Functional Genome Analysis  (B070)
Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580
D-69120 Heidelberg, Germany.




  Transcript Studies

Blood-based microRNA Diagnostics
Other microRNA Studies
mRNA Studies

       - Liquid biopsy for accurate IPMN stratification 
    - Melanoma tumour-niche formation

       - Liquid biopsy for colorectal cancer diagnosis
    - Pancreatic cancer progression
       - Detailed review of blood-based diagnosis
         of pancreatic cancer


For the understanding of the complex regulative mechanisms and the investigation of  the cellular control management, a simultaneous analysis of the expression of all genes of an organism under various conditions and over time is indispensable. Our emphasis is on studying human cancer material and analyses particularly at the level of microRNA, with other RNA types also being worked at, although to a lesser extent. Information is gathered for enabling early diagnosis and accurate prognosis, the identification of potentially interesting avenues for therapy as well as the evaluation of the success of disease treatment. For this, the measurements of transcriptional variations are combined with the analysis of epigenetic modulations of the genomic DNA and actual protein expression. For particular microRNA molecules, their mode of action is studied in detail, elucidating the mechanisms by which their activity is transformed into function.



Blood-based diagnosis and risk stratification of patients with intraductal papillary mucinous neoplasm (IPMN) to decide on surgical intervention

Intraductal papillary mucinous neoplasm (IPMN) is a precursor of PDAC. Patients with low-grade dysplasia have a relatively good prognosis and are kept under surveillance to monitor disease development, whereas high-grade dysplasia and IPMN invasive carcinoma require tumour resection. Diagnostic distinction of the two groups is difficult, however.

We aimed to identify variations in protein concentration in peripheral blood for accurate discrimination. Sera from IPMN patients and health
y donors were analysed on microarrays made of antibodies for studying protein level variations. For microRNA (miRNA) biomarkers, a PCR-based screen was performed and biomarker candidates confirmed by quantitative PCR.

A support vector machine (SVM) algorithm defined classifiers, which were validated on a separate sample set. A panel of five proteins and three miRNAs could distinguish high- and low-risk IPMN with an accuracy of 97%. This is substantially better than the accuracy obtained in the same patient cohort by using the guideline criteria for decision-making on performing surgery or not. The precise blood-based diagnosis and risk stratification will improve patient management and thus the prognosis of IPMN patients. In addition to the main finding, highly accurate discrimination was also achieved between other patient subgroups
Zhang et al. (2023) Clin. Cancer Res. 29, 1535-1545. pdf icon

Figure legend: (Left)
Diagnostic performance of clinical parameters to discriminate high-risk from low-risk IPMN according to current guidelines. (Right) Much better results were obtained by a combined panel of 5 protein and 3 miRNA biomarkers. The results are presented as ROC curves and corresponding AUC values as determined in the training and validation cohorts, respectively.


MicroRNAs in blood act as biomarkers of colorectal cancer and indicate potential therapeutic targets

Association studies have linked alterations of blood-derived microRNAs (miRNAs) with colorectal cancer (CRC). We performed a microarray-based comparison of the profiles of 2,549 miRNAs in 80 blood samples from healthy donors and patients with colorectal adenomas, colorectal diverticulitis and CRC at different stages. Confirmation by quantitative real-time PCR (RT-PCR) was complemented by validation of identified molecules in another 36 blood samples.


No variations in miRNA levels were observed in samples from patients with colorectal adenomas and diverticulitis or from healthy donors. However, there were 179 CRC-associated miRNAs of differential abundance compared to healthy controls. Only three – miR-1225-5p, miR-1207-5p and miR-4459 – exhibited increased levels at all CRC stages. Most deregulated miRNAs (128/179, 71%) specifically predicted metastatic CRC. Pathway analysis found several cancer-related pathways to which the miRNAs contribute in various ways. In conclusion, miRNA levels in blood vary throughout CRC progression and affect cellular functions relevant to haematogenous CRC progression and dissemination.

Stang et al. (2021) Mol. Oncol. 15, 2480-2490. 
pdf icon

Blood biomarkers for differential diagnosis and early detection of pancreatic cancerr

Pancreatic cancer is currently the most lethal tumour entity and case numbers are rising. It will soon be the second most frequent cause of cancer-related death in the Western world. Mortality is close to incidence and patient survival after diagnosis stands at about five months.
Blood-based diagnostics could be a crucial factor for improving this dismal situation and is at a stage that could make this possible. We reviewed in much detail the current state of affairs with its problems and promises, looking at various molecule types including microRNAs. Reported results were evaluated in the overall context. Also, we proposed steps toward clinical utility that should advance the development toward clinical application by improving biomarker quality but also by defining distinct clinical objectives and the respective diagnostic accuracies required to achieve them. Many of the discussed points and conclusions are highly relevant to other solid tumours, too.

Al-Shaheri et al. (2021) Cancer Treat. Rev. 96, 102193.  pdf icon


Figure legend. Aspects of PDAC tumour development and possible application areas of liquid biopsy diagnostics. Many processes during tumorigenesis result in molecular changes that may be detectable in peripheral blood. After transformation, factors released for niche formation or as part of the molecular communication between cells of the tumour microenvironment could circulate in the blood and permit detection at early stages. Furthermore, such biomarkers could provide valuable information for a differential diagnosis, discriminating malign from benign diseases, for example, or allowing therapy monitoring.

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