Cigarette Smoking and E-cigarette Use Induce Shared DNA Methylation Changes Linked to Carcinogenesis.

Tobacco use is a major modifiable risk factor for adverse health outcomes, including cancer, and elicits profound epigenetic changes thought to be associated with long-term cancer risk. While electronic cigarettes (e-cigarettes) have been advocated as harm reduction alternatives to tobacco products, recent studies have revealed potential detrimental effects, highlighting the urgent need for further research into the molecular and health impacts of e-cigarettes. Here, we applied computational deconvolution methods to dissect the cell- and tissue-specific epigenetic effects of tobacco or e-cigarette use on DNA methylation (DNAme) in over 3,500 buccal/saliva, cervical, or blood samples, spanning epithelial and immune cells at directly and indirectly exposed sites. The 535 identified smoking-related DNAme loci [cytosine-phosphate-guanine sites (CpG)] clustered into four functional groups, including detoxification or growth signaling, based on cell type and anatomic site. Loci hypermethylated in buccal epithelial cells of smokers associated with NOTCH1/RUNX3/growth factor receptor signaling also exhibited elevated methylation in cancer tissue and progressing lung carcinoma in situ lesions, and hypermethylation of these sites predicted lung cancer development in buccal samples collected from smokers up to 22 years prior to diagnosis, suggesting a potential role in driving carcinogenesis. Alarmingly, these CpGs were also hypermethylated in e-cigarette users with a limited smoking history. This study sheds light on the cell type-specific changes to the epigenetic landscape induced by smoking-related products. SIGNIFICANCE: The use of both cigarettes and e-cigarettes elicits cell- and exposure-specific epigenetic effects that are predictive of carcinogenesis, suggesting caution when broadly recommending e-cigarettes as aids for smoking cessation.

Cancer-specific risk prediction with a serum microRNA signature.

We recently derived and validated a serum-based microRNA risk score (miR-score) that predicted colorectal cancer (CRC) occurrence with very high accuracy within 14 years of follow-up in a population-based cohort study from Germany (ESTHER cohort). Here, we aimed to evaluate associations of the CRC-specific miR-score with the risk of developing other common cancers, including female breast cancer (BC), lung cancer (LC), and prostate cancer (PC), in the ESTHER cohort. MicroRNAs (miRNAs) were profiled by quantitative real-time PCR in serum samples collected at baseline from randomly selected incident cases of BC (n = 90), LC (n = 88), and PC (n = 93) and participants without diagnosis of CRC, LC, BC, or PC (controls, n = 181) until the end of the 17-year follow-up. Multivariate logistic regression models were used to evaluate the associations of the miR-score with BC, LC, and PC incidence. The miR-score showed strong inverse associations with BC and LC incidence [odds ratio per 1 standard deviation increase: 0.60 (95% confidence interval [CI] 0.43-0.82), p = 0.0017, and 0.64 (95% CI 0.48-0.84),p = 0.0015, respectively]. Associations with PC were not statistically significant but pointed in the positive direction. Our study highlights the potential of serum-based miRNA biomarkers for cancer-specific risk prediction. Further large cohort studies aiming to investigate, validate, and optimize the use of circulating miRNA signatures for cancer risk assessment are warranted.

Potential of Fecal Carcinoembryonic Antigen for Noninvasive Detection of Colorectal Cancer: A Systematic Review.

Carcinoembryonic antigen (CEA) is more abundant in feces than in serum; however, evidence for the role of fecal CEA (FCEA) in the detection of colorectal cancer (CRC) is limited. We conducted a systematic review of studies that evaluated FCEA for the noninvasive detection and diagnosis of CRC. PubMed and Web of Science were searched for relevant studies published until 18 January 2023. Information on publication year, study design, country, study population characteristics, FCEA and serum CEA (SCEA) concentrations, and diagnostic performance was summarized. Two authors independently extracted data and assessed the risk of bias and applicability of each included study. Seven studies published between 1979 and 2021, all conducted in clinical settings and together involving 399 CRC patients and 889 controls, were identified. Significant differences in FCEA concentrations were observed between CRC and control groups in all studies. Methods for detecting FCEA varied, with the electronic chemiluminescence immunoassay (ECLIA) being used in the most recent studies. Reported sensitivities, specificities, and area under the curves of FCEA ranged from 50.0% to 85.7%, 73.0% to 100.0%, and 0.704 to 0.831, respectively. In direct comparisons, the diagnostic performance of FCEA was better than that of SCEA. The potential role of FCEA as a novel, noninvasive, easily measurable biomarker for the diagnosis of CRC requires further evaluation in screening settings.

Assessment of a Serum Microrna Risk Score for Colorectal Cancer among Participants of Screening Colonoscopy at Various Stages of Colorectal Carcinogenesis.

