Lower Incidence of Colorectal Cancer and Later Age of Disease Onset in 27 Families With Pathogenic MSH6 Germline Mutations Compared With Families With MLH1 or MSH2 Mutations: The German Hereditary Nonpolyposis Colorectal Cancer Consortium

Plaschke, Jens; Engel, Christoph; Krüger, Stefan; Holinski‐Feder, Elke; Pagenstecher, Constanze; Mangold, Elisabeth; Möeslein, Gabriela; Schulmann, Karsten; Gebert, Johannes; Doeberitz, Magnus von Knebel; Rüschoff, Josef; Loeffler, Markus; Schackert, Hans K.

doi:10.1200/jco.2004.02.033

Cited by 219 publications

(193 citation statements)

References 32 publications

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“…Several investigations suggest that neither MSA nor IHC should be a definitive selection criterion for MSH6 mutation analysis, as some mutations may not be detected by either method. 29,41,42 Thus, more sophisticated strategies may be needed if also cost-effective detection of MSH6 mutations is required.…”

Section: Discussionmentioning

confidence: 99%

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Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Engel

Forberg

Holinski‐Feder

et al. 2005

Intl Journal of Cancer

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Clinical criteria, microsatellite analysis (MSA) and immunohistochemistry (IHC) are important diagnostic tools for identification of hereditary nonpolyposis colorectal cancer (HNPCC) patients who are likely to carry pathogenic germline mutations in mismatch repair genes. Based on MSA and IHC results and subsequent mutation analyses of 1,119 unrelated index patients meeting the Amsterdam II criteria or the classical Bethesda guidelines, we analyzed the value of these tools to predict MLH1 and MSH2 mutations with the aim of establishing optimal strategies for their most efficient sequential use. The overall prevalence of pathogenic germline mutations in our cohort was 20.6% (95% CI 5 18.3-23.0%) and 61.8% (95% CI 5 56.8-66.6%), respectively, after MSA/IHC-based preselection. IHC was highly predictive (99.1%) and specific (99.6%) with regard to MSA. However, 14 out of 230 mutations (6%) escaped detection by IHC. Thus, IHC cannot be recommended to substitute MSA fully. Nonetheless, IHC is important to indicate the gene that is likely to be affected. To combine both methods efficiently, we propose a novel screening strategy that provides 2 alternative ways of sequential IHC and MSA application, either using IHC or MSA in the first place. A logistic regression model based on the age of the index patient at first tumor diagnosis and the number of fulfilled HNPCC criteria is used to allocate individual patients to that alternative pathway that is expected to be least expensive. A cost analysis reveals that about 25% of the costs can be saved using this strategy. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

“…Descriptions of the mutation spectrum found in the families of the German HNPCC Consortium, genotype-phenotype correlations and pathology are reported in separate studies. [26][27][28][29] The study has been approved by the local ethics committees of the participating centers.…”

Section: Patient Recruitment and Diagnostic Proceduresmentioning

confidence: 99%

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Engel

Forberg

Holinski‐Feder

et al. 2005

Intl Journal of Cancer

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“…1) (Aarnio et al, 1999;Abdel-Rahman et al, 2006;Grover et al, 2009;Hampel et al, 2005;Vasen et al, 2007;Vasen et al, 2001b). This risk varies depending both on the affected MMR gene and on the gene loci involved (Plaschke et al, 2004;ten Broeke et al, 2015;Vasen et al, 2001a;Wijnen et al, 2009). To facilitate genetic counselling and clinical practice, an interactive website providing the complete distributions of all cancer types, depending on gene defect, from any age is now available at is available at http://www.lscarisk.org .…”

Section: Lynch Syndromementioning

confidence: 99%

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Ryan

Sheahan

Creavin

et al. 2017

Critical Reviews in Oncology/Hematology

118

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“…Instead, we chose four additional monomorphic markers that are mono-nucleotide repeats proved to be informative for the detection of microsatellite instability (MSI) in Lynch associated with the loss of MSH6. [33][34][35] DNA samples were isolated from eight normal donors and nine ALK ϩ ALCL tumors. Tumor DNA was isolated from paraffin curls using the Qiagen Blood and Tissue Kit (Qiagen, Mississagua, ON, Canada).…”

Section: Detection Of Microsatellite Instability In Alk ϩ Alcl Tumorsmentioning

confidence: 99%

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

Young

Bone

Wang

et al. 2011

The American Journal of Pathology

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The fusion tyrosine kinase NPM-ALK is central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK ؉ ALCL). We recently identified that MSH2, a key DNA mismatch repair (MMR) protein integral to the suppression of tumorigenesis, is an NPM-ALK-interacting protein. In this study, we found in vitro evidence that enforced expression of NPM-ALK in HEK293 cells suppressed MMR function. Correlating with these findings, six of nine ALK ؉ ALCL tumors displayed evidence of microsatellite instability, as opposed to none of the eight normal DNA control samples (P ‫؍‬ 0.007, Student's t-test). Using co-immunoprecipitation, we found that increasing levels of NPM-ALK expression in HEK293 cells resulted in decreased levels of MSH6 bound to MSH2, whereas MSH2·NPM-ALK binding was increased. The NPM-ALK·MSH2 interaction was dependent on the activation/autophosphorylation of NPM-ALK, and the Y191 residue of NPM-ALK was a crucial site for this interaction and NPM-ALK-mediated MMR suppression. MSH2 was found to be tyrosine phosphorylated in the presence of NPM-ALK. Finally, NPM-ALK impeded the expected DNA damage-induced translocation of MSH2 out of the cytoplasm. To conclude, our data support a model in which the suppression of MMR by NPM-ALK is attributed to its ability to interfere with normal MSH2 biochemistry and function.

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Lower Incidence of Colorectal Cancer and Later Age of Disease Onset in 27 Families With Pathogenic MSH6 Germline Mutations Compared With Families With MLH1 or MSH2 Mutations: The German Hereditary Nonpolyposis Colorectal Cancer Consortium

Cited by 219 publications

References 32 publications

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

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