APA
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Kumbrink, J., Bohlmann, L., Mamlouk, S., Redmer, T., Peilstöcker, D., Li, P., … Holch, J. (2022). Serial Analysis of Gene Mutations and Gene Expression during First-Line Chemotherapy against Metastatic Colorectal Cancer: Identification of Potentially Actionable Targets within the Multicenter Prospective Biomarker Study REVEAL. Cancers.
Chicago/Turabian
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Kumbrink, J., Lisa Bohlmann, S. Mamlouk, T. Redmer, Daniela Peilstöcker, Pan Li, S. Lorenzen, et al. “Serial Analysis of Gene Mutations and Gene Expression during First-Line Chemotherapy against Metastatic Colorectal Cancer: Identification of Potentially Actionable Targets within the Multicenter Prospective Biomarker Study REVEAL.” Cancers (2022).
MLA
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Kumbrink, J., et al. “Serial Analysis of Gene Mutations and Gene Expression during First-Line Chemotherapy against Metastatic Colorectal Cancer: Identification of Potentially Actionable Targets within the Multicenter Prospective Biomarker Study REVEAL.” Cancers, 2022.
BibTeX Click to copy
@article{j2022a,
title = {Serial Analysis of Gene Mutations and Gene Expression during First-Line Chemotherapy against Metastatic Colorectal Cancer: Identification of Potentially Actionable Targets within the Multicenter Prospective Biomarker Study REVEAL},
year = {2022},
journal = {Cancers},
author = {Kumbrink, J. and Bohlmann, Lisa and Mamlouk, S. and Redmer, T. and Peilstöcker, Daniela and Li, Pan and Lorenzen, S. and Algül, H. and Kasper, S. and Hempel, D. and Kaiser, F. and Michl, M. and Bartsch, H. and Neumann, J. and Klauschen, F. and von Bergwelt-Baildon, M. and Modest, D. and Stahler, A. and Stintzing, S. and Jung, A. and Kirchner, T. and Schäfer, R. and Heinemann, V. and Holch, J.}
}
Simple Summary The emergence of resistant cells remains a major obstacle for chemotherapy treatment of metastatic colorectal cancers. Improvement of the therapeutic response requires a thorough understanding of the mechanisms of resistance as well as informative biomarkers. In the REVEAL study, we have systematically compared the mutational patterns and expression profiles of primary tumor specimens before and after first-line chemotherapy treatment in the metastatic situation. In addition, we analyzed liquid biopsies pre, during, and after treatment. Alterations in gene expression appeared as the major drivers of chemotherapy resistance. We identified a gene expression signature differentiating primary tumors and metastases and validated this signature in two independent patient cohorts. Moreover, we evaluated the expression of two signature genes, SFRP2 and SPP1, as prognostic and potentially druggable biomarkers. Abstract Most metastatic colorectal cancer (mCRC) patients succumb to refractory disease due to secondary chemotherapy resistance. To elucidate the molecular changes associated with secondary resistance, we recruited 64 patients with mCRC and hepatic metastases before standard first-line chemotherapy between 2014 and 2018. We subjected DNA from primary tumor specimens (P), hepatic metastasis specimens after treatment (M), and liquid biopsies (L) taken prior to (pre), during (intra), and after (post) treatment to next generation sequencing. We performed Nanostring expression analysis in P and M specimens. Comparative bioinformatics and statistical analysis revealed typical mutational patterns with frequent alterations in TP53, APC, and KRAS in P specimens (n = 48). P and pre-L (n = 42), as well as matched P and M (n = 30), displayed a similar mutation spectrum. In contrast, gene expression profiles classified P (n = 31) and M (n = 23), distinguishable by up-regulation of immune/cytokine receptor and autophagy programs. Switching of consensus molecular subtypes from P to M occurred in 58.3% of cases. M signature genes SFRP2 and SPP1 associated with inferior survival, as validated in an independent cohort. Molecular changes during first-line treatment were detectable by expression profiling rather than by mutational tumor and liquid biopsy analyses. SFRP2 and SPP1 may serve as biomarkers and/or actionable targets.
