Team of the Research Group Oncogenetics

Research Group Oncogenetics

Hereditary cancer syndromes

HBOC & DNA-repair

BRCA1 and BRCA2 were the first two genes identified to cause hereditary breast and ovarian cancer. There is a life-time risk of developing breast (40-80%) and ovarian (11-40%) for mutation careers of these two genes. The penetrance of BRCA1 mutations ranges from 50-80% for breast cancer and the overall risk of developing breast cancer for BRCA2 mutation careers is 40-70%. Moreover penetrance can greatly differ between families with the same mutation or within a family between different members of family. The causes of the difference are both environmental and genetic factors. GWAS identified several loci which are likely to modify the age at onset but each locus only explain small part of differences in penetrance. Benefiting from Next Generation Sequencing we introduce a different approach to penetrance prediction by detection of mutation load in 312 genes which are parts of DNA-repair machinery or directly interact with BRCA1/2. We plan to analyze two cohorts from the German Familial Breast Cancer Group: 100 patients harboring a BRCA1/2 mutation manifesting with an early-onset breast cancer below age of 35, and 100 unaffected BRCA1/2 mutation carriers aged above 60 years. With our results, we hope to be able to predict the age of onset based on an “individual mutation load” of low risk gene variants that were not analyzed by GWAS studies that contribute to an early disease onset in BRCA1/2 mutation carriers.

Somatic oncogenetics

In the past 20 years next-generation sequencing open the field for new individualized cancer treatment. The comprehensive and massively sequencing helped to establish a cancer genomic landscape (Vogelstein et al., 2013). This enables physician to check for certain genetic alterations, genetic biomarkers, that help guiding a patient specific therapy. Very well-known examples for a tumor specific treatment, would be the inhibition of tyrosine signaling cascades with vemurafenib in melanomas or the EGFR - inhibition with gefitinib and erlotinib in colon carcinomas.

The standard procedure to sustain tumor DNA is by biopsy or from FFPE samples. Another less invasive approach is the “liquid biopsy”. This method is used to isolate cell free tumor DNA (ctDNA) from the patient’s blood – more precisely plasma – and subsequent search for genetic biomarkers. Because of the constant turn-over in the tumor mass, ctDNA is frequently released into the blood stream. The “liquid biopsy” is due to its sequential applicability a perfect method for the monitoring of desease progression or remission of cancer patients under therapy and beyond treatment.

New strategies are under way to fight cancer in a very specific. The idea is to utilize the processing steps of the immune system. A genetically altered gene product which is processed in the endoplasmatic reticulum, will be presented on the surface of cancer cells. The processed molecules are presented by the MHC molecules to the cells of the immune system. This mechanism will be used in cooperation with clinicians, pathologists, bioinformaticians and immunologists to develop a vaccination based treatment for cancer patients.

 

Email Contact:

Christopher Schroeder, Franz-Joachim Hilke

 

Literature:

Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. a, & Kinzler, K. W. (2013). Cancer genome landscapes. Science (New York, N.Y.), 339, 1546-58. doi:10.1126/science.1235122