Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes

• Published in: Nature communications 2016-07, Vol.7 (1), p.12072-12072, Article 12072
• Main Authors: Cereda, Matteo, Gambardella, Gennaro, Benedetti, Lorena, Iannelli, Fabio, Patel, Dominic, Basso, Gianluca, Guerra, Rosalinda F., Mourikis, Thanos P., Puccio, Ignazio, Sinha, Shruti, Laghi, Luigi, Spencer, Jo, Rodriguez-Justo, Manuel, Ciccarelli, Francesca D.
• Format: Article
• Language: English
• Subjects: 13/51; 38/91; 631/208/68; 631/208/737; 631/67/2329; 692/699/67/1504/1885; Adult; Aged; Aged, 80 and over; Case-Control Studies; Clone Cells; Cloning; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Cytokines - genetics; Cytokines - immunology; Female; Gastroenterology; Genetic Heterogeneity; Genetic Predisposition to Disease; Genomes; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humanities and Social Sciences; Humans; Male; multidisciplinary; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; Neoplasms, Multiple Primary - genetics; Neoplasms, Multiple Primary - immunology; Neoplasms, Multiple Primary - pathology; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Science; Science (multidisciplinary); Toll-Like Receptors - genetics; Toll-Like Receptors - immunology; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12072

Synchronous colorectal cancers (syCRCs) are physically separated tumours that develop simultaneously. To understand how the genetic and environmental background influences the development of multiple tumours, here we conduct a comparative analysis of 20 syCRCs from 10 patients. We show that syCRCs have independent genetic origins, acquire dissimilar somatic alterations, and have different clone composition. This inter- and intratumour heterogeneity must be considered in the selection of therapy and in the monitoring of resistance. SyCRC patients show a higher occurrence of inherited damaging mutations in immune-related genes compared to patients with solitary colorectal cancer and to healthy individuals from the 1,000 Genomes Project. Moreover, they have a different composition of immune cell populations in tumour and normal mucosa, and transcriptional differences in immune-related biological processes. This suggests an environmental field effect that promotes multiple tumours likely in the background of inflammation. Some individuals present with multiple synchronous colorectal tumours, but the genetic understanding of this is unclear. Here, the authors use a sequencing strategy to show that the synchronous tumours are genetically independent and the patients harbour rare germline damaging mutations in genes associated with the immune system.