We recently derived and validated a serum-based microRNA risk score (miR-score) which predicted colorectal cancer (CRC) occurrence with very high accuracy within 14 years of follow-up in a large population-based cohort. Here, we aimed to assess and compare the distribution of the miR-score among participants of screening colonoscopy at various stages of colorectal carcinogenesis. MicroRNAs (miRNAs) were profiled by quantitative-real-time-polymerase-chain-reaction in the serum samples of screening colonoscopy participants with CRC (n = 52), advanced colorectal adenoma (AA, n = 100), non-advanced colorectal adenoma (NAA, n = 88), and participants free of colorectal neoplasms (n = 173). The mean values of the miR-score were compared between groups by the Mann-Whitney U test. The associations of the miR-score with risk for colorectal neoplasms were evaluated using logistic regression analyses. MicroRNA risk scores were significantly higher among participants with AA than among those with NAA (p = 0.027) and those with CRC (p = 0.014), whereas no statistically significant difference was seen between those with NAA and those with no colorectal neoplasms (p = 0.127). When comparing adjacent groups, miR-scores were inversely associated with CRC versus AA and positively associated with AA versus NAA [odds ratio (OR), 0.37 (95% confidence interval (CI), 0.16-0.86) and OR, 2.22 (95% CI, 1.06-4.64) for the top versus bottom tertiles, respectively]. Our results are consistent with the hypothesis that a high miR-score may be indicative of an increased CRC risk by an increased tendency of progression from non-advanced to advanced colorectal neoplasms, along with a change of the miR-patterns after CRC manifestation.

A microRNA panel compared to environmental and polygenic scores for colorectal cancer risk prediction.

Circulating microRNAs (miRNAs) could improve colorectal cancer (CRC) risk prediction. Here, we derive a blood-based miRNA panel and evaluate its ability to predict CRC occurrence in a population-based cohort of adults aged 50-75 years. Forty-one miRNAs are preselected from independent studies and measured by quantitative-real-time-polymerase-chain-reaction in serum collected at baseline of 198 participants who develop CRC during 14 years of follow-up and 178 randomly selected controls. A 7-miRNA score is derived by logistic regression. Its predictive ability, quantified by the optimism-corrected area-under-the-receiver-operating-characteristic-curve (AUC) using .632+ bootstrap is 0.794. Predictive ability is compared to that of an environmental risk score (ERS) based on known risk factors and a polygenic risk score (PRS) based on 140 previously identified single-nucleotide-polymorphisms. In participants with all scores available, optimism-corrected-AUC is 0.802 for the 7-miRNA score, while AUC (95% CI) is 0.557 (0.498-0.616) for the ERS and 0.622 (0.564-0.681) for the PRS.

Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review.

BACKGROUND: DNA methylation biomarkers in stool may have applications in early colorectal cancer (CRC) detection; however, their association with stages of CRC carcinogenesis or their performance in detecting various stages is unclear. We aimed to systematically review the evidence for DNA methylation markers in stool for risk stratification or detection of specific CRC stages, as well as precursors of CRC. METHODS: We conducted a systematic search in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 14th January 2020. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, odds ratios (ORs), overall and stage-specific sensitivities, specificities, areas under the receiver operating characteristics curve, and p-values for statistical significance for OR and for association of methylation levels with stage. RESULTS: Twenty-seven studies that reported stage-specific associations or performances of fecal DNA methylation markers for detecting colorectal neoplasms were identified. All studies used methylation-specific polymerase chain reaction for assessing methylation levels in the promoter or exon 1 regions of targeted genes. However, most studies were underpowered and limited by their case-control design. Furthermore, the stage-specific associations or sensitivities were validated for two markers (hypermethylation of GATA4 and VIM) only. CONCLUSION: Methylation markers in stool may be useful for detection of CRC precursors or CRC staging, but promising candidate markers need to be validated in longitudinal studies on large screening populations, performing epigenome-wide analyses. Identification of stage-specific DNA methylation biomarkers in stool could boost current strategies towards early detection and enable different approaches to precision medicine for CRC.

Individual and joint contributions of genetic and methylation risk scores for enhancing lung cancer risk stratification: data from a population-based cohort in Germany.

BACKGROUND: Risk stratification for lung cancer (LC) screening is so far mostly based on smoking history. This study aimed to assess if and to what extent such risk stratification could be enhanced by additional consideration of genetic risk scores (GRSs) and epigenetic risk scores defined by DNA methylation. METHODS: We conducted a nested case-control study of 143 incident LC cases and 1460 LC-free controls within a prospective cohort of 9949 participants aged 50-75 years with 14-year follow-up. Lifetime smoking history was obtained in detail at recruitment. We built a GRS based on 31 previously identified LC-associated single-nucleotide polymorphisms (SNPs) and a DNA methylation score (MRS) based on methylation of 151 previously identified smoking-associated cytosine-phosphate-guanine (CpG) loci. We evaluated associations of GRS and MRS with LC incidence by logistic regression models, controlling for age, sex, smoking status, and pack-years. We compared the predictive performance of models based on pack-years alone with models additionally including GRS and/or MRS using the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: GRS and MRS showed moderate and strong associations with LC risk even after comprehensive adjustment for smoking history (adjusted odds ratio [95% CI] comparing highest with lowest quartile 1.93 [1.05-3.71] and 5.64 [2.13-17.03], respectively). Similar associations were also observed within the risk groups of ever and heavy smokers. Addition of GRS and MRS furthermore strongly enhanced LC prediction beyond prediction by pack-years (increase of optimism-corrected AUC among heavy smokers from 0.605 to 0.654, NRI 26.7%, p = 0.0106, IDI 3.35%, p = 0.0036), the increase being mostly attributable to the inclusion of MRS. CONCLUSIONS: Consideration of MRS, by itself or in combination with GRS, may strongly enhance LC risk stratification.

