Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. Patients affected will inevitably undergo abdominal surgery due to the malignant transformation of one or more adenomas. The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways. These factors represent promising targets of future therapies and chemoprevention, aiming to alter the progressive nature of the disease and improve the quality of life of families affected. Therefore, we performed a narrative review about the current knowledge of the aforementioned pathways involved in colorectal cancer pathogenesis in FAP, exploring the genetic and environmental factors that may contribute to the development of CRC in FAP.

https://www.mdpi.com/1422-0067/24/6/5687/pdf?version=1678957250

Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis

Simple Summary Racial disparities exist within colorectal cancer (CRC) incidence and mortality, with African Americans (AA) exhibiting a greater risk of developing and dying from the disease than European Americans (EA). This disparity is mirrored in scientific research, where an inadequate number of omic-based studies have sought to recruit AA populations, severely limiting the scope of subsequent findings. Aberrant DNA methylation is a hallmark of CRC, with global and region-specific differences being attributed to disease subtype, pathogenesis and survival. However, studies on cancerous tissue are limited in their ability to infer risk mechanisms occurring in healthy cells. Here, we explore the effects of aging, a well-known CRC risk factor, on DNA methylation in normal rectum of AA and EA subjects. Our findings highlight an interplay between race and age that impacts DNA methylation and, potentially, rectal cancer risk. Abstract Approximately 90% of colorectal cancer (CRC) develop over the age of 50, highlighting the important role of aging in CRC risk. African Americans (AAs) shoulder a greater CRC burden than European Americans (EA) and are more likely to develop CRC at a younger age. The effects of aging in AA and EA normal rectal tissue have yet to be defined. Here, we performed epigenome-wide DNA methylation analysis in the first, large-scale biracial cohort of normal rectum (n = 140 samples). We identified increased epigenetic age acceleration in EA than AA rectum (p = 3.91 × 10−4) using linear regression. We also identified differentially methylated regions (DMRs) associated with chronological aging in AA and EA, separately using DMRcate. Next, a consensus set of regions associated with cancer was identified through DMR analysis of two rectal cancer cohorts. The vast majority of AA DMRs were present in our analysis of aging in rectum of EA subjects, though rates of epigenetic drift were significantly greater in AA (p = 1.94 × 10−45). However, 3.66-fold more DMRs were associated with aging in rectum of EA subjects, many of which were also associated with rectal cancer. Our findings reveal a novel relationship between race, age, DNA methylation and rectal cancer risk that warrants further investigation.

https://www.mdpi.com/2072-6694/15/1/45/pdf?version=1671679888

A Race-Specific, DNA Methylation Analysis of Aging in Normal Rectum: Implications for the Biology of Aging and Its Relationship to Rectal Cancer

N-acetyltransferase 10 (NAT10), a versatile enzyme, has gained considerable attention as a significant player in the complex realm of cancer biology. Its enigmatic role in tumorigenesis extends across a wide array of cellular processes, impacting cell growth, differentiation, survival, and genomic stability. Within the intricate network of oncogenic signaling, NAT10 emerges as a crucial agent in multiple cancer types, such as breast, lung, colorectal, and leukemia. This compelling research addresses the intricate complexity of the mechanistic role of NAT10 in cancer development. By elucidating its active participation in essential physiological processes, we investigate the regulatory role of NAT10 in cell cycle checkpoints, coordination of chromatin remodeling, and detailed modulation of the delicate balance between apoptosis and cell survival. Perturbations in NAT10 expression and function have been linked to oncogenesis, metastasis, and drug resistance in a variety of cancer types. Furthermore, the bewildering interactions between NAT10 and key oncogenic factors, such as p53 and c-Myc, are deciphered, providing profound insights into the molecular underpinnings of cancer pathogenesis. Equally intriguing, the paradoxical role of NAT10 as a potential tumor suppressor or oncogene is influenced by context-dependent factors and the cellular microenvironment. This study explores the fascinating interplay of genetic changes, epigenetic changes, and post-translational modifications that shape the dual character of NAT10, revealing the delicate balance between cancer initiation and suppression. Taken together, this overview delves deeply into the enigmatic role of NAT10 in cancer, elucidating its multifaceted roles and its complex interplay with oncogenic networks. 

