Adenoma to Colorectal Cancer Estimated Transition Rates Stratified by BMI Categories—A Cross-Sectional Analysis of Asymptomatic Individuals from Screening Colonoscopy Program

Most colorectal cancers (CRC) assumedly develop from precursor lesions, i.e., colorectal adenomas (adenoma-carcinoma sequence). Epidemiological and clinical data supporting this hypothesis are limited. Therefore, the aim of the present study is to estimate relative dynamics of colorectal adenoma-carcinoma sequence for groups of screenees stratified by BMI (body mass index) based on prevalence data from Polish Colonoscopy Screening Program (PCSP). We performed a cross-sectional analysis of database records of individuals who entered the national opportunistic colonoscopy screening program for CRC in Poland. We calculated prevalence of adenomas and CRCs adjusted for sex, 5-year age group, family history of CRC, smoking, diabetes and use of aspirin, hormonal therapy and proton-pump inhibitors use. Thereafter we calculated estimated transition rate (eTR) with confidence intervals (CIs) defined as adjusted prevalence of more advanced lesion divided by adjusted prevalence of less advanced lesion. All analyzes were stratified according to the BMI categories: normal (BMI 18.0 to <25.0), overweight (BMI 25.0 to <30.0) and obese (BMI ≥ 30.0). Results are reported in the same respective order. After exclusions we performed analyses on 147 385 individuals. We found that prevalence of non-advanced adenomas is increasing with BMI category (12.19%, 13.81%, 14.70%, respectively; p < 0.001). Prevalence of advanced adenomas was increasing with BMI category (5.20%, 5.77%, 6.61%, respectively; p < 0.001). Early CRCs prevalence was the highest for obese individuals (0.55%) and the lowest for overweight individuals (0.44%) with borderline significance (p = 0.055). For advanced CRC we found that prevalence seems to be inversely related to BMI category, however no statistically significant differences were observed (0.35%, 0.31%, 0.28%; p = 0.274). eTR for non-advanced adenoma to advanced adenoma is higher for obese individuals than for overweight individuals with bordering CIs (42.65% vs. 41.81% vs. 44.95%) eTR for advanced adenoma to early CRC is highest for normal individuals, however CIs are overlapping with remaining BMI categories (9.02% vs. 7.67% vs. 8.39%). eTR for early CRC to advanced CRC is lower for obese individuals in comparison to both normal and overweight individuals with marginally overlapping CIs (73.73% vs. 69.90% vs. 50.54%). Obese individuals are more likely to develop adenomas, advanced adenomas and early CRC but less likely to progress to advanced CRC. Therefore, this study provides new evidence that obesity paradox exists for colorectal cancer.

Highly-specific early detection of colorectal cancer by novel non-invasive serum methylation biomarkers

Early detection has proven to be the most effective strategy to reduce the incidence and mortality of colorectal cancer (CRC). Nevertheless, most current screening programs suffer from low participation rates. A blood test may improve both the adherence to screening and the selection to colonoscopy. In this study, we conducted a serum-based discovery and validation of cfDNA methylation biomarkers for CRC screening in a multicentre cohort of 453 serum samples including healthy controls, benign pathologies, advanced adenomas (AA), and CRC. First, we performed an epigenome-wide methylation analysis with the MethylationEPIC array using a sample pooling approach, followed by a robust prioritization of candidate biomarkers for the detection of advanced neoplasia (AN: AA and CRC). Then, candidate biomarkers were validated by pyrosequencing in independent individual cfDNA samples. We report GALNT9, UPF3A, WARS, and LDB2 as new non-invasive biomarkers for the early detection of AN. The combination of GALNT9/UPF3A by logistic regression discriminated AN with 78.8% sensitivity and 100% specificity, outperforming the commonly used fecal immunochemical test and the methylated SEPT9 blood test. Overall, our results suggest that the combination methylated GALNT9/UPF3A has the potential to serve as a highly specific and sensitive blood-based test for screening and early detection of CRC.

Faecal Diagnostic Biomarkers for Colorectal Cancer

Background: Colorectal cancer (CRC) is a major cause of cancer-related death worldwide. Cancer progression, including invasion and metastasis, is a major cause of death among CRC patients. Current methods for CRC screening commonly consist of a combination of faecal immunochemical test (FIT) for stool occult blood detection and invasive procedures such as colonoscopy. Considering the slow progression of CRC, and that symptoms usually emerge at advanced stages, its early diagnostic can limit cancer’s spread and provide a successful treatment. Biomarkers have a high potential for the diagnosis of CRC in either blood or stool samples. Methods: In this study, we analysed the diagnostic value of six different biomarkers in stool samples of patients with CRC, advanced adenomas, other lesions and healthy individuals. We have also assessed the overall performance of the combination of these biomarkers for CRC detection. Results: The results indicate that haemoglobin (Hb) and M2-pyruvate kinase (M2-PK) levels were increased in CRC patients in comparison to the controls. Conversely, the concentrations of matrix metalloproteinase (MMP)-2, MMP-9, and tumour necrosis factor-alpha (TNF-α) were not significantly different between the tested groups. Conclusion: The combination of FIT-Hb with the M2-PK levels increased the specificity or sensitivity for CRC detection and thus present potential as faecal diagnostic biomarkers for CRC.

