINE?

Hitchins

Burn

2011

Cancer Prevention Research

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Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline loss of a DNA mismatch repair gene. In a significant proportion of cases, loss of function of the MSH2 mismatch repair gene is caused by large heterogeneous deletions involving MSH2 and/or the adjacent EPCAM gene. These deletions usually result from homologous malrecombination events between Alu elements, a family of short interspersed nuclear elements (SINE). Recent recognition that the extent of these deletions influences phenotypic outcome provided new impetus for fine-mapping the breakpoints. In doing so, P erezCabornero and colleagues uncovered new evidence for Alu-mediated ancestral founder deletions within

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A large MSH2 Alu insertion mutation causes HNPCC in a German kindred

Cited by 31 publications

References 25 publications

Novel MLH1 duplication identified in Colombian families with Lynch syndrome

Novel MLH1 duplication identified in Colombian families with Lynch syndrome

BRAF V600E‐specific immunohistochemistry for the exclusion of Lynch syndrome in MSI‐H colorectal cancer

Alu in Lynch Syndrome: A Danger SINE?

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