Developing an optimal stratification model for colorectal cancer screening and reducing racial disparities in multi-center population-based studies.

BACKGROUND: Early detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population. METHODS: To develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants. RESULTS: Three trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose-response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32). CONCLUSIONS: Our comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity.

Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment.

The development of an effective survival prediction tool is key for reducing colorectal cancer mortality. Here, we apply a three-stage study to devise a polygenic prognostic score (PPS) for stratifying colorectal cancer overall survival. Leveraging two cohorts of 3703 patients, we first perform a genome-wide survival association analysis to develop eight candidate PPSs. Further using an independent cohort with 470 patients, we identify the 287 variants-derived PPS (i.e., PPS287) achieving an optimal prediction performance [hazard ratio (HR) per SD = 1.99, P = 1.76 × 10-8], accompanied by additional tests in two external cohorts, with HRs per SD of 1.90 (P = 3.21 × 10-14; 543 patients) and 1.80 (P = 1.11 × 10-9; 713 patients). Notably, the detrimental impact of pathologic characteristics and genetic risk could be attenuated by a healthy lifestyle, yielding a 7.62% improvement in the 5-year overall survival rate. Therefore, our findings demonstrate the integrated contribution of pathologic characteristics, germline variants, and lifestyle exposure to the prognosis of colorectal cancer patients.

Independent and joint associations of general and abdominal obesity with the risk of conventional adenomas and serrated polyps: A large population-based study in East Asia.

Evidence regarding associations of general and abdominal obesity with the risk of conventional adenomas (ADs) and serrated polyps (SPs) from Asian population is scarce. Our study aimed to investigate the independent and joint associations of general obesity assessed by body mass index (BMI) and abdominal obesity assessed by waist circumference (WC) or waist-to-hip ratio (WHR) with the risk of ADs and SPs among 25 222 participants recruited by a population-based screening program. Compared to participants with normal BMI, those with a BMI ≥28 kg/m2 had increased risk of ADs (odds ratio [OR] 1.52, 95% confidence interval [CI]: 1.36-1.70) and SPs (OR 1.69, 95% CI: 1.38-2.07). For participants with a WC ≥102 cm (≥88 cm for females), the risk of ADs (OR 1.37, 95% CI: 1.25-1.51) and SPs (OR 1.81, 95% CI: 1.52-2.16) was higher than that of the reference group. For participants with a WHR ≥0.95 (≥0.90 for females), the risk of ADs (OR 1.26, 95% CI: 1.16-1.36) and SPs (OR 1.46, 95% CI: 1.26-1.69) was higher than that of the reference group. Moreover, participants with both BMI ≥28 kg/m2 and WC ≥102 cm (≥88 cm for females) had 61% and 119% higher risk of ADs (OR 1.61, 95% CI: 1.39-1.85) and SPs (OR 2.19, 95% CI: 1.70-2.82) compared to those with both normal BMI and WC. These findings indicate that both general and abdominal obesity are associated with SPs and ADs, presenting stronger association with SPs than ADs. Moreover, the association is more evident when both obesities exist.

Hypermethylation of tumor suppressor lncRNA MEF2C-AS1 frequently happened in patients at all stages of colorectal carcinogenesis.

BACKGROUND: The novel long noncoding RNA MEF2C-AS1 has been identified to play suppressor roles during tumorigenesis. DNA methylation has a regulatory effect on gene expression in cancer initiation and progression. However, the methylation status of MEF2C-AS1 and its role in colorectal cancer (CRC) development remain unclear. METHODS: The expression and methylation levels of MEF2C-AS1 were systematically analyzed among 31 cancers with available qualified data in GEPIA and UCSC Xena databases. Then, the MEF2C-AS1 methylation status was firstly examined among 12 CRCs by Illumina Infinium MethylationEPIC BeadChip in in-house step 1 and further quantified among 48 CRCs by the MassARRAY method in in-house step 2. Subsequently, its methylation and expression levels were quantified among 81 non-advanced adenomas (NAAs), 81 advanced adenomas (AAs), and 286 CRCs using the MassARRAY method, and among 34 NAAs, 45 AAs, and 75 CRCs by qRT-PCR, in in-house step 3, respectively. The effect of MEF2C-AS1 methylation on CRC survival was analyzed by the Kaplan-Meier method. Additionally, in vitro cell proliferation, migration and invasion assays, and bioinformatics analysis were performed to explore the role of MEF2C-AS1 in colorectal carcinogenesis. RESULTS: Lower expression and higher methylation of MEF2C-AS1 were found in CRC by online databases. In the comparisons of lesion tissues with adjacent normal tissues, MEF2C-AS1 hypermethylation of each individual site and mean level was found among CRC patients in in-house step 1 and step 2, more meaningfully, among NAA patients, AA patients, and CRC patients at all stages during colorectal carcinogenesis in in-house step 3 (all p < 0.05). Further comparisons demonstrated significant differences between CRC and NAA (p = 0.025), AA and NAA (p = 0.020). Moreover, MEF2C-AS1 hypermethylation was associated with poorer disease-specific survival of CRC patients (p = 0.044). In addition, hypermethylation and lower expression of MEF2C-AS1 were verified in RKO cells, and the MEF2C-AS1 overexpression significantly suppressed RKO cell proliferation, migration, and invasion. CONCLUSIONS: The findings reveal that MEF2C-AS1 hypermethylation might be an early driven event during colorectal carcinogenesis. It might serve as a promising prognostic biomarker for CRC survival. Our study also indicates the potential tumor-suppressing role of MEF2C-AS1 in CRC.