Improvements in the Effectiveness of Early Detection in Colorectal Cancer with Open-Label Randomised Study

Introduction: The general objective of this research is to improve the quality of colorectal cancer screening (CRC) by assessing, as an indicator of effectiveness, the ability of colonoscopy to detect more advanced adenomas in the exposed group than in the control group. Material and Methods: The present work is designed as an open-label randomized study on cancer screening, using two groups based on their exposure to the protocol: an exposed to intervention group (EIG, 167), and a control group (CG, 167), without the intervention of the protocol and by 1:1 matching. Results: In 167 patients in the GEI, 449 polyps are visualized and 274 are adenomas (80.58%), of which 100 (36.49%) are advanced adenomas. In the CG (n = 174), there are 321 polyps and 152 adenomas (82.60%). The variables significantly associated by logistic regression to the detection of adenomas are the male sex with an OR of 2.52. The variable time to withdrawal, ≥9 min, is significant at 99% confidence (p = 0.002/OR 34.67) and the fractional dose is significant at 99% (p = 0.009, OR 7.81). Conclusion: Based on the observations made, our study suggests that the intervention in collaboration between primary care and hospital care is effective from a preventive point of view and achieves the objective of effectiveness and quality of the PCCR.

Estrogen Receptors in Colorectal Cancer: Facts, Novelties and Perspectives

Colorectal cancer (CRC) is the second cause of cancer-related death in both sexes worldwide. As pre-menopausal women are less likely to develop CRC compared to age-matched men, a protective role for estrogens has been hypothesized. Indeed, two isoforms of nuclear estrogen receptors (ER) have been described: ERα and ERβ. While the binding of 17beta-estradiol to ERα activates anti-apoptotic pathways, the interaction with ERβ activates caspase-3, inducing apoptosis. In this regard, several pieces of evidence show that ERβ tends to be under-regulated in advanced adenomas and CRC, with an opposite trend for ERα. Furthermore, ERβ stimulation slows adenomatous polyp growth and modulates relevant CRC pathways. Based on such considerations, dietary modulation of ER is promising, particularly in subjects with genetic predisposition for CRC. Nevertheless, the main limitation is the lack of clinical trials on a large population scale.

Multiple Biomarker-Combined Screening for Colorectal Cancer Based on Bisulfate Conversion-Free Detection of Fecal DNA Methylation

To evaluate the applicability of bisulfate conversion-free methylation assay based on enzyme digestion in fecal screening for colorectal cancer (CRC). Stool samples were collected from a total of 1142 participants with intestinal abnormalities, including 180 positive cases, 60 advanced adenomas, and 902 negative cases. DNA from reference cell lines and clinical samples was extracted and digested with an enzyme to detect the methylation of CRC markers SEPT9, SDC2, NDRG4, SFRP2, and BMP3 genes. Statistical analysis was then used to determine the ability of the markers, both individually and in combination, to detect CRC and adenoma. Our results showed that the enzyme digestion method could suitably detect DNA marker methylation in as low as 1% of the cell lines. BMP3 had a considerably low detection rate in all clinical samples, with only 6 positive cases detected out of 180 cancer samples. Our findings showed that the combination of SEPT9, SDC2, and SFRP2 had an area under the receiver operation curve of 0.937, sensitivity of 94.11%, and specificity of 89.21% for detecting CRC. Moreover, the detection sensitivity of adenoma can also reach 38.33%. After innovatively utilizing bisulfate conversion-free methylation assay for CRC screening, this study verified the potential clinical applicability of combining multiple biomarkers for CRC screening in a large number of samples.

The Prevalence of Adenomas, AAs, and CRCs in Colonoscopy Screening Among Average-Risk Individuals in China

Background: Screening colonoscopy has historically been recommended starting at the age of 50. However, the recommended age for beginning screening has recently been reduced to 45 independent of sex. However, studies on screening colonoscopies of average-risk individuals in China are sparse. This study aimed to determine and compare the prevalence of adenomas, advanced adenomas (AAs), and colorectal cancers (CRCs) and the number of individuals needing screening in an average-risk Chinese population of different ages and sexes.Methods: A total of 53,152 individuals undergoing colonoscopy were included from January 2013 to December 2019. We analysed and compared the prevalence of adenomas, AAs, and CRCs and the number of individuals needing screening in different age groups of men and women.Results: The average age of males was 48.80 years (SD, 8.47 years), that of females was 50.00 years (SD, 9.00 years), and the sex ratio was 66.28% (n=35,226) vs. 33.72% (n=17,926). The prevalence of adenomas, AAs, serrated adenomas and CRCs was 14.51% ([95% CI 14.21–14.81], n=7713), 3.04% ([95% CI 2.90–3.19], n=1617), 1.23% ([95% CI 1.01–1.32], n=653) and 0.59% ([95% CI 0.52–0.65], n=313), respectively. Male sex was significantly associated with a high prevalence of adenomas (17.14% [95% CI 16.74–17.53] vs 9.36% [95% CI 8.94–9.79], P<0.001), AAs (3.67% [95% CI 3.47–3.87] vs 1.81% [95% CI 1.61–2.00], P<0.001) and serrated adenomas (1.56% [95% CI 1.43–1.69] vs. 0.59% [95% CI 0.47–0.70], P<0.001). The prevalence of AAs in 45- to 49-year-old individuals was 3.17% (95% CI 2.80–3.55) in men and 1.49% (95% CI 1.12–1.86) in women. The number of men needing screening(NNS) was 31.55 (95% CI 28.17–35.71), while the number of women was 67.11 (95% CI 53.76–89.29). The prevalence and number of patients needing screening for AAs in men aged 45–49 years were close to those in women aged 65–69 years (31.55 [95% CI, 28.17–35.71] vs. 29.07 [95% CI, 21.05–46.73]).Conclusions: The prevalence of adenomas, AAs, and serrated adenomas increased with age. Males had a higher prevalence rate than females. The prevalence and NNS of AAs in 45- to 49-year-old men were close to those in 65- to 69-year-old women.