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Original research
Genomic and transcriptomic profiling of carcinogenesis in patients with familial adenomatous polyposis
  1. Jingyun Li1,2,3,4,
  2. Rui Wang1,2,4,
  3. Xin Zhou1,
  4. Wendong Wang1,
  5. Shuai Gao1,
  6. Yunuo Mao1,
  7. Xinglong Wu1,
  8. Limei Guo5,
  9. Haijing Liu5,
  10. Lu Wen1,
  11. Wei Fu1,
  12. Fuchou Tang1,2,3,4
  1. 1 Beijing Advanced Innovation Center for Genomics, Department of General Surgery, College of Life Sciences, Third Hospital, Peking University, Beijing, China
  2. 2 Biomedical Pioneering Innovation Center & Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing, China
  3. 3 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
  4. 4 Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
  5. 5 Department of Pathology, School of Basic Medical Sciences, Third Hospital, Peking University Health Science Center, Peking University, Beijing, China
  1. Correspondence to Professor Fuchou Tang, Beijing Advanced Innovation Center for Genomics, Department of General Surgery, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, China; tangfuchou{at}pku.edu.cn; Professor Wei Fu, Beijing Advanced Innovation Center for Genomics, Department of General Surgery, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, China, Beijing, China; fuwei{at}bjmu.edu.cn

Abstract

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
http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • 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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