Predictive and prognostic biomarkers in locally advanced rectal cancer, and prospects for risk-adapted tailoring (individualization) of multimodal therapy

• Applicant: Professor Dr. Torsten Liersch
• Subject Area: General and Visceral Surgery
• Term: from 2007 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 33996666

Tumors with a mutator phenotype can be separated from tumors caused by the suppressor pathway in their clinical as well as biological aspects and can be identified on a molecular level. These tumors revealed alterations in length in simple repetitive sequences in tumor DNA when compared with normal DNA of the same patient, the so-called RER (replication error) or MSI (microsatellite instability). The underlying molecular defect is a loss of the MMR (mismatch repair) function, leading to global genomic instability in simple repetitive sequences. In a hereditary form (known as hereditary nonpolyposis colorectal cancer [HNPCC] syndrome), it is responsible for 3-8 percent of all colorectal cancers (CRCs), but the clinical relevance of MSI has been shown in about 15-20 percent of non-hereditary sporadic tumors. When they are compared with MSS (microsatellite-stable) tumors, the prognosis for MSI tumors seems more favorable. Even more interestingly, MSI cells seem to be resistant to some chemotherapeutic drugs but more sensitive to radiation. However, these data are mainly found in vitro or in nonrandomized studies and are somewhat controversial. The controversial data may be caused by the location of the MMR defect, which leads to a mutated but in part functional protein, or by frameshift mutations in both proliferation-regulating and apoptosis-regulating genes such as transforming growth factor beta (TGF-ß) Type II receptor, BAX, or E2F-4. The aim of the subproject is to identify the two basic functions of MMR genes, i.e., the MMR by MSI testing and regulation of the G2/M checkpoint by determination of cell death (apoptotic rate). The expression of the underlying MMR genes (MSH2, MLH1, MSH6, and PMS2) will be quantified by reverse transcription-polymerase chain reaction (RT-PCR) and image analysis so as to further define the threshold values that determine either loss of repair or loss of cell death signaling. Because methylation is a major regulatory mechanism of MMR function in sporadic carcinomas, this aspect will be assessed by analyzing promoter methylation at MLH1 and histone methylation at H3 histone. All data will be correlated to the response to chemoradiotherapy and prognosis.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 179: Biological Basis of Individual Tumour Response in Patients with Rectal Cancer
• Participating Person: Professor Dr. Josef Rüschoff