The molecular landscape of synchronous colorectal cancer reveals genetic heterogeneity

Abstract

Synchronous colorectal cancers (syCRCs), which present two or more lesions at diagnosis, are rare and pose a great challenge for clinical management. Although some predisposing factors associated with syCRCs have been studied with limited accession, the full repertoire of genomic events among the lesions within an individual and the causes of syCRCs remain unclear. We performed whole-exome sequencing of 40 surgical tumour samples of paired lesions from 20 patients to characterize the genetic alterations. Lesions from same patient showed distinct landscapes of somatic aberrations and shared few mutations, which suggests that they originate and develop independently, although they shared the similar genetic background. Canonical genes, such as APC, KRAS, TP53 and PIK3CA, were frequently mutated in the syCRCs, and most of them show different mutation profile compared with solitary colorectal cancer. We identified a recurrent somatic alteration (K15fs) in RPL22 in 25% of the syCRCs. Functional analysis indicated that mutated RPL22 may suppress cell apoptosis and promote the epithelial–mesenchymal transition (EMT). Potential drug targets were identified in several signalling pathways, and they present great discrepancy between lesions from the same patient. Our data show that the syCRCs within the same patient present great genetic heterogeneity, and they may be driven by distinct molecular events and develop independently. The discrepancy of potential drug targets and mutation burden in lesions from one patient provides valuable information in clinical management for patients with syCRCs.

Exome and immune cell score analyses reveal great variation within synchronous primary colorectal cancers

“…8,[13][14][15] Thus far, there has been only a few exome-wide studies on SCRC and one study including whole-genome sequencing data of a SCRC case. [16][17][18][19] In general, these studies have supported the idea of independent origins of synchronous tumours. Another hypothesis underlying SCRC, in addition to a common progenitor, is the field effect.…”

Personalised mapping of tumour development in synchronous colorectal cancer patients

“…In patient C, this shared mutation could either suggest a common tumour origin or is a striking example of convergent evolution in tumour development, likely arising via the serrated BRAF pathway from sessile serrated polyp precursors. However, overall our results suggest syCRCs have a tendency to originate independently, while often accessing the same mutational processes 29,30,32 . In terms of the temporal development of the tumours, for the older patients B (79 years of age) and C (70 years of age) there are no records of prior endoscopy or biopsies prior to the index admission.…”

“…Predisposing known genetic conditions are causative for about only 10% of syCRCs 27 , suggesting that other genetic and environmental risk factors are involved. 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] . Although prognosis of syCRC patients does not seem to vary significantly from that of solitary CRC patients 30,33 , an understanding of the mechanisms implicated in this phenomenon is still limited and no specific guidelines are currently available for the management and treatment of synchronous cases.…”

Tumor Seeding During Colonoscopy as a Possible Cause for Metachronous Colorectal Cancer

“…However, this is not supported by previous studies that showed distinct molecular profiles in synchronous and metachronous tumors, nor is it supported by the distinct molecular profiles that we observed in our control group (Table 3). 13,14 Moreover, the experiments conducted do not exclude possibilities of tumor transmission other than working channel contamination, such as exfoliation of cancer cells passively being taken up into biopsied or polypectomy site tissue. 7 Studies on tumor regrowth based on exfoliated cells performed in rats showed that colon cancer cells have the ability to regrow on damaged mucosa in a minority of cases, whereas an intact mucosa was seen to be completely resistant.…”