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Colorectal Cancer Is Associated with the Presence of Cancer Driver Mutations in Normal Colon
Julia Matas1,2, Brendan Kohrn1, Jeanne Fredrickson1
1Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington.
Cancer Research
|April 15, 2022
Summary
Normal colon tissue from patients with colorectal cancer harbors more mutations than healthy tissue. Ultrasensitive testing reveals these early genetic changes may predict cancer risk.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Somatic mutations in colorectal cancer are known, but their presence in normal colon tissue prior to cancer development is poorly understood.
- Understanding early mutational events in the colon is crucial for identifying individuals at higher risk for colorectal cancer.
Purpose of the Study:
- To investigate the accumulation and characteristics of somatic mutations in normal colon tissue.
- To determine if these mutations differ between individuals with and without colorectal cancer.
- To explore the potential of ultrasensitive mutation detection for predicting colorectal cancer risk.
Main Methods:
- Development and application of an ultrasensitive, single-molecule mutational test utilizing CRISPR-DS technology.
- Detection of mutations at very low frequencies (<0.001) in normal colon tissue samples.
- Analysis of mutations in common colorectal cancer genes, including KRAS and TP53.
Main Results:
- Normal colon tissue from both cancer patients and healthy individuals contains mutations in common colorectal cancer genes.
- Mutations are significantly more abundant in normal colon tissue from patients with colorectal cancer.
- Oncogenic KRAS mutations were found in approximately one-third of normal colon samples from colorectal cancer patients, but none from healthy controls.
- TP53 mutations were more frequent, pathogenic, and formed larger clones in patients with colorectal cancer, particularly early-onset cases.
- Most mutations in normal colon tissue were distinct from tumor driver mutations, suggesting independent clonal evolution.
Conclusions:
- Somatic evolution and clonal expansion occur in the normal colon, a process enhanced in individuals who develop colorectal cancer.
- The presence of pathogenic KRAS and TP53 mutations in normal colon tissue is a common event preceding colorectal cancer development.
- Ultrasensitive gene sequencing of normal colon tissue shows promise for predicting colorectal cancer risk, especially for early-onset disease.
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