Haploinsufficient phenotypes promote selection of PTEN and ARID1A deficient clones in human colon.

Normal human tissues are known to be composed of a pactchwork of mutant clones but with limited implications on cancer risk. PTEN and ARID1A deficient clones were detected in the human colon using immunohistrochemistry and were found to be the product of monoallelic loess. They were associated with a bias in clone dynamics which resulted in positive selection in the tissue. Heterozygous mutations were introduced in intestinal organoids which were subjected to bulk RNA-seq to describe the molecular mechanisms behind their positive selection. Although PTEN het organoids were associated with an advantageous phenotype in organoids, which was recapitulated in the transcriptomic analysis with increase proliferation and upregulation of developmental/regenerative processes and metabolic reprogramming, the ARID1A het organoids showed reduced growth which was seen as upregulation of apoptosis and downregulation of DNA replication. The discrepancy between the tissue and organoid phenotype for ARID1A was later explained due to the impact on stromal cells which are found in the tissue and are mediating the selective advantage. Importantly these molecular alterations and behaviours arise due to haploinsufficiency of these tumour suppressors in a pre-neoplastic context.