Abstract
Synchronous colorectal cancers (syCRCs) are two or more primary tumours identified simultaneously in a patient. Previous studies report high inter-tumour heterogeneity between syCRCs, suggesting independent origin and different treatment response, making their management particularly challenging, with no specific guidelines currently in place. Here, we performed in-depth bioinformatic analyses of genomic and transcriptomic data of a total of eleven syCRCs and one metachronous CRC collected from three patients. We found mixed microsatellite status between and within patients. Overlap of mutations between synchronous tumours was consistently low (<0.5%) and heterogeneity of driver events across syCRCs was high in all patients. Microbial analysis revealed the presence of Fusobacterium nucleatum species in patients with MSI tumours, while quantification of tumour immune infiltration showed varying immune responses between syCRCs. Our results suggest high heterogeneity of syCRCs within patients but find clinically actionable biomarkers that help predict responses to currently available targeted therapies. Our study highlights the importance of personalised genome and transcriptome sequencing of all synchronous lesions to aid therapy decision and improve management of syCRC patients.
Highlights
Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and the fourth leading cause of cancer-related deaths worldwide[1]
The shared molecular subtype of A1 and A2 is not unexpected, as Increasing numbers of synchronous CRCs (syCRCs) are identified as early diagnosis technologies improve. syCRCs have distinguishing features to solitary CRCs, with currently no specific guidelines to their management[27,28]
Our results show a high degree of genetic heterogeneity between syCRCs
Summary
Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and the fourth leading cause of cancer-related deaths worldwide[1]. Knowledge on the status of said features in a cancer provides biomarkers that predict its response to targeted therapies, such as KRAS wild type status for anti-EGFR therapy, BRAF mutant status for combined BRAF and MEK inhibition therapy, MSI status for immunotherapy, high CIN for VEGF-A combination therapy, and Fusobacterium-load for antimicrobial intervention[10,11,12,13,14,15,16,17,18,19,20,21]. Previous studies on syCRCs have reported high heterogeneity of variants between synchronous tumours, with distinct mutations occurring in known CRC genes, and variation between tumour signature content, immune cell scores and MSI status[29,30,31,32]. We assessed the extent of genetic overlap between synchronous tumours and examined associations between clinicopathological information and the molecular, microbial and immune features of each tumour genome
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