Personalised mapping of tumour development in synchronous colorectal cancer patients

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.

Multifocal organoids reveal clonal associations between synchronous intestinal tumors with pervasive heterogeneous drug responses

“…A total of 1032 mutations were detected in PDO samples, 108 mutations (10%) were concordantly found in all PDO regions, and 6–26 (0.58–2.5%) mutations were overlapped between PDOs. Our result was accordant with previous studies of SIC that reported intersection of mutations between tumors was consistently low 4 . Prevalent genetic alterations in CRC such as inactivating mutations in FBXW7 (p.Try545Cys and p.Arg479*), APC ( p.Thr621fs and p.Ser1415fs), and TP53 (p.Arg306*) as well as activating mutations in KRAS (p.Gly12Phe) and PIK3CA (p.Glu545Gly) were detected in all tumors with variant allele frequencies (VAFs) of ~0.5 except for TP53 [variant allele frequency (VAF) = ~1.0].…”

“…Although the clinicopathologic evaluation and a few genetic predispositions verified the intertumoral heterogeneity of multifocal CRCs, the clonal association among multiple tumors with respect to molecular characteristics remains unexplained. Only a few recent studies using multiregional sequencing approaches have indicated that the multifocal CRCs are not entirely independent of each other but clonally related in terms of mutational profiles and DNA copy numbers 3 , 4 . Nevertheless, the clonal relationship of multifocal CRCs at transcriptomic and epigenomic levels has not been thoroughly investigated, and more importantly, its implication with clinically applicable therapeutic compounds was not determined.…”

Molecular characterization of ulcerative colitis-associated colorectal carcinomas

“…Despite multifocality, we observed a strong convergent evolution for TP53 mutations shaping the genomic alterations in UC-CRC in addition to chromosomal aneuploidies, underlining the critical role of TP53 in UC-related colorectal carcinogenesis. Interestingly, synchronous CRCs not associated with IBD show more variation in terms of affected driver genes, most frequently affecting APC , KRAS , TP53 and PIK3CA , and molecular alterations of lesions from the same patient are usually distinct, indicating independent development of synchronous non-IBD-related CRCs ( 68 – 70 ).…”

Genome Sequencing of Multiple Primary Lung Cancers Harbouring Mixed Histology and Spontaneously Regressing Small-Cell Lung Cancer

“…The analysis of multi-region biopsies should be considered in the future, as this might provide key information on the evolutionary relationship between lesions. As reported in other cancer types [ 36 ], patients with multiple primary lesions present complex scenarios that need to be carefully assessed. Our study revealed the status of several known targetable biomarkers for each MPLC, providing essential information for the personalised treatment of the patient.…”