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Cancer Genetics Katharina Wimmer, Julia Vogt, Johannes Zschocke This research group is strongly associated with the molecular diagnostic lab of the institute that offers molecular genetic investigations for a broad spectrum of cancer susceptibility syndromes. One of the major aims of the research lab is the development and improvement of diagnostic tools for the identification and classification of mutations that escape standard techniques. The lab developed RNA-based assays that substantially increase mutation detection rates in several tumour suppressor genes. These approaches can effectively uncover splice  alterations caused by mutations that either fully escape the detection of gDNA based assays or cannot be readily be  classified as deleterious from the analysis of gDNA only. The evaluation of these ‘atypical’ splice mutations e.g. in NF1 also allowed  elucidating basic mechanism of splice site definition and inactivation. RNA-based assays also proved to be  pivotal to circumvent diagnostic obstacles that are caused by the presence of pseudogenes of the mismatch repair gene  PMS2. We are now planning to transfer the experience and knowledge gained with RNA-based mutation analysis by  Sanger sequencing into the massive parallel/ next generation sequencing (NGS) era. A second aim of the research lab is the genetic and clinical characterization of constitutive mismatch repair deficiency  (CMMRD) syndrome, a rare autosomal recessively inherited cancer susceptibility syndrome caused by biallelic mutations  in one of the four DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. Biallelic PMS2 mutations, for  which we developed highly sensitive and reliable analysis, account for approximately 60% of all cases of this syndrome.  CMMRD shows clinical overlap with other cancer susceptibility syndromes, in particular neurofibromatosis type 1 (NF1),  familial adenomatous polyposis and Lynch syndrome, and  has only recently been recognized as a distinct childhood  cancer susceptibility syndrome. As such, there is still a lack of knowledge on the natural history of this syndrome. A third cancer research project, in close collaboration with the University Hospital of Gynaecology and Obstetrics, is  aimed at the molecular characterization of ovarian cancer tissue by tumour-based massive parallel sequencing analyses. Major achievements: RNA-based assays for comprehensive characterization of mutations e.g. in the NF1 and PMS2  genes; substantial and ongoing contributions to the delineation of tumour spectrum and non-neoplastic features in  CMMRD; lead development of clinical diagnostic criteria for the diagnosis CMMRD in a European consortium;  identification of a prevalent BRCA1 mutation in the Tyrolean Zillertal and Lower Inn valleys which impacts on cancer  incidence and patient care in this region. Future goals: evaluation of ‘atypical’ splice mutations with the aim to deduce commonly applicable rules for the selection of variants likely to affect mRNA splicing for further mRNA analyses; development of strategies for the detection of  mutation-induced splice alterations by NGS; delineation of the pathogenetic mechanisms, in particular secondary  somatic mutations, underlying the development of neoplastic and non-neoplastic features in CMMRD patients;  evaluation of clinical data on CMMRD patients in close collaboration with the European consortium and with the ultimate goal to improve the management of CMMRD patients
Forschung / Research Lehre Mitarbeiterinnen und Mitarbeiter Formulare und Dokumente Kontakt / Anfahrt Sprechstunden Konsile Molekulargenetik Zytogenetik