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

Matteo Cereda, Gennaro Gambardella, Lorena Benedetti, Fabio Iannelli, Dominic Patel, Gianluca Basso, Rosalinda F. Guerra, Thanos P. Mourikis, Ignazio Puccio, Shruti Sinha, Luigi Laghi, Jo Spencer, Manuel Rodriguez-Justo and Francesca D. Ciccarelli ()
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Matteo Cereda: King’s College London
Gennaro Gambardella: King’s College London
Lorena Benedetti: King’s College London
Fabio Iannelli: IFOM, FIRC Institute of Molecular Oncology
Dominic Patel: Cancer Institute, University College London
Gianluca Basso: Laboratory of Molecular Gastroenterology, Humanitas Research Hospital
Rosalinda F. Guerra: King’s College London
Thanos P. Mourikis: King’s College London
Ignazio Puccio: Cancer Institute, University College London
Shruti Sinha: King’s College London
Luigi Laghi: Laboratory of Molecular Gastroenterology, Humanitas Research Hospital
Jo Spencer: King’s College London
Manuel Rodriguez-Justo: Cancer Institute, University College London
Francesca D. Ciccarelli: King’s College London

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12072

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