The mechanistic role of NAT10 in cancer: Unraveling the enigmatic web of oncogenic signaling.

Colon cancer epidemiology, race and socioeconomic status: Comparing trends in counties served by an urban hospital in Newark, NJ with overall NJ-state and nation-wide patterns.

To explore the clinical value of human fecal Syndecan-2 (SDC2) gene methylation in colorectal cancer screening.There were 30 patients with colorectal cancer receiving treatment in Zhangjiakou First Hospital from January 2019 to December 2019 collected as the tumor group. There were 30 healthy people determined by a physical examination in 2019 collected as the normal group. The methylation level of fecal SDC2 gene and the level of serum tumor markers including carcinoembryonic antigen (CEA) and Carbohydrate antigen 19-9 (CA19-9) were analyzed. The diagnostic effects of fecal SDC2 methylation and serum tumor markers on colorectal cancer were compared. The area under curve (AUC) of different methods for colorectal cancer diagnosis were evaluated based on the receiver operating characteristic (ROC) curve.There was no distinction between the tumor group and the normal group in clinical basic data, including gender, age, and body mass index (P > 0.05), revealing the comparability between the two groups. The level of fecal SDC2 methylation in the tumor group was lower than that in the normal group (P < 0.05). CEA and CA19-9 in the tumor group were higher than those in the normal group (P < 0.05). Among the 30 colorectal cancers, 28 (93.33%) were positive for SDC2 gene methylation, 18 (60%) were positive for serum CEA, and 19 (63.33%) were positive for serum CA19-9. This indicated that the true positive rate of SDC2 gene methylation was higher than that of serum tumor markers (P < 0.05). The AUC of fecal SDC2 gene methylation was 0.981. These were higher than that of serum tumor markers (P < 0.05).Fecal SDC2 gene detection has a high sensitivity and specificity for colorectal cancer. It has a very ideal detection effect in detecting colorectal cancer patients in the population. 

Diagnostic value of human fecal SDC2 gene in colorectal cancer.

Familial adenomatous polyposis (FAP) is an inherited colorectal cancer (CRC) syndrome resulting from germ line mutations in the adenomatous polyposis coli (APC) gene. While FAP accounts for less than 1% of all CRC cases, loss of APC expression is seen in > 80% of non-hereditary CRCs. To better understand molecular mechanisms underlying APC-driven CRC, we performed an epigenome-wide analysis of colon organoids derived from normal-appearing colons of FAP patients versus healthy subjects to identify differentially methylated regions (DMRs) that may precede the onset of CRC.We identified 358 DMRs when comparing colon organoids of FAP patients to those of healthy subjects (FDR < 0.05, |mean beta difference| = 5%). Of these, nearly 50% of DMRs were also differentially methylated in at least one of three CRC tumor and normal adjacent tissue (NAT) cohorts (TCGA-COAD, GSE193535 and ColoCare). Moreover, 27 of the DMRs mapped to CRC genome-wide association study (GWAS) loci. We provide evidence suggesting that some of these DMRs led to significant differences in gene expression of adjacent genes using quantitative PCR. For example, we identified significantly greater expression of five genes: Kazal-type serine peptidase inhibitor domain 1 (KAZALD1, P = 0.032), F-Box and leucine-rich repeat protein 8 (FBXL8, P = 0.036), TRIM31 antisense RNA 1 (TRIM31-AS1, P = 0.036), Fas apoptotic inhibitory molecule 2 (FAIM2, P = 0.049) and (Collagen beta (1-0)galactosyltransferase 2 (COLGALT2, P = 0.049). Importantly, both FBXL8 and TRIM31-AS1 were also significantly differentially expressed in TCGA-COAD tumor versus matched NAT, supporting a role for these genes in CRC tumor development.We performed the first DNA methylome-wide analysis of normal colon organoids derived from FAP patients compared to those of healthy subjects. Our results reveal that normal colon organoids from FAP patients exhibit extensive epigenetic differences compared to those of healthy subjects that appear similar to those exhibited in CRC tumor. Our analyses therefore identify DMRs and candidate target genes that are potentially important in CRC tumor development in FAP, with potential implications for non-hereditary CRC. 

