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Background DNA double-strand breaks may evoke cell death or cancer. Cells have developed two fundamentally different mechanisms of DNA double-strand repair: the accurate mechanism of homologous recombination repair and the error-prone nonhomologous end joining. The deficiency of homologous recombination repair (HRD) is a frequent feature of several solid tumor entities and is associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitor therapy. Objectives Among other biomarkers, HRD testing provides an opportunity to guide PARP inhibitor therapy in solid tumors, but the basic principles are complex and the use and benefits of the different methodologies remain controversial. Knowledge of the underlying mechanisms at the molecular level will advance our understanding and will pave the way to introduce the testing of new biomarkers. Methods An overview of the fundamental mechanisms of DNA repair is provided. Important terms like HRR, HRD, and BRCAness are defined, and analysis methods are described, especially with regard to their integration in molecular pathology routine diagnostics. Results Currently, at least testing of the BRCA mutation status and genomic instability using a composite HRD score should be implemented in laboratories to identify subgroups of patients who might benefit from PARP inhibitor therapies. A broad range of testing methods is available with pros and cons for introduction in the clinical setting. They have to be validated carefully to reliably inform treatment selection. Conclusions Biomarkers to identify current homologous recombination deficiency status are needed to predict the benefit from PARP inhibitors and stratify their use in clinical management. Besides commercial assays, different tests might be used for the analysis of HRD. The application depends, among other things, on the local situation and has to be extensively validated.

Background Technical advancement and availability of high-throughput analysis has advanced molecular subtyping of most cancers. Thus, new possibilities for precision oncology have emerged. Aim Therefore, we aimed to collect data regarding availability and use of next generation sequencing (NGS) for urothelial cancer within the uropathology working group of the German Society of Pathology. Methods We collected data by questionnaires and additionally asked for sequencing results of bladder cancers in the participating institutions. Results A total of 13 university-affiliated institutes of pathology took part in the survey. All university institutes offer NGS-based molecular panel diagnostics and provide panels covering between 15 and 170 genes. Altogether, only 20 bladder cancers were sequenced in routine diagnostics and for 10 cancers potential targeted treatment options were available. Discussion So far, despite availability of NGS diagnostics at university institutes of pathology, only few bladder cancer samples have been sequenced. Based on current data from the molecular subtyping of bladder cancers, we recommend a step-by-step protocol with basic immunohistochemistry analysis and subsequent subtype-dependent analyses, e.g., alterations of the fibroblast growth factor receptors (FGFR) or comprehensive gene panel analyses.

Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.

Bei dem gleichzeitigen Auftreten von congenitaler bilateraler Innenohrschwerhörigkeit und Hypothyreose mit Struma wird differentialdiagnostisch an ein Pendred-Syndrom gedacht.Berichtet wird über ein mittlerweile 19 Monate altes Kleinkind, bei welchem im Rahmen des Neugeborenenscreenings eine Hypothyreose entdeckt wurde. Bei der im Alter von 4 Wochen durchgeführten audiologischen Diagnostik ließen sich TEOAE bei reizlosen Mittelohrverhältnissen nicht messen, in der BERA waren die Potentiale JV ab 50 bzw. 55 dB ableitbar. Im Alter von 4 Monaten ließen sich die Potentiale JV bei 30 bzw. 35 dB ableiten. Bis zum Alter von 18 Monaten ist die Hörschwelle stabil geblieben, so dass eine Hörbahnreifungsverzögerung diskutiert werden muss. Molekulargenetisch wurden 3 Mutationen auf zwei verschiedenen Genen, eine heterozygote Mutation im SLC26A4/PDS-Gen sowie zwei compound heterozygote Mutationen im Thyroidperoxidase-Gen, nachgewiesen. Auf dieser Grundlage werden verschiedene Hypothesen zur Erklärung der komplexen Symptomatik diskutiert.