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

SIMPLE SUMMARY: The increase in early onset colorectal cancer (EOCRC) rates places a new, heavy burden on a younger population. Current studies in EOCRC are often affected by factors such as increased cellular heterogeneity, which mask biological signal. We overcome this using the colon organoid model, which is composed of cells from which CRC is believed to originate. We perform gene expression analysis on colon organoids derived from healthy and familial adenomatous polyposis patients, who are genetically predisposed to develop CRC at a young age, to identify differences that may be used for early monitoring of CRC development. We contextualize our findings in the framework of existing CRC and EOCRC data. We also show that ethanol, a CRC risk factor, may play an important role in further driving aberrant gene expression at EOCRC relevant genes. Functional analysis of these genes may shed new insight into EOCRC. 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.