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Phenotypic plasticity and genetic control in colorectal cancer evolution
Jacob Househam1,2, Timon Heide1,3, George D Cresswell1
1Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
Nature
|October 26, 2022
Summary
Most genetic changes in colorectal cancer (CRC) do not impact gene expression or tumor evolution. Instead, transcriptional plasticity, or the ability of genes to change their activity, is widespread within tumors.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Intratumour heterogeneity arises from genetic and epigenetic variation, and transcriptional plasticity.
- The specific contributions of these processes to tumour evolution are not fully understood.
Purpose of the Study:
- To investigate the interplay between genetic ancestry, gene expression, and subclonal evolution in colorectal cancer (CRC).
- To determine the extent to which intratumour genetic variation influences phenotypic traits and tumour progression.
Main Methods:
- Spatially resolved paired whole-genome and transcriptome sequencing of colorectal cancer (CRC) samples.
- Somatic expression quantitative trait loci (eQTL) analysis to identify genetic controls of gene expression.
- Computational inference of tumour phylogenies to analyze spatial patterning and subclonal selection.
Main Results:
- Intratumour genetic ancestry infrequently affects gene expression and subclonal evolution in CRC.
- The majority of intratumour gene expression variation is plastic, not heritable.
- Most genetic variations within CRC tumors have limited phenotypic consequences, while transcriptional plasticity is prevalent.
Conclusions:
- Transcriptional plasticity plays a more significant role than genetic variation in shaping the phenotype of colorectal cancer (CRC) tumors.
- Understanding these dynamics is crucial for developing targeted therapies and predicting treatment response in CRC.
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