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[Scientific research] Genome and transcriptome analysis of carcinogenesis in patients with familial

Today, I will analyze an article published in GUT by Peking University Tang Fuchou's research group, titled: 'Genomic and transcriptomic profiling of carcinogenesis in patients with familial adenomatous polyposis'. In this article, adjacent normal tissues, adenomas and carcinomas of different stages from the same patient were collected simultaneously, and a multi-regional sampling strategy was used to study intratumor heterogeneity. Three sets of data were collected simultaneously for each lesion: WES, WGS, and single-cell RNA-seq data. A comprehensive study of the genomic landscape and clonal structure of lesions in different stages of the same FAP patient was performed. In addition, we used single-cell RNA-seq data to investigate transcriptome heterogeneity between multi-regional lesions in the same FAP patient and to explore transcriptome dynamics in tumor cells during colorectal adenoma initiation and carcinogenesis.

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome mainly caused by inherited mutations in the gene APC. Patients with FAP develop hundreds to thousands of adenomas in the colon and rectum, which will inevitably develop into adenocarcinomas if left untreated.

Compared with non-FAP colorectal cancer patients, the diseased tissue in FAP patients will be in multiple stages, that is, there are different lesions such as normal epithelium, different grades of adenoma, early cancer, and advanced cancer in the same patient. This makes FAP an ideal natural model for tracking the occurrence and development of colorectal cancer.

result 1:Title Genome-altering landscape


The cohort of this study included 6 patients with FAP, 1 patient with MUTHY-associated polyposis (MAP), and 2 patients with sporadic colorectal cancer. A total of 56 samples were collected: 6 peripheral blood, 12 adjacent normal tissues, 23 low-grade adenomas, 5 high-grade adenomas, and 10 cancer samples. The smallest adenoma was 2 mm in diameter and the largest carcinoma was 50 mm in diameter.

Through WES data analysis, a total of 8327 somatic mutations were found in 67 samples. A total of 4,220 potential pathogenic variants were identified after screening. The article counts somatic mutations, copy number deletions and copy number alterations (CNAs), and the results show that APC has the highest mutation frequency. Low-grade adenomas already have more somatic mutations than adjacent normal tissue. Cancer tissue samples had a relatively higher mutational load compared with low-grade adenomas.


Result 2: The clonal structure of lesions in different stages of the same FAP patient

A lineage tree was constructed for the somatic mutation profiles of different sites in a single patient. The shared mutations in the FAP1 samples were higher than the non-shared mutations, indicating that these spatially separated lesions were monoclonal and originated from the same cell. The same phenomenon was seen in other samples, suggesting that precancerous cells accumulate potentially pathogenic mutations that give them a proliferative advantage, and then their daughter cells expand into adjacent regions through crypt fission, and as other pathogenic events accumulate, form Spatially separated lesions. This phenomenon suggests that causative events may exist before clinically identifiable adenomas appear.


Result 3: Normal epithelial cell metabolic process and proliferative activity are enhanced in FAP patients

In this paper, the transcriptome data of epithelial cells from patients with FAP and normal sporadic colorectal cancer were compared and analyzed, and the most significantly up-regulated gene in the epithelium of FAP was OLFM4, which was reported as a marker of intestinal stem cells and CRC cell subsets; One up-regulated gene, ATF3, is an oncogenic repressor transcription factor that can be induced by hypoxia. Pathway enrichment analysis showed that up-regulated genes in FAP patients had strong enrichment signals in metabolic processes such as peptide biosynthesis, nucleotide metabolism, amino acid metabolism, lipid metabolism and carbohydrate metabolism.



Results 4: Transcriptome heterogeneity in different evolutionary stages of FAP

In this paper, we analyze the transcriptional heterogeneity in the process of FAP through single-cell sequencing data of patients with FAP. All FAP1 epithelial cells were divided into 4 groups by tSNE analysis. The 4 groups of cell samples were divided into adenoma and carcinoma groups according to their different spatial locations, and each group had its own distinct transcriptomic signature. These results suggest that the transcriptomic heterogeneity of tumors may be determined by their spatial location. , and is affected by the surrounding microenvironment. However, no spatial region-specific transcriptomic signature was found in low-grade adenoma samples of FAP4 and FAP5.


Finding 5: The metabolic signature of cancer has been established in precancerous adenomas

This paper analyzes the dynamic changes of the transcriptome during the transition from adenocarcinoma to cancer, and divides the genes into 4 groups according to the different trends. The first group of genes showed increased expression levels in the adjacent normal epithelium. During carcinogenesis, these genes are first down-regulated in early lesion stages and then up-regulated in later stages. These genes are involved in the tricarboxylic acid cycle (TCA) cycle, respiratory electron transport, glucose production, mitochondrial activity, and more. This result is consistent with previous findings that cancer cells primarily use glycolysis rather than the TCA pathway for energy production. Most genes involved in the TCA cycle were first downregulated from adjacent normal epithelium to adenomas and then slightly upregulated from adenomas to carcinomas, suggesting that the TCA pathway has been strongly repressed in precancerous adenomas.

Genes in group 2 also showed down-regulation in early stages of carcinogenesis, whereas genes in group 3 were not down-regulated until later stages of carcinogenesis. Genes in group 2 were enriched in metabolic signaling pathways, while those in group 3 were enriched in ionostatic and apoptotic signaling pathways. Genes in group 4 are up-regulated late in cancer development and are enriched in bone marrow leukocyte activation, wound healing, and cellular responses to acidic chemicals.



【1】Li J, Wang R, Zhou X, et al. Genomic and transcriptomic profiling of carcinogenesis in patients with familial adenomatous polyposis[J]. Gut, 2020, 69(7): 1283-1293.

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