Promoter hypermethylation of GALR1 acts as an early epigenetic susceptibility event in colorectal carcinogenesis.

Epigenetics play an essential role in colorectal neoplasia process. There is a need to determine the appropriateness of epigenetic biomarkers for early detection as well as expand our understanding of the carcinogenic process. Therefore, the aim of the study was to assess how DNA methylation pattern of GALR1 gene evolves in a sample set representing colorectal neoplastic progression. The study was designed into three phases. Firstly, Methylation status of GALR1 was assessed with genome-wide DNA methylation beadchip and pyrosequencing assays in colorectal lesions and paired normal tissues. Then, linear mixed-effects modeling analyses were applied to describe the trend of DNA methylation during the progression of colorectal neoplasia. In the third phase, quantitative RT-PCR was used to examine GALR1 expression in patients with precursor lesion and colorectal cancer. We found that significant hypermethylation of GALR1 promoter was a widely existent modification in CRCs (P < 0.001). When further examined methylation pattern of GALR1 during neoplastic progression of CRC, we found that DNA methylation level of GALR1 showed a significant stepwise increase from normal to hyperplastic polyps, to adenomas and to carcinoma samples (P < 0.001). Besides, loss of mRNA expression is a common accompaniment to adenomas and carcinomas. Public omics data analyses showed an inverse correlation between gene expression and DNA methylation (P < 0.001). Our findings indicate that epigenetic alteration of GALR1 promoter is gradually accumulated during the colorectal neoplastic progression. It can potentially be a promising biomarker used for screening and surveillance of colorectal cancer.

Healthy lifestyle and the risk of conventional adenomas and serrated polyps: Findings from a large colonoscopy screening population.

Evidence on the link between healthy lifestyle and colorectal cancer (CRC) precursors is limited. Our study aimed to examine and compare the associations of healthy lifestyle with CRC precursors in adenoma (AD)-carcinoma and serrated pathways. A total of 24 480 participants including 6309 ADs, 1343 serrated polyps (SPs), and 16 828 polyp-free controls were included. A healthy lifestyle score (HLS) was constructed based on five lifestyle factors including cigarette smoking, alcohol drinking, physical activity, diet and body weight, and categorized into least, slightly, moderately and most healthy. Multivariable logistic regressions were used to estimate odds ratio (OR) and 95% confidence interval (CI). Inverse dose-response associations between the HLS and risk of ADs were observed (OR per 1 score increment for ADs: 0.82 [95% CI 0.79-0.84]; for SPs: 0.73 [95% CI 0.69-0.78]), and the association with SPs was more evident than with ADs (OR 0.90, 95% CI 0.85-0.96). Compared to participants with the least healthy lifestyle, those with the most healthy lifestyle had 47% lower risk of ADs (OR 0.53, 95% CI 0.47-0.59) and 70% lower risk of SPs (OR 0.30, 95% CI 0.23-0.39), respectively. These inverse associations were consistent across lesion stage and anatomic subsite and not modified by any stratification factors. The risk advancement periods for the most vs the least healthy lifestyle were -9.49 years for ADs and -20.69 years for SPs. Our findings help confirm the preventive role of healthy lifestyle in colorectal carcinogenesis.

Worldwide trends in cervical cancer incidence and mortality, with predictions for the next 15 years.

