# The landscape of somatic mutation in normal colorectal epithelial cells

Source: https://onco.cc/key-papers/paper-lee-six-somatic-mutation-normal-colorectal-crypts-nature-2019/  
OnCo record `paper-lee-six-somatic-mutation-normal-colorectal-crypts-nature-2019` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Reading the whole genome of hundreds of individual healthy bowel glands from 42 people found that about one in a hundred already carries a cancer-driving mutation by middle age. Polyps and cancers are the rare survivors of a process happening everywhere in the bowel lining.

## Summary

Whole-genome sequencing was used to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed: some ubiquitous and continuous, others found only in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers showed substantially increased mutational burdens relative to normal cells.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature
- Year: 2019
- DOI: 10.1038/s41586-019-1672-7
- Authors: Lee-Six H, Olafsson S, Ellis P, et al.
- Findings: Probable driver mutations in about 1% of normal colorectal crypts in middle age.; Multiple mutational processes, some universal and continuous, others individual or episodic.; Cancers carry substantially higher mutation burdens than normal crypts.
- What it means: It sets the baseline the adenoma-carcinoma sequence starts from and warns against reading a driver mutation found in tissue, or in stool or blood, as evidence of cancer.
- Caveats: 42 individuals, mostly from surgical specimens.; Crypt-level whole-genome sequencing is laborious, so the sample of crypts per person is small.

## Sources

- Lee-Six et al., Nature 2019: whole genomes of hundreds of normal colorectal crypts from 42 people: https://doi.org/10.1038/s41586-019-1672-7
- PubMed: https://pubmed.ncbi.nlm.nih.gov/31645730/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [Single-cell & spatial profiling](https://onco.cc/technologies/single-cell-spatial/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [APC](https://onco.cc/targets/apc/), [KRAS](https://onco.cc/targets/kras/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Field cancerisation](https://onco.cc/pathways/field-cancerisation/), [Mutagenesis & mutational signatures](https://onco.cc/pathways/mutagenesis-signatures/)
- terms: [Driver mutation](https://onco.cc/terms/driver-mutation/), [Mutational signature](https://onco.cc/terms/mutational-signature/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)
- journals: [Nature](https://onco.cc/journals/nature/)

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