PI: Judith Karner-Hanusch, M.D.
Associate Professor for Surgery
Lab Location: AKH, Level 8G/H
Associated Clinical Department: General Surgery
E-mail: judith.karner-hanusch@meduniwien.ac.at
Phone: +43 1 40400 5621
Research focus:
Colorectal cancer progression is associated with a sequence of genetic alterations in oncogenes and tumour suppressor genes. In our work, we aim to discover associations between genetic alterations of tumours and response to chemotherapy as well as patient prognosis. Furthermore, some genetic risk factors are known to constitute a predisposition to colorectal cancer. In this context, we focus on the investigation genes involved in hereditary colorectal cancer syndromes and their correlation to the respective disease phenotype.
Current Projects
- Hereditary colorectal cancer Syndromes – genotype and phenotype Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC) and Familial Adenomatous Polyposis (FAP) are the most common hereditary colorectal cancer syndromes. Typically, these syndromes are caused by a germ-line mutation in one of the misamtch-repair genes (MSH2, MLH1, MSH6, and PMS2) in case of Lynch Syndrome or in the APC gene for FAP. Less frequently, mutations in EXO1 or MLH3 may cause Lynch Syndrome. Mutations in the base excision repair gene MutYH have been associated with an attenuated polyposis phenotype and recessive inheritance.
Aim of this project is to investigate genotype-phenotype associations in families with classical forms of hereditary cancer syndromes to optimise surveillance protocols and maintain a high quality of life level for mutation carriers as long as possible.
For individuals with a less clear family history we aim to unravel the genetic background of the disease to provide pre-symptomatic genetic diagnosis and develop adequate surveillance protocols.
- Microsatellite instability as prognostic and predictive marker for chemotherapy regimens used in colorectal cancer patients. A significant proportion of CRCs is based on a pathway characterised by mismatch repair (MMR) defects, leading to replication errors, which means a high mutation rate in repetitive DNA sequences (microsatellite instability; MSI).
This MMR-deficient genotype is accompanied by frameshift mutations in tumour-suppressor genes leading to a characteristic tumour phenotype and behaviour.
The aim of this research focus is to analyse the predictive value of MSI for survival benefit from chemotherapy in colon carcinoma. Thereby we intend to identify parameters that may support classification of tumours into pathogenetic subtypes with distinct clinical characteristics to enable clinicians to target therapy.
Collaborations
- International Mismatch Repair Consortium (IMRC)
The major groups in the world, including centres in Africa, Asia, Australasia, Europe, North and South America, who provide clinical care and conduct research on Lynch Syndrome families, formed a consortium to address critical research needs in this field. Collectively, over 7000 families and 17000 MMR gene mutation carriers with pedigree and screening data allow the conduction of a number of studies to answer the following questions:
• enetrance of MMR gene mutations:
• Heterogeneity of penetrance according to mutation type and position
• Personal cancer risk tool
We collaborate in this consortium with our patients, families and knowledge. - Research Center for Molecular Medicine (CeMM) – Kaan Boztug, MD
In 10-50 % of patients apparently bearing an inherited predisposition for colorectal cancer, no causative mutation can be detected. Genome-wide analyses performed in collaboration with researchers at the CeMM will be used to identify new cancer genes potentially involved in hereditary colorectal cancer syndromes - Institute of Cancer Research – Andrea Gsur, PhD
Genome-wide SNP analysis (Affymetrix SNP 6.0 Array) in the first stage of the project will be used to identify genetic variants associated with an increased cancer risk. The second stage analyses will verify these results in 5000 individuals with or without colorectal cancer.