Clinical Multigene Panel Sequencing Identifies Distinct Mutational Association Patterns in Metastatic Colorectal Cancer

Francesca Belardinilli, Carlo Capalbo, Umberto Malapelle, Pasquale Pisapia, Domenico Raimondo, Edoardo Milanetti, Mahdavian Yasaman, Carlotta Liccardi, Paola Paci, Pasquale Sibilio, Francesco Pepe, Caterina Bonfiglio, Silvia Mezi, Valentina Magri, Anna Coppa, Arianna Nicolussi, Angela Gradilone, Marialaura Petroni, Stefano Di Giulio, Francesca FabrettiPaola Infante, Sonia Coni, Gianluca Canettieri, Giancarlo Troncone, Giuseppe Giannini

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number560
JournalFrontiers in Oncology
Volume10
DOIs
Publication statusPublished - May 7 2020

Keywords

  • genes
  • mCRC
  • molecular stratification
  • mutation
  • NGS

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Clinical Multigene Panel Sequencing Identifies Distinct Mutational Association Patterns in Metastatic Colorectal Cancer'. Together they form a unique fingerprint.

Cite this