title: Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes.
abstract: 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.
authors.affiliation: Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cereda
authors.affiliation: Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Gambardella
authors.affiliation: Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Lorena
authors.initials: L
authors.lastname: Benedetti
authors.affiliation: IFOM, FIRC Institute of Molecular Oncology, Milan 20139, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Iannelli
authors.affiliation: Department of Research Pathology, Cancer Institute, University College London, London WC1E 6JJ, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Patel
authors.affiliation: Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Research Hospital, Rozzano (MI) 20089, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Basso
authors.affiliation: Department of Craniofacial Development &Stem Cell Biology, King's College London, London SE1 9RT, UK.
authors.forename: Rosalinda F
authors.initials: RF
authors.lastname: Guerra
authors.affiliation: Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Thanos P
authors.initials: TP
authors.lastname: Mourikis
authors.affiliation: Department of Research Pathology, Cancer Institute, University College London, London WC1E 6JJ, UK.
authors.forename: Ignazio
authors.initials: I
authors.lastname: Puccio
authors.affiliation: Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Research Hospital, Rozzano (MI) 20089, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Laghi
authors.affiliation: Department of Immunobiology, King's College London, London, SE1 9RT, UK.
authors.forename: Jo
authors.initials: J
authors.lastname: Spencer
authors.affiliation: Department of Research Pathology, Cancer Institute, University College London, London WC1E 6JJ, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.affiliation: Division of Cancer Studies, King's College London, London SE1 1UL, UK.
authors.forename: Francesca D
authors.initials: FD
authors.lastname: Ciccarelli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002999:Clone Cells; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D051193:Toll-Like Receptors