Clinical implications of intra-tumour heterogeneity in colon cancer
Colorectal cancer (CRC) is the second most common cancer in Czech Republic and one of the leading causes of death. Despite recent advances, the recognition of high risk cases in early stages and the identification of the effective drug regimen remain challenging. A key factor limiting our ability to identify accurate prognostic and predictive biomarkers is the intra-tumour heterogeneity (ITH) (McGranahan, Swanton Cell 2017). Hence, there is an immediate need to understand to what extent our current molecular tests are influenced by ITH and whether a more targeted tumour sampling would lead to more accurate prognostic and predictive biomarkers.
The current proposal aims at studying the clinical implications of ITH by using multi-region tumour sampling. DNA and RNA will be extracted from morphologically distinct tumour regions (e.g. serrated/papillary, invasion front, etc.) and used for the identification of clinically actionable biomarkers. The project has two major directions of investigation. A first one studies the mutation heterogeneity of primaries for tumours with short vs longer progression-free survival in metastatic setting under anti-EGFR first line treatment. The second direction addresses the question of ITH impact on predicting the time-to-relapse for stage II patients not undergoing adjuvant chemotherapy.
The use of more uniform regions (from a cell composition perspective) may allow unveiling novel biomarkers that otherwise would be obscured by the dominant cell population from bulk tumour sampling. Also, by anchoring the tumour sampling to clearly identifiable morphological region, these biomarkers would be reproducible across studies, bringing them closer to a clinical application.