New publication in the Mathematics in Oncology collaboration

Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics (doi: 10.1002/ijc.33273)

In frame of the “Mathematics in Oncology” collaborative initiative between EMCL and the Department of Applied Tumor Biology (ATB), Heidelberg University Hospital (, we aim to gain novel insights into cancer evolution through mathematical modeling of the underlying complex biological processes.

We focus on microsatellite-unstable (MSI) cancers, which show a high number of mutations due to a deficiency of the DNA mismatch repair system responsible for repairing mistakes occuring during DNA replication. MSI cancers develop in elderly patients sporadically and in younger patients in the context of Lynch syndrome, the most common inherited colorectal cancer syndrome. Lynch syndrome is associated with an increased life time risk of developing cancer in the large bowel (colorectal cancer), the endometrium and other organs.

Lynch syndrome is estimated to affect 1 out of 280 individuals, yet often remains undiagnosed. Thus, a diagnostic procedure with high sensitivity and specificity is of central clinical significance. As BRAF V600E mutations have been reported to be associated with sporadic MSI cancers, current international diagnostic guidelines recommend using BRAF mutations in order to distinguish between sporadic and likely hereditary MSI colorectal cancer. Due to a significant difference in age at diagnosis between sporadic and hereditary MSI CRC patients, we hypothesized that the performance of BRAF testing for identifying sporadic MSI CRC could be age-dependent.

In our recent study, we systematically analyzed data from published studies, public databases and population-base patient cohorts. In addition, we performed sensitivity analysis as well as cost calculations of BRAF testing. We identified that though being highly effective in older patients, BRAF testing led to a high risk of missing Lynch syndrome patients and increased costs at age <50 years, thereby showing its poor performance in this age group. We therefore suggest to directly refer MSI CRC patients <50 years to genetic counseling without BRAF testing.

The study was developed through the active Mathematics in Oncology collaboration (Link: with the Department of Applied Tumor Biology (ATB, Head: Magnus von Knebel Doeberitz), Heidelberg University Hospital, together with the Department of General Pathology, Institute of Pathology, University Hospital Leipzig and various institutions of other German universities. Hendrik Bläker from the University Hospital Leipzig, Michael Hoffmeister from the Division of Clinical Epidemiology and Aging Research, DKFZ (German Cancer Research Center), Aysel Ahadova and Matthias Kloor, both from ATB, designed the study, collected and analyzed data from different sources. From EMCL, Saskia Haupt and Vincent Heuveline were strongly involved in the analysis and interpretation of the data. The study titled “Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics” (doi: 10.1002/ijc.33273) was recently published in the International Journal of Cancer.