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

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Matteo Cereda ; Gennaro Gambardella ; Lorena Gabriela Benedetti ; Fabio Iannelli ; Dominic Patel ; Gianluca Basso ; Rosalinda Guerra ; Thanos P. Mourikis ; Ignazio Puccio ; Shruti Sinha ; Luigi Laghi ; Jo Spencer ; Manuel Rodriguez-Justo ; Francesca Donatella Ciccarelli

Original languageEnglish
JournalNature Communications
DOIs
StatePublished - 5 Jul 2016

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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 1000 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.

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