Analysis of blood methylation quantitative trait loci in East Asians reveals ancestry-specific impacts on complex traits.

Methylation quantitative trait loci (mQTLs) are essential for understanding the role of DNA methylation changes in genetic predisposition, yet they have not been fully characterized in East Asians (EAs). Here we identified mQTLs in whole blood from 3,523 Chinese individuals and replicated them in additional 1,858 Chinese individuals from two cohorts. Over 9% of mQTLs displayed specificity to EAs, facilitating the fine-mapping of EA-specific genetic associations, as shown for variants associated with height. Trans-mQTL hotspots revealed biological pathways contributing to EA-specific genetic associations, including an ERG-mediated 233 trans-mCpG network, implicated in hematopoietic cell differentiation, which likely reflects binding efficiency modulation of the ERG protein complex. More than 90% of mQTLs were shared between different blood cell lineages, with a smaller fraction of lineage-specific mQTLs displaying preferential hypomethylation in the respective lineages. Our study provides new insights into the mQTL landscape across genetic ancestries and their downstream effects on cellular processes and diseases/traits.

Genetic association between smoking and DLCO in idiopathic pulmonary fibrosis patients.

BACKGROUND: Observational studies have shown that smoking is related to the diffusing capacity of the lungs for carbon monoxide (DLCO) in individuals with idiopathic pulmonary fibrosis (IPF). Nevertheless, further investigation is needed to determine the causal effect between these two variables. Therefore, we conducted a study to investigate the causal relationship between smoking and DLCO in IPF patients using two-sample Mendelian randomization (MR) analysis. METHODS: Large-scale genome-wide association study (GWAS) datasets from individuals of European descent were analysed. These datasets included published lifetime smoking index (LSI) data for 462,690 participants and DLCO data for 975 IPF patients. The inverse-variance weighting (IVW) method was the main method used in our analysis. Sensitivity analyses were performed by MR‒Egger regression, Cochran's Q test, the leave-one-out test and the MR-PRESSO global test. RESULTS: A genetically predicted increase in LSI was associated with a decrease in DLCO in IPF patients [ORIVW = 0.54; 95% CI 0.32-0.93; P = 0.02]. CONCLUSIONS: Our study suggested that smoking is associated with a decrease in DLCO. Patients diagnosed with IPF should adopt an active and healthy lifestyle, especially by quitting smoking, which may be effective at slowing the progression of IPF.

Neofunctionalization of an OMT cluster dominates polymethoxyflavone biosynthesis associated with the domestication of citrus.

Polymethoxyflavones (PMFs) are a class of abundant specialized metabolites with remarkable anticancer properties in citrus. Multiple methoxy groups in PMFs are derived from methylation modification catalyzed by a series of hydroxylases and O-methyltransferases (OMTs). However, the specific OMTs that catalyze the systematic O-methylation of hydroxyflavones remain largely unknown. Here, we report that PMFs are highly accumulated in wild mandarins and mandarin-derived accessions, while undetectable in early-diverging citrus species and related species. Our results demonstrated that three homologous genes, CreOMT3, CreOMT4, and CreOMT5, are crucial for PMF biosynthesis in citrus, and their encoded methyltransferases exhibit multisite O-methylation activities for hydroxyflavones, producing seven PMFs in vitro and in vivo. Comparative genomic and syntenic analyses indicated that the tandem CreOMT3, CreOMT4, and CreOMT5 may be duplicated from CreOMT6 and contributes to the genetic basis of PMF biosynthesis in the mandarin group through neofunctionalization. We also demonstrated that N17 in CreOMT4 is an essential amino acid residue for C3-, C5-, C6-, and C3'-O-methylation activity and provided a rationale for the functional deficiency of OMT6 to produce PMFs in early-diverging citrus and some domesticated citrus species. A 1,041-bp deletion in the CreOMT4 promoter, which is found in most modern cultivated mandarins, has reduced the PMF content relative to that in wild and early-admixture mandarins. This study provides a framework for reconstructing PMF biosynthetic pathways, which may facilitate the breeding of citrus fruits with enhanced health benefits.

Single extracellular vesicle surface protein-based blood assay identifies potential biomarkers for detection and screening of five cancers.