Individual and joint performance of DNA methylation profiles, genetic risk score and environmental risk scores for predicting breast cancer risk.

DNA methylation patterns in the blood, genetic risk scores (GRSs), and environmental risk factors can potentially improve breast cancer (BC) risk prediction. We assessed the individual and joint predictive performance of methylation, GRS, and environmental risk factors for BC incidence in a prospective cohort study. In a cohort of 5462 women aged 50-75 from Germany, 101 BC cases were identified during 14 years of follow-up and were compared to 263 BC-free controls in a nested case-control design. Three previously suggested methylation risk scores (MRSs) based on methylation of 423, 248, and 131 cytosine-phosphate-guanine (CpG) loci, and a GRS based on the risk alleles from 269 recently identified single nucleotide polymorphisms were constructed. Additionally, multiple previously proposed environmental risk scores (ERSs) were built based on environmental variables. Areas under the receiver operating characteristic curves (AUCs) were estimated for evaluating BC risk prediction performance. MRS and ERS showed limited accuracy in predicting BC incidence, with AUCs ranging from 0.52 to 0.56 and from 0.52 to 0.59, respectively. The GRS predicted BC incidence with a higher accuracy (AUC = 0.61). Adjusted odds ratios per standard deviation increase (95% confidence interval) were 1.07 (0.84-1.36) and 1.40 (1.09-1.80) for the best performing MRS and ERS, respectively, and 1.48 (1.16-1.90) for the GRS. A full risk model combining the MRS, GRS, and ERS predicted BC incidence with the highest accuracy (AUC = 0.64) and might be useful for identifying high-risk populations for BC screening.

Whole-blood DNA Methylation Markers for Risk Stratification in Colorectal Cancer Screening: A Systematic Review.

DNA methylation profiles within whole-blood samples have been reported to be associated with colorectal cancer (CRC) occurrence and might enable risk stratification for CRC. We systematically reviewed and summarized studies addressing the association of whole-blood DNA methylation markers and risk of developing CRC or its precursors. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 12th November 2018. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, methylation levels of patients in comparison to healthy controls, p-values, and odds ratios of the markers. Overall, 19 studies reporting 102 methylation markers for risk assessment of colorectal neoplasms met our inclusion criteria. The studies mostly used Methylation Specific Polymerase Chain Reaction (MS-PCR) for assessing the methylation status of a defined set of genes. Only two studies applied array-based genome-wide assays to assess the methylation levels. Five studies incorporated panels consisting of 2-10 individual methylation markers to assess their potential for stratifying the risk of developing colorectal neoplasms. However, none of these associations was confirmed in an independent cohort. In conclusion, whole-blood DNA methylation markers may be useful as biomarkers for risk stratification in CRC screening, but reproducible risk prediction algorithms are yet to be established by large scale epigenome-wide studies with thorough validation of results in prospective study cohorts including large screening populations. The possibilities of enhancing predictive power by combining methylation data with polygenetic risk scores and environmental risk factors need to be explored.

Proportion of Orofacial Clefts Attributable to Recognized Risk Factors.

OBJECTIVE: Estimate the population attributable fraction (PAF) for a set of recognized risk factors for orofacial clefts. DESIGN: We used data from the National Birth Defects Prevention Study. For recognized risk factors for which data were available, we estimated crude population attributable fractions (cPAFs) to account for potential confounding, average-adjusted population attributable fractions (aaPAFs). We assessed 11 modifiable and 3 nonmodifiable parental/maternal risk factors. The aaPAF for individual risk factors and the total aaPAF for the set of risk factors were calculated using a method described by Eide and Geffler. SETTING: Population-based case-control study in 10 US states. PARTICIPANTS: Two thousand seven hundred seventy-nine cases with isolated cleft lip with or without cleft palate (CL±P), 1310 cases with isolated cleft palate (CP), and 11 692 controls with estimated dates of delivery between October 1, 1997, and December 31, 2011. MAIN OUTCOME MEASURES: Crude population attributable fraction and aaPAF. RESULTS: The proportion of CL±P and CP cases attributable to the full set of examined risk factors was 50% and 43%, respectively. The modifiable factor with the largest aaPAF was smoking during the month before pregnancy or the first month of pregnancy (4.0% for CL±P and 3.4% for CP). Among nonmodifiable factors, the factor with the largest aaPAF for CL±P was male sex (27%) and for CP it was female sex (16%). CONCLUSIONS: Our results may inform research and prevention efforts. A large proportion of orofacial cleft risk is attributable to nonmodifiable factors; it is important to better understand the mechanisms involved for these factors.