1. Clinical Multigene Panel Sequencing Identifies Distinct Mutational Association Patterns in Metastatic Colorectal Cancer
- Author
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Paola Infante, Arianna Nicolussi, Francesca Fabretti, Gianluca Canettieri, Carlotta Liccardi, Umberto Malapelle, Mahdavian Yasaman, Giancarlo Troncone, Valentina Magri, Paola Paci, Francesca Belardinilli, Edoardo Milanetti, Stefano Di Giulio, Pasquale Pisapia, Caterina Bonfiglio, Anna Coppa, Francesco Pepe, Carlo Capalbo, Silvia Mezi, Pasquale Sibilio, Domenico Raimondo, Angela Gradilone, Marialaura Petroni, Giuseppe Giannini, Sonia Coni, Belardinilli, F., Capalbo, C., Malapelle, U., Pisapia, P., Raimondo, D., Milanetti, E., Yasaman, M., Liccardi, C., Paci, P., Sibilio, P., Pepe, F., Bonfiglio, C., Mezi, S., Magri, V., Coppa, A., Nicolussi, A., Gradilone, A., Petroni, M., Di Giulio, S., Fabretti, F., Infante, P., Coni, S., Canettieri, G., Troncone, G., and Giannini, G.
- Subjects
0301 basic medicine ,Cancer Research ,molecular stratification ,mCRC, NGS, molecular stratification, mutation, genes ,Colorectal cancer ,Disease ,Computational biology ,Gene mutation ,Biology ,lcsh:RC254-282 ,Tumor heterogeneity ,DNA sequencing ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Epigenetics ,gene ,genes ,Gene ,Original Research ,Oncogene ,COMPUTATIONAL AND SYSTEMS BIOLOGY ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Oncology ,mCRC ,030220 oncology & carcinogenesis ,NGS ,mutation - Abstract
Extensive molecular characterization of human colorectal cancer (CRC) via Next Generation Sequencing (NGS) indicated that genetic or epigenetic dysregulation of a relevant, but limited, number of molecular pathways typically occurs in this tumor. The molecular picture of the disease is significantly complicated by the frequent occurrence of individually rare genetic aberrations, which expand tumor heterogeneity. Inter- and intratumor molecular heterogeneity is very likely responsible for the remarkable individual variability in the response to conventional and target-driven first-line therapies, in metastatic CRC (mCRC) patients, whose median overall survival remains unsatisfactory. Implementation of an extensive molecular characterization of mCRC in the clinical routine does not yet appear feasible on a large scale, while multigene panel sequencing of most commonly mutated oncogene/oncosuppressor hotspots is more easily achievable. Here, we report that clinical multigene panel sequencing performed for anti-EGFR therapy predictive purposes in 639 formalin-fixed paraffin-embedded (FFPE) mCRC specimens revealed previously unknown pairwise mutation associations and a high proportion of cases carrying actionable gene mutations. Most importantly, a simple principal component analysis directed the delineation of a new molecular stratification of mCRC patients in eight groups characterized by non-random, specific mutational association patterns (MAPs), aggregating samples with similar biology. These data were validated on a The Cancer Genome Atlas (TCGA) CRC dataset. The proposed stratification may provide great opportunities to direct more informed therapeutic decisions in the majority of mCRC cases.
- Published
- 2019