Extracellular vesicles (EVs) and EV proteins are promising biomarkers for cancer liquid biopsy. Herein, we designed a case-control study involving 100 controls and 100 patients with esophageal, stomach, colorectal, liver, or lung cancer to identify common and type-specific biomarkers of plasma-derived EV surface proteins for the five cancers. EV surface proteins were profiled using a sequencing-based proximity barcoding assay. In this study, five differentially expressed proteins (DEPs) and eight differentially expressed protein combinations (DEPCs) showed promising performance (area under curve, AUC > 0.900) in pan-cancer identification [e.g., TENM2 (AUC = 0.982), CD36 (AUC = 0.974), and CD36-ITGA1 (AUC = 0.971)]. Our classification model could properly discriminate between cancer patients and controls using DEPs (AUC = 0.981) or DEPCs (AUC = 0.965). When distinguishing one cancer from the other four, the accuracy of the classification model using DEPCs (85-92%) was higher than that using DEPs (78-84%). We validated the performance in an additional 14 cancer patients and 14 controls, and achieved an AUC value of 0.786 for DEPs and 0.622 for DEPCs, highlighting the necessity to recruit a larger cohort for further validation. When clustering EVs into subpopulations, we detected cluster-specific proteins highly expressed in immune-related tissues. In the context of colorectal cancer, we identified heterogeneous EV clusters enriched in cancer patients, correlating with tumor initiation and progression. These findings provide epidemiological and molecular evidence for the clinical application of EV proteins in cancer prediction, while also illuminating their functional roles in cancer physiopathology.

The causal relationship between physical activity, sedentary time and idiopathic pulmonary fibrosis risk: a Mendelian randomization study.

BACKGROUND: Several observational studies have found that physical inactivity and sedentary time are associated with idiopathic pulmonary fibrosis (IPF) risk. However, the causality between them still requires further investigation. Therefore, our study aimed to investigate the causal effect of physical activity (PA) and sedentary time on the risk of IPF via two-sample Mendelian randomization (MR) analysis. METHODS: Multiple genome-wide association study (GWAS) data involving individuals of European ancestry were analyzed. The datasets encompassed published UK Biobank data (91,105-377,234 participants) and IPF data (2018 cases and 373,064 controls) from FinnGen Biobank. The inverse variance weighting (IVW) method was the primary approach for our analysis. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger regression, MR-PRESSO global test, and leave-one-out analysis. RESULTS: Genetically predicted self-reported PA was associated with lower IPF risk [OR = 0.27; 95% CI 0.09-0.82; P = 0.02]. No causal effects of accelerometry-based PA or sedentary time on the risk of IPF were observed. CONCLUSIONS: Our findings supported a protective relationship between self-reported PA and the risk for IPF. The results suggested that enhancing PA may be an effective preventive strategy for IPF.

Trace elements in hair or fingernail and gastroesophageal cancers: results from a population-based case-control study.

BACKGROUND: Growing evidence suggests that environmental factors probably play important roles in the development of gastroesophageal cancers (GOC), however, the effects of trace elements on GOC remain unclear. OBJECTIVE: To assess the effect of trace elements on GOC and the effect modification by other factors. METHODS: Hair and fingernail samples were collected from GOC cases and controls in a population-based case-control study in Taixing, China, and were used to detect the concentrations of 12 trace elements using inductively coupled plasma mass spectrometry. Unconditional logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for concentrations of 12 trace elements in association with GOC after adjusting the other factors. RESULTS: A total of 830 hair samples (581 controls and 249 cases) and 895 fingernail samples (559 controls and 336 cases) were included. Compared to the lowest-tertile concentration, the higher tertiles of Ca, Zn, Fe, Al, Cr, Pb, Se, and V were positively associated with GOC, while the higher tertiles of Mg, Mn, Sr, and As were inversely associated with GOC. Significant interactions between the hair level of Cr and two other risk factors, including smoking (P for interaction = 0.044) and alcohol drinking (P for interaction = 0.028), were observed in association with GOC. SIGNIFICANCE: The current study reveals that these 12 trace elements in hair and fingernails are associated with GOC to varying degrees. Further studies and animal experiments are needed to clarify the associations and explore potential mechanisms. IMPACT STATEMENT: The role of trace elements in the development or inhibition of gastroesophageal cancers (GOC) remains unclear. In this study, we further explored the associations between 12 trace elements and GOC based on a population-based case-control study conducted in Taixing, China. Higher levels of Ca, Zn, Fe, Al, Cr, Pb, Se, and V were positively associated with increased GOC, while inverse associations between higher levels of Mg, Mn, Sr, As, and GOC were observed. Observed associations were consistent in hair and fingernail samples. Moreover, interaction effects between hair level of Cr and smoking or alcohol drinking were identified.

The effects of altered DNA damage repair genes on mutational processes and immune cell infiltration in esophageal squamous cell carcinoma.

