Journal Article

Genomic and transcriptomic profiling of carcinogenesis in patients with familial adenomatous polyposis

Gao, Shuai, Tang, Fuchou, Wu, Xinglong, Wen, Lu, Wang, Wendong, Zhou, Xin, Guo, Limei, Li, Jingyun, Mao, Yunuo, Wang, Rui, Liu, Haijing, Fu, Wei

2020

Overview

ObjectiveFamilial 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.DesignWhole-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.ResultsGenomic 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.ConclusionsThe 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adenocarcinoma / Adenoma / Adenomatous Polyposis Coli - genetics / Adenomatous Polyposis Coli - metabolism / associated polyposis (MAP) / Carbohydrate metabolism / Carbohydrates / Carcinogenesis / Carcinogenesis - genetics / Carcinogenesis - metabolism / Carcinoma / Cell adhesion & migration / Colon / colon carcinogenesis / colorectal adenomas / Colorectal cancer / Colorectal carcinoma / Copy number / Deoxyribonucleic acid / DNA / Epithelium / Familial adenomatous polyposis / Familial adenomatous polyposis (FAP) / Female / Field cancerization / Gene expression / Gene Expression Profiling / Genes / Genetic disorders / Genomes / Genomics / Humans / Life sciences / Male / Metabolic Networks and Pathways - genetics / Metabolism / Mutation / Patients / Pedigree / Polyps / Precancerous Conditions - genetics / Precancerous Conditions - metabolism / Rectum / Ribonucleic acid / RNA / Sequence Analysis, RNA / Single-Cell Analysis / Single-cell transcriptome profiling / Transcriptomics / Tricarboxylic acid cycle / Tumor heterogeneity / Tumors / Whole Exome Sequencing / Whole Genome Sequencing