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Background: The incidence of colorectal cancer (CRC) has been steadily increasing in younger individuals over the past several decades for reasons that are incompletely defined. Identifying differences in gene expression profiles, or transcriptomes, in early-onset colorectal cancer (EOCRC, < 50 years old) patients versus later-onset colorectal cancer (LOCRC, > 50 years old) patients is one approach to understanding molecular and genetic features that distinguish EOCRC., Methods: We performed RNA-sequencing (RNA-seq) to characterize the transcriptomes of patient-matched tumors and adjacent, uninvolved (normal) colonic segments from EOCRC (n=21) and LOCRC (n=22) patients. The EOCRC and LOCRC cohorts were matched for demographic and clinical characteristics. We used The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) database for validation. We used a series of computational and bioinformatic tools to identify EOCRC-specific differentially expressed genes, molecular pathways, predicted cell populations, differential gene splicing events, and predicted neoantigens., Results: We identified an eight-gene signature in EOCRC comprised of ALDOB , FBXL16 , IL1RN , MSLN , RAC3 , SLC38A11 , WBSCR27 and WNT11 , from which we developed a score predictive of overall CRC patient survival. On the entire set of genes identified in normal tissues and tumors, cell type deconvolution analysis predicted a differential abundance of immune and non-immune populations in EOCRC versus LOCRC. Gene set enrichment analysis identified increased expression of splicing machinery in EOCRC. We further found differences in alternative splicing (AS) events, including one within the long non-coding RNA, HOTAIRM1 . Additional analysis of AS found seven events specific to EOCRC that encode potential neoantigens., Conclusion: Our transcriptome analyses identified genetic and molecular features specific to EOCRC which may inform future screening, development of prognostic indicators, and novel drug targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Marx, Mankarious, Koltun and Yochum.)

Introduction: Chronic inflammation of the intestinal epithelium is an underlying cause of the two main types of inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD). Ex vivo organoids derived from the intestinal epithelium are a useful model to study IBD. Whether such cultures can be established from surgically resected diseased IBD intestinal tissues has not been fully explored. In this study, we tested our ability to establish organoids from nondiseased and diseased IBD intestinal tissues., Materials and Methods: From 12 UC patients (n = 54 tissues) and 20 CD patients (n = 49 tissues), tissues were collected from multiple colonic regions, and for CD, the terminal ileum was also surveyed. Organoids were cultured in Matrigel domes using defined media. In primary tissues, we conducted immunohistochemical analysis for mucin 2 (MUC2) and Alcian blue staining for goblet cells. Organoids were stained for Ki67, E-cadherin, and MUC2., Results: For UC, we were highly successful establishing organoids from nondiseased tissue (n = 12 of 13, 92%). This success rates dropped from tissues with mild (n = 6 of 9, 67%), moderate (n = 2 of 9, 22%), or severe disease (n = 1 of 23, 4%). The rates from nondiseased CD tissues were reduced (n = 11 of 23, 48%) in comparison to such tissues from UC patients. In UC, goblet cells and MUC2 were reduced in diseased tissues and these phenotypes were retained in organoids., Conclusions: Organoids can be readily derived from nondiseased surgically resected IBD tissues. While more work is needed to improve their derivation from diseased tissue, our study supports the use of organoids to study IBD pathophysiology., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Mutations in components of the Wnt/β-catenin signaling pathway drive colorectal cancer (CRC), in part, by deregulating expression of genes controlled by the T-cell factor (TCF) family of transcription factors. TCFs contain a conserved DNA binding domain that mediates association with TCF binding elements (TBEs) within Wnt-responsive DNA elements (WREs). Intestinal stem cell marker, leucine-rich-repeat containing G-protein-coupled receptor 5 (LGR5), is a Wnt target gene that has been implicated in CRC stem cell plasticity. However, the WREs at the LGR5 gene locus and how TCF factors directly regulate LGR5 gene expression in CRC have not been fully defined. Here, we report that TCF family member, TCF7L1, plays a significant role in regulating LGR5 expression in CRC cells. We demonstrate that TCF7L1 binds to a novel promoter-proximal WRE through association with a consensus TBE at the LGR5 locus to repress LGR5 expression. Using CRISPR activation and interference (CRISPRa/i) technologies to direct epigenetic modulation, we demonstrate that this WRE is a critical regulator of LGR5 expression and spheroid formation capacity of CRC cells. Furthermore, we found that restoring LGR5 expression rescues the TCF7L1-mediated reduction in spheroid formation efficiency. These results demonstrate a role for TCF7L1 in repressing LGR5 gene expression to govern the spheroid formation potential of CRC cells.

Despite a global decrease in colorectal cancer (CRC) incidence, the prevalence of early-onset colorectal cancer (EOCRC), or those occurring in individuals before the age of 50, has steadily increased over the past several decades. When compared to later onset colorectal cancer (LOCRC) in individuals over 50, our understanding of the genetic and molecular underpinnings of EOCRCs is limited. Here, we conducted transcriptomic analyses of patient-matched normal colonic segments and tumors to identify gene expression programs involved in carcinogenesis. Amongst differentially expressed genes, we found increased expression of the c-MYC proto-oncogene ( MYC ) and its downstream targets in tumor samples. We identified tumors with high and low differential MYC expression and found patients with high- MYC tumors were older and overweight or obese. We also detected elevated expression of the PVT1 long-non-coding RNA (lncRNA) in most tumors and found gains in copy number for both MYC and PVT1 gene loci in 35% of tumors evaluated. Our transcriptome analyses indicate that EOCRC can be sub-classified into groups based on differential MYC expression and suggest that deregulated MYC contributes to CRCs that develop in younger patients.

A review of the Journal of the History of the Behavioral Sciences revealed that all of the author's opinions on historiography have been well represented. Warning against the development of the history of psychology as a parochial superspecialty, the author proposes an interactional conceptualization of historical work which explicates the historian's presuppositions and deals with issues relevant to contemporary psychology.