BACKGROUND: Cervical cancer is 1 of the most common cancers in females worldwide. Understanding the most recent global patterns and temporal trends of cervical cancer burden might be helpful for its prevention and control. METHODS: Data on cervical cancer (International Classification of Diseases, Tenth Revision, code C53) incidence and mortality in 2018 were extracted from the GLOBOCAN 2018 database and further analyzed for their correlations with the Human Development Index. Temporal trends were analyzed using the annual percent change with joinpoint analysis among 31 countries with highly qualified data from the Cancer Incidence in Five Continents Plus and World Health Organization mortality databases. Future trends for the next 15 years were predicted using an open-source age-period-cohort model. RESULTS: Cervical cancer incidence and mortality rates were both negatively correlated with the Human Development Index (r = -0.56 for incidence, r = -0.69 for mortality; P < .001) in cross-sectional analysis, and both remained stable in 12 countries or even decreased in 14 and 18 countries for incidence and mortality, respectively, during the most recent 10 data years. Similar findings were observed for the next 15 years. CONCLUSIONS: Cervical cancer burden was correlated with socioeconomic development. An overwhelming majority of countries had stable or decreasing trends in incidence and mortality rates, especially in those with effective cervical cancer screening programs and human papillomavirus vaccination. LAY SUMMARY: The authors investigated the most up-to-date data from official databases released by the International Agency for Research on Cancer and found that cervical cancer incidence and mortality were negatively correlated with socioeconomic development. Among the 31 countries analyzed, most (26 countries were analyzed for incidence, and 30 were analyzed for mortality) had stable or even decreasing temporal trends over the most recent 10 years, especially in those with effective cervical cancer screening programs. In addition, the predicted trends for the next 15 years were basically consistent with the observed trends among most of the analyzed countries (19 countries for incidence and 26 countries for mortality).

Genome-Wide Methylation Profiling of lncRNAs Reveals a Novel Progression-Related and Prognostic Marker for Colorectal Cancer.

Sporadic colorectal cancer (CRC) develops principally through the adenoma-carcinoma sequence. Previous studies revealed that DNA methylation alterations play a significant role in colorectal neoplastic transformation. On the other hand, long noncoding RNAs (lncRNAs) have been identified to be associated with some critical tumorigenic processes of CRC. Accumulating evidence indicates more intricate regulatory relationships between DNA methylation and lncRNAs in CRC. Nevertheless, the methylation alterations of lncRNAs at different stages of colorectal carcinogenesis based on a genome-wide scale remain elusive. Therefore, in this study, we first used an Illumina MethylationEPIC BeadChip (850K array) to identify the methylation status of lncRNAs in 12 pairs of colorectal cancerous and adjacent normal tissues from cohort I, followed by cross-validation with The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. Then, the abnormal hypermethylation of candidate genes in colorectal lesions was successfully confirmed by MassARRAY EpiTYPER in cohort II including 48 CRC patients, and cohort III including 286 CRC patients, 81 advanced adenoma (AA) patients and 81 nonadvanced adenoma (NAA) patients. DLX6-AS1 hypermethylation was detected at all stages of colorectal neoplasms and occurred as early as the NAA stage during colorectal neoplastic progression. The methylation levels were significantly higher in the comparisons of CRC vs. NAA (P < 0.001) and AA vs. NAA (P = 0.004). Moreover, the hypermethylation of DLX6-AS1 promoter was also found in cell-free DNA samples collected from CRC patients as compared to healthy controls (P adj = 0.003). Multivariate Cox proportional hazards regression analysis revealed DLX6-AS1 promoter hypermethylation was independently associated with poorer disease-specific survival (HR = 2.52, 95% CI: 1.35-4.69, P = 0.004) and overall survival (HR = 1.64, 95% CI: 1.02-2.64, P = 0.042) in CRC patients. Finally, a nomogram was constructed and verified by a calibration curve to predict the survival probability of individual CRC patients (C-index: 0.789). Our findings indicate DLX6-AS1 hypermethylation might be an early event during colorectal carcinogenesis and has the potential to be a novel biomarker for CRC progression and prognosis.

Association between short-term exposure to ambient air pollution and hospital visits for depression in China.

Depression is one of the leading causes of disability, but the etiology remains unclear. Recently, it has been suggested that air pollution is a potential risk factor for depression. However, the results remained inconsistent. So we conducted this study to assess the association between short-term exposure to ambient air pollution and hospital visits for depression in China. Daily hospital visits for depression from January 18, 2013 to June 10, 2018 were extracted from a regional health information system (HIS) covered 1.34 million population in Ningbo, China. We collected daily air pollutant concentrations and meteorological data from environmental air quality monitoring sites and meteorological stations in the study area. Quasi-Poisson regression models with generalized additive models (GAM) were applied to explore the associations between air pollution and hospital visits for depression. Stratified analyses were also conducted by gender, age, and season to examine the effects modification. The results disclosed that air pollutants including PM2.5, PM10, SO2, CO, and NO2 were positively correlated with hospital visits for depression. The strongest effects all occurred on lag0 (the same) day, and the corresponding excess risks (ERs) were 2.59 (95%CI: 0.72, 4.49) for PM2.5, 3.08 (95%CI: 1.05, 5.16) for PM10, 3.22 (95%CI: 1.16, 5.32) for SO2, 4.38 (95%CI: 1.83, 6.99) for CO, and 4.94 (95%CI: 2.03, 7.92) for NO2 per IQR increase, respectively. The associations were found to be stronger in the elderly (≥65 years) and cold season. Furthermore, the effects of CO and NO2 remained significant in most two-pollutant models, suggesting that traffic-related air pollutants might be more important triggers of depression.