BACKGROUND: Defects in DNA damage repair (DDR) pathways lead to genomic instability and oncogenesis. DDR deficiency is prevalent in esophageal squamous cell carcinoma (ESCC), but the effects of DDR alterations on mutational processes and tumor immune microenvironment in ECSS remain unclear. METHODS: Whole-exome and transcriptome sequencing data of 45 ESCC samples from Taizhou, China, were used to identify genomic variations, gene expression modulation in DDR pathways, and the abundance of tumor-infiltrating immune cells. Ninety-six ESCC cases from The Cancer Genome Atlas (TCGA) project were used for validation. RESULTS: A total of 57.8% (26/45) of the cases in the Taizhou data and 70.8% (68/96) of the cases in the TCGA data carried at least one functional impact DDR mutation. Mutations in the DDR pathways were associated with a high tumor mutation burden. Several DDR deficiency-related mutational signatures were discovered and were associated with immune cell infiltration, including T cells, monocytes, dendritic cells, and mast cells. The expression levels of two DDR genes, HFM1 and NEIL1, were downregulated in ESCC tumor tissues and had an independent effect on the infiltration of mast cells. In the Taizhou data, increased expression of HFM1 was associated with a poor prognosis, and the increased expression of NEIL1 was associated with a good outcome, but no reproducible correlation was observed in the TCGA data. CONCLUSION: This research demonstrated that DDR alterations could impact mutational processes and immune cell infiltration in ESCC. The suppression of HFM1 and NEIL1 could play a crucial role in ESCC progression and may also serve as prognostic markers.

The role of metabolites under the influence of genes and lifestyles in bone density changes.

Purpose: Osteoporosis is a complex bone disease influenced by numerous factors. Previous studies have found that some metabolites are related to bone mineral density (BMD). However, the associations between metabolites and BMD under the influence of genes and lifestyle have not been fully investigated. Methods: We analyzed the effect of metabolites on BMD under the synergistic effect of genes and lifestyle, using the data of 797 participants aged 55-65 years from the Taizhou Imaging Study. The cumulative sum method was used to calculate the polygenic risk score of SNPs, and the healthful plant-based diet index was used to summarize food intake. The effect of metabolites on BMD changes under the influence of genes and lifestyle was analyzed through interaction analysis and mediation analysis. Results: Nineteen metabolites were found significantly different in the osteoporosis, osteopenia, and normal BMD groups. We found two high-density lipoprotein (HDL) subfractions were positively associated with osteopenia, and six very-low-density lipoprotein subfractions were negatively associated with osteopenia or osteoporosis, after adjusting for lifestyles and genetic factors. Tea drinking habits, alcohol consumption, smoking, and polygenic risk score changed BMD by affecting metabolites. Conclusion: With the increased level of HDL subfractions, the risk of bone loss in the population will increase; the risk of bone loss decreases with the increased level of very-low-density lipoprotein subfractions. Genetic factors and lifestyles can modify the effects of metabolites on BMD. Our results show evidence for the precise prevention of osteoporosis.

Identification of Candidate Therapeutic Genes for More Precise Treatment of Esophageal Squamous Cell Carcinoma and Adenocarcinoma.

The standard therapy administered to patients with advanced esophageal cancer remains uniform, despite its two main histological subtypes, namely esophageal squamous cell carcinoma (SCC) and esophageal adenocarcinoma (AC), are being increasingly considered to be different. The identification of potential drug target genes between SCC and AC is crucial for more effective treatment of these diseases, given the high toxicity of chemotherapy and resistance to administered medications. Herein we attempted to identify and rank differentially expressed genes (DEGs) in SCC vs. AC using ensemble feature selection methods. RNA-seq data from The Cancer Genome Atlas and the Fudan-Taizhou Institute of Health Sciences (China). Six feature filters algorithms were used to identify DEGs. We built robust predictive models for histological subtypes with the random forest (RF) classification algorithm. Pathway analysis also be performed to investigate the functional role of genes. 294 informative DEGs (87 of them are newly discovered) have been identified. The areas under receiver operator curve (AUC) were higher than 99.5% for all feature selection (FS) methods. Nine genes (i.e., ERBB3, ATP7B, ABCC3, GALNT14, CLDN18, GUCY2C, FGFR4, KCNQ5, and CACNA1B) may play a key role in the development of more directed anticancer therapy for SCC and AC patients. The first four of them are drug targets for chemotherapy and immunotherapy of esophageal cancer and involved in pharmacokinetics and pharmacodynamics pathways. Research identified novel DEGs in SCC and AC, and detected four potential drug targeted genes (ERBB3, ATP7B, ABCC3, and GALNT14) and five drug-related genes.

Limb development genes underlie variation in human fingerprint patterns.

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized "pattern-block" correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.

Association of Helicobacter pylori and gastric atrophy with adenocarcinoma of the esophagogastric junction in Taixing, China.

