Objective Familial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of adenomas at different evolutionary stages in the colon and rectum that will inevitably progress to adenocarcinomas if left untreated. Here, we investigated the genetic alterations and transcriptomic transitions from precancerous adenoma to carcinoma.
Design Whole-exome sequencing, whole-genome sequencing and single-cell RNA sequencing were performed on matched adjacent normal tissues, multiregionally sampled adenomas at different stages and carcinomas from six patients with FAP and one patient with MUTYH-associated polyposis (n=56 exomes, n=56 genomes and n=8,757 single cells). Genomic alterations (including copy number alterations and somatic mutations), clonal architectures and transcriptome dynamics during adenocarcinoma carcinogenesis were comprehensively investigated.
Results Genomic evolutionary analysis showed that adjacent lesions from the same patient with FAP can originate from the same cancer-primed cell. In addition, the tricarboxylic acid cycle pathway was strongly repressed in adenomas and was then slightly alleviated in carcinomas. Cells from the ‘normal’ colon epithelium of patients with FAP already showed metabolic reprogramming compared with cells from the normal colon epithelium of patients with sporadic colorectal cancer.
Conclusions The process described in the previously reported field cancerisation model also occurs in patients with FAP and can contribute to the formation of adjacent lesions in patients with FAP. Reprogramming of carbohydrate metabolism has already occurred at the precancerous adenoma stage. Our study provides an accurate picture of the genomic and transcriptomic landscapes during the initiation and progression of carcinogenesis, especially during the transition from adenoma to carcinoma.
- colon carcinogenesis
- colorectal adenomas
- Familial adenomatous polyposis (FAP)
- MUTYH-associated polyposis (MAP)
- Field cancerization
- Single-cell transcriptome profiling
- Tumor heterogeneity
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JL, RW, XZ and WW contributed equally.
Contributors FT, WF and XZ conceived the project. JL designed and performed the single cell RNA-seq, whole-exome sequencing and whole-genome sequencing experiments, with the help of XZ, SG, YM, XW, LG and HL. XZ performed the patient’s enrollment. XZ and WW performed tissue sampling and the H&E and immunohistochemical staining. RW conducted the bioinformatics analyses with the help of JL. HL and LG performed the histopathological reviews. JL and FT wrote the manuscript with the help from all authors.
Funding This study was funded by Beijing Advanced Innovation Center for Genomics.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval Our study was approved by the Ethics Committee of Peking University Third Hospital (M2016170), and informed consent was signed by all involved patients before surgery.
Provenance and peer review Not commissioned; externally peer reviewed.
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