Evaluating the predictive value of genetic risk score in colorectal cancer among Chinese Han population.

Increasing single nucleotide polymorphisms (SNPs) have been identified to be associated with colorectal cancer (CRC). We aimed to investigate whether genetic risk scores (GRS) that aggregate information from multiple genetic variants can predict the risk of CRC in a Chinese population. Fifty candidate SNPs were selected to explore the associations with CRC in a discovery sample with 1002 CRC cases and 999 healthy controls. We modeled the significant SNPs identified by the case-control study as a multilocus weighted GRS and estimated the association of GRS with CRC. Furthermore, 300 pairs of cases and controls were included as a validation sample to confirm the finding. Area under the receiver operating characteristic curve (AUROC) was used to evaluate the predictive power of GRS in CRC. A total of seven SNPs were found to increase the risk of CRC, and two SNPs were found to be negatively associated with CRC in the discovery sample. Relative to participants with the lowest quartile of GRS, those with the highest quartile had a 2.64-fold (95% CI: 1.99-3.51) higher risk for CRC. For every 0.1 point of GRS increase, the risk of CRC increase by 11% (95% CI: 8-14%). AUROC for GRS alone were 0.59 (95% CI: 0.57-0.62) and 0.52 (95% CI: 0.46-0.58) in the discovery and validation sample, respectively. AUROC increased to 0.62 (95% CI: 0.59-0.64) and 0.71 (95% CI: 0.65-0.76) by combining environmental risk factors. Our findings support an association between GRS and risk of CRC, which provides evidence of improved prediction model for CRC in China.

Genome-wide methylation profiling identified novel differentially hypermethylated biomarker MPPED2 in colorectal cancer.

BACKGROUND: Epigenetic alternation is a common contributing factor to neoplastic transformation. Although previous studies have reported a cluster of aberrant promoter methylation changes associated with silencing of tumor suppressor genes, little is known concerning their sequential DNA methylation changes during the carcinogenetic process. The aim of the present study was to address a genome-wide search for identifying potentially important methylated changes and investigate the onset and pattern of methylation changes during the progression of colorectal neoplasia. METHODS: A three-phase design was employed in this study. In the screening phase, DNA methylation profile of 12 pairs of colorectal cancer (CRC) and adjacent normal tissues was analyzed by using the Illumina MethylationEPIC BeadChip. Significant CpG sites were selected based on a cross-validation analysis from The Cancer Genome Atlas (TCGA) database. Methylation levels of candidate CpGs were assessed using pyrosequencing in the training dataset (tumor lesions and adjacent normal tissues from 46 CRCs) and the validation dataset (tumor lesions and paired normal tissues from 13 hyperplastic polyps, 129 adenomas, and 256 CRCs). A linear mixed-effects model was used to examine the incremental changes of DNA methylation during the progression of colorectal neoplasia. RESULTS: The comparisons between normal and tumor samples in the screening phase revealed an extensive CRC-specific methylomic pattern with 174,006 (21%) methylated CpG sites, of which 22,232 (13%) were hyermethylated and 151,774 (87%) were hypomethylated. Hypermethylation mostly occurred in CpG islands with an overlap of gene promoters, while hypomethylation tended to be mapped far away from functional regions. Further cross validation analysis from TCGA dataset confirmed 265 hypermethylated promoters coupling with downregulated gene expression. Among which, hypermethylated changes in MEEPD2 promoter was successfully replicated in both training and validation phase. Significant hypermethylation appeared since precursor lesions with an extensive modification in CRCs. The linear mixed-effects modeling analysis found that a cumulative pattern of MPPED2 methylation changes from normal mucosa to hyperplastic polyp to adenoma, and to carcinoma (P < 0.001). CONCLUSIONS: Our findings indicate that epigenetic alterations of MPPED2 promoter region appear sequentially during the colorectal neoplastic progression. It might be able to serve as a promising biomarker for early diagnosis and stage surveillance of colorectal tumorigenesis.