A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome

<p>Abstract</p> <p>Background</p> <p>An unclassified variant (UV) in exon 1 of the <it>MLH1 </it>gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this <it>MLH1 </it>variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives.</p> <p>Methods</p> <p>We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples.</p> <p>Results</p> <p>The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families.</p> <p>Conclusions</p> <p>We conclude that the <it>MLH1 </it>variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.</p

Added Value of 50-Gene Panel Sequencing to Distinguish Multiple Primary Lung Cancers from Pulmonary Metastases: A Systematic Investigation

Differentiation between multiple primary lung cancers and pulmonary metastases (PM) has important implications in staging, prognosis, and treatment strategies. Clinical and immunohistopathologic criteria have been standardized; however, a substantial number of cases remain difficult to classify. Using next-generation sequencing, it is now possible to improve the classification of multiple lung cancer lesions. This study systematically investigated the value of routine morphologic and IHC characteristics, p53 protein expression, TP53 mutation analysis, and 50-gene panel sequencing (GPS) in 111 lesions from 50 patients with multiple lung lesions. Based on immunohistopathologic criteria, 32 paired lesions were classified as multiple primary lung cancer (MPLC) and 21 as PM. TP53 mutation analysis indicated MPLC in 23 and PM in 6 pairs, but in the majority of cases (n = 28, 49%) no mutation was observed and no conclusion could be drawn. In contrast, only 2 pairs were not conclusive using GPS. In a significant number of matching tumor samples (n = 19, 39%), sequencing results were contradictory to the initial immunohistopathology diagnosis. No separation in overall survival for classifications based on immunohistopathology was observed, while a clear but nonsignificant trend was observed concerning survival in MPLC patients (hazard ratio = 3.98) using 50-gene GPS. In about one-third of the patients, GPS provided additional information to improve the differentiation between MPLC and PM

EGFR and KRAS quality assurance schemes in pathology: generating normative data for molecular predictive marker analysis in targeted therapy

Item does not contain fulltextINTRODUCTION: The aim of this study was to compare the reproducibility of epidermal growth factor receptor (EGFR) immunohistochemistry (IHC), EGFR gene amplification analysis, and EGFR and KRAS mutation analysis among different laboratories performing routine diagnostic analyses in pathology in The Netherlands, and to generate normative data. METHODS: In 2008, IHC, in-situ hybridisation (ISH) for EGFR, and mutation analysis for EGFR and KRAS were tested. Tissue microarray sections were distributed for IHC and ISH, and tissue sections and isolated DNA with known mutations were distributed for mutation analysis. In 2009, ISH and mutation analysis were evaluated. False-negative and false-positive results were defined as different from the consensus, and sensitivity and specificity were estimated. RESULTS: In 2008, eight laboratories participated in the IHC ring study. In only 4/17 cases (23%) a consensus score of >/=75% was reached, indicating that this analysis was not sufficiently reliable to be applied in clinical practice. For EGFR ISH, and EGFR and KRAS mutation analysis, an interpretable result (success rate) was obtained in >/=97% of the cases, with mean sensitivity >/=96% and specificity >/=95%. For small sample proficiency testing, a norm was established defining outlier laboratories with unsatisfactory performance. CONCLUSIONS: The result of EGFR IHC is not a suitable criterion for reliably selecting patients for anti-EGFR treatment. In contrast, molecular diagnostic methods for EGFR and KRAS mutation detection and EGFR ISH may be reliably performed with high accuracy, allowing treatment decisions for lung cancer.1 oktober 201

Revisiting the Mamlūk empire : political action, relationships of power, entangled networks, and the sultanate of Cairo in late medieval Syro-Egypt

This chapter’s questions the commonly assumed link between political practices of integration and integrity on the one hand – which appear as empirical realities from many sources and studies – and the Syro-Egyptian Sultanate of Cairo (13th-16th centuries) as a dominant, autonomous and imperial historical actor on the other. It problematizes in particular the holistic nature of these assumptions, their merely descriptive value for understanding the region’s history, and the potentially misleading consequences of their normative character. At the same time, this chapter proposes to reflect further on the powerful idea of the Sultanate as an empire. It actually considers this notion of “empire” as a useful way out of this predicament, because it invites to engage with insights from other fields of historical research and to define valuable analytical tools, including from social network theory, to further and refine current assumptions about and understandings of late medieval Syro-Egyptian political action. Confronting such tools with various cases from the center and the peripheries of that Syro-Egyptian political action, this chapter argues that the imperial appearances of the Syro-Egyptian Sultanate were always constructed in the micro-history of people and their negotiation of particular cultural, socio-economic and political relationships, which were extremely fluid and multivalent, permeable, and continuously organized around the court in Cairo