Insights into Early Onset Colorectal Cancer through Analysis of Normal Colon Organoids of Familial Adenomatous Polyposis Patients

Abstract

Early onset colorectal cancer (EOCRC) rates have increased in recent decades. While lowering the recommended age for routine colonoscopies to 45 may reduce this burden, such measures do not address those who develop CRC before that age. Additional measures are needed to identify individuals at-risk for CRC. To better define transcriptomic events that precede the development of CRC, we performed RNA-sequencing analysis in colon organoids derived from seven healthy and six familial adenomatous polyposis (FAP) patients. This led to the identification of 2635 significant differentially expressed genes (FDR < 0.05). Through secondary analysis of publicly available datasets, we found that these genes were enriched for significant genes also present in FAP CRC and non-hereditary CRC datasets, including a subset that were unique to EOCRC. By exposing FAP colon organoids to a three-day ethanol treatment, we found that two EOCRC-relevant genes were also targets of CRC related lifestyle factors. Our data provides unique insight into the potential, early mechanisms of CRC development in colon epithelial cells, which may provide biomarkers for patient monitoring. We also show how modifiable lifestyle factors may further alter genes relevant to EOCRC, adding weight to the hypothesis that such factors represent an important contributor to increased EOCRC incidence.

Risk factors, histopathological landscape, biomarkers, treatment patterns and survival of early‐onset colorectal cancer: A narrative review

“…This is significant as a dysregulated innate immune response has been found to be the main driver behind “inflammaging”, a phenomenon characterized by persistent low levels of systemic and tissue microenvironment inflammation 32 . Other studies investigating the relationship between certain environmental exposures and EOCRC‐related gene and metabolomic modifications have established links between inflammation, obesity, and the NOTCH1‐GATA4‐IRG1 axis, alcohol consumption and overexpression of NOTUM/GDF11, and red meat consumption and choline/tryptophan/bile acid accumulation and upregulation of phosphatidylcholine and tryptophan biosynthesis genes in EOCRC patients 33–35 . A Westernised diet has also been correlated with an EOCRC fecal taxa signature characterized by an abundance of Falvonifractor plautii, B. vulgatus, Alistipes putredinis, and Intestinomonas butyriciproducens species, resulting in decreased flavonoid degradation, increased proteolytic and elastase deficiency and thus inflammation 34,36 .…”

“…32 Other studies investigating the relationship between certain environmental exposures and EOCRCrelated gene and metabolomic modifications have established links between inflammation, obesity, and the NOTCH1-GATA4-IRG1 axis, alcohol consumption and overexpression of NOTUM/GDF11, and red meat consumption and choline/tryptophan/bile acid accumulation and upregulation of phosphatidylcholine and tryptophan biosynthesis genes in EOCRC patients. [33][34][35] A Westernised diet has also been correlated with an EOCRC fecal taxa signature characterized by an abundance of Falvonifractor plautii, B. vulgatus, Alistipes putredinis, and Intestinomonas butyriciproducens species, resulting in decreased flavonoid degradation, increased proteolytic and elastase deficiency and thus inflammation. 34,36 Although studies have demonstrated the correlation between numerous genes, inflammation and EOCRC, a reproducibly implicated gene remains to be identified and future research is needed.…”

Application Prospect of Induced Pluripotent Stem Cells in Organoids and Cell Therapy

“…With the change of modern lifestyle, the incidence of colitis has gradually increased, and the prone population is very wide, difficult to cure, and the cancer rate is high, so it’s listed as one of the modern difficult diseases by the World Health Organization [ 91 ]. Long-term colitis and adenomatous polyposis can lead to contractions, perforations, and even bowel cancer [ 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 ]. Colon cancer organoids can be derived based on iPSC technology [ 101 ].…”