/pdf/dna-methylation-analysis-of-normal-colon-organoids-from-f5z794jv.pdf

DNA methylation analysis of normal colon organoids from familial adenomatous polyposis patients reveals novel insight into colon cancer development

Numerous demographic factors have been associated with colorectal cancer (CRC) risk. To better define biological mechanisms underlying these associations, we performed RNA sequencing of stem-cell-enriched organoids derived from the healthy colons of seven European Americans and eight African Americans. A weighted gene co-expression network analysis was performed following RNA sequencing. Module–trait relationships were determined through the association testing of each module and five CRC risk factors (age, body mass index, sex, smoking history, and race). Only modules that displayed a significantly positive correlation for gene significance and module membership were considered for further investigation. In total, 16 modules were associated with known CRC risk factors (p < 0.05). To contextualize the role of risk modules in CRC, publicly available RNA-sequencing data from TCGA-COAD were downloaded and re-analyzed. Differentially expressed genes identified between tumors and matched normal-adjacent tissue were overlaid across each module. Loci derived from CRC genome-wide association studies were additionally overlaid across modules to identify robust putative targets of risk. Among them, MYBL2 and RXRA represented strong plausible drivers through which cigarette smoking and BMI potentially modulated CRC risk, respectively. In summary, our findings highlight the potential of the colon organoid system in identifying novel CRC risk mechanisms in an ancestrally diverse and cellularly relevant population.

Assessment of Colorectal Cancer Risk Factors through the Application of Network-Based Approaches in a Racially Diverse Cohort of Colon Organoid Stem Cells

68 Background: Obesity and adult weigh gain are established risk factors for colorectal cancer (CRC). Few studies have investigated the association between adult body weight change over time and risk of colorectal adenoma. We hypothesize adult BMI change over time is associated with risk in the development of colorectal adenomas. Methods: We tested this hypothesis in 2,993 patients undergoing screening colonoscopy from 2007–2017. Weight at age 20, 30, 40, and 50 were self-reported via computer assisted personal interviews. Height and weight at recruitment were measured at the time of colonoscopy exam. BMI (kg/m2) change was calculated as the difference of BMI at recruitment from the BMI estimate for each of the age periods. Results: Of the 2,993 patients, 984 had pathologically confirmed diagnosis of colon adenoma. Multivariate logistic regression adjusted for potential confounders and BMI at recruitment showed statistically significant increase of risk of adenoma with increase of BMI since age 30, age 40, and age 50. Compared to those with BMI change of less than 5, the ORs for those with BMI gain of 5-10 and ≥10 were: 1) 1.16 (0.92-1.46) and 1.48 (1.08-2.03) respectively for change from age 30 (ptrend = 0.05); 2) 1.11 (0.87-1.43) and 1.60 (1.09-2.35) respectively for change from age 40 (ptrend = 0.05); and 3) 1.36 (0.95-1.94) and 2.95 (1.33-6.90) respectively for change from age 50 (ptrend = 0.01). Stratified analysis did not reveal noticeable gender differences. Conclusions: Large adult weight gain over time is an independent risk factor for colorectal adenoma. Our results suggest maintaining healthy body weight throughout adulthood is an important preventive measure against the development of early colorectal neoplasia. [Table: see text]

Adult BMI change over time and risk of colorectal adenoma.

Tu1161: ASSOCIATIONS BETWEEN BMI AND NORMAL COLORECTAL BIOPSY DNA METHYLATION: INSIGHT INTO RISK MECHANSIMS OF COLORECTAL CANCER SIDEDNESS.

493: defining a mechanistic role of fructose in colorectal cancer risk

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