Gastric atrophy caused by Helicobacter pylori infection was suggested to influence the risk of adenocarcinoma of the esophagogastric junction (AEGJ), however, the evidence remains limited. We aimed to examine the associations of H. pylori infection and gastric atrophy (defined using serum pepsinogen [PG] I to PGII ratio) with AEGJ risk, based on a population-based case-control study in Taixing, China (2010-2014), with 349 histopathologically confirmed AEGJ cases and 1859 controls. We explored the potential effect modification by H. pylori serostatus and sex on the association of serum PGs with AEGJ risk. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). H. pylori seropositivity was associated with an elevated AEGJ risk (OR = 1.95, 95% CI: 1.47-2.63). Neither CagA-positive nor VacA-positive strains dramatically changed this association. Gastric atrophy (PGI/PGII ratio ≤4) was positively associated with AEGJ risk (OR = 2.36, 95% CI: 1.72-3.22). The fully adjusted ORs for AEGJ progressively increased with the increasing levels of PGII (P-trend <.001). H. pylori showed nonsignificant effect modification (P-interaction = .385) on the association of gastric atrophy with AEGJ. In conclusion, H. pylori and gastric atrophy were positively associated with AEGJ risk. These results may contribute evidence to the ongoing research on gastric atrophy-related cancers and guide the prevention and control of AEGJ.

Poor oral hygiene behavior is associated with an increased risk of gastric cancer: A population-based case-control study in China.

BACKGROUND: Poor oral health may be a significant risk factor for gastric cancer (GC); however, previous results are not consistent. Here, we investigated the effect of oral health on GC and effect modification by other factors. METHODS: We conducted a population-based case-control study in Taixing, China. Participants aged between 40 and 85 years and who had lived in Taixing for at least 5 years were included. The GC cases were confirmed by endoscopy and pathological diagnosis, and the controls were randomly selected using the frequency-matching method. Unconditional logistic regression models were used to derive odds ratios (ORs) and 95% confidence intervals (CIs) of oral health for GC risk after adjusting for confounders and risk factors. RESULTS: Overall, 901 GC cases and 1972 controls were included. Tooth loss was not significantly associated with an increased risk of GC (yes vs. no, OR = 1.08, 95% CI 0.88 to 1.33). Compared with toothbrushing at least twice per day, toothbrushing once per day or less was associated with an increased risk of GC (OR = 2.39, 95% CI 1.94 to 2.94), and was more pronounced in esophagogastric junction cancer and intestinal-type GC. There was no significant interaction between the indicators of oral health and age, sex, tobacco smoking, alcohol drinking, and Helicobacter pylori seropositivity. CONCLUSION: Poor oral hygiene behavior is associated with an increased risk of GC, and this positive association is consistent across all GC subgroups classified by anatomy and histology. Further studies are needed to explore the possible mechanisms behind this association.

Changes of Body Mass Index and Body Shape in relation to risk of Gastric Cancer: A population-based case-control study.

Background: The results of previous studies are heterogeneous about the effect of body fatness on risk of gastric cancer (GC). Herein we investigated the effect of changes of BMI and body shape on risk of GC. Methods: A population-based case-control study enrolled 1989 controls and 937 GC cases. Logistic regression models were used to calculate odd ratios (ORs) and 95% confidence intervals (CIs) for BMI and body shape in association with GC risk, according to anatomical subsite, Laurén's classification, sex and Helicobacter pylori (Hp) infection. Results: Subjects with higher BMI or body shape 10 years before interview had a lower risk of GC regardless of anatomical subsite, Laurén's classification, and sex (all P for trend <0.05). But the relative risk patterns were different by Hp status. When checking the effect of changes of body fatness, in Hp+ stratum, the ORs (95% CI) were 0.40 (0.17-0.93) for subjects who were underweight at age 20 but had increased BMI afterwards, and 0.48 (0.32-0.73) for those of body shape 1/2 at age 20 but increased body shape subsequently, compared to subjects with stable BMI or body shape. When subjects had a normal BMI or 3/4 body shape at age 20, weight loss nearly doubled the risk of GC, and weight gain would decrease the risk. Conclusion: The association between body fatness and GC risk might differ by time point of measurement and Hp-infection status. Further, the influence of changes of body fatness might be different by baseline body fatness and Hp-infection status.

Tumor infiltrating lymphocyte signature is associated with single nucleotide polymorphisms and predicts survival in esophageal squamous cell carcinoma patients.

PURPOSE: Esophageal cancer is the sixth leading cause of cancer-related death worldwide, and is associated with a poor prognosis. Stromal tumor infiltrating lymphocytes (sTIL) and certain single nucleotide polymorphisms (SNPs) have been found to be predictive of patient survival. In this study, we explored the association between SNPs and sTIL regarding the predictability of disease-free survival in patients with esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: We collected 969 pathologically confirmed ESCC patients from 2010 to 2013 and genotyped 101 SNPs from 59 genes. The number of sTIL for each patient was determined using an automatic algorithm. A Kruskal-Wallis test was used to determine the association between genotype and sTIL. The genotypes and clinical factors related to survival were analyzed using a Kaplan-Meier curve, Cox proportional hazards model, and log-rank test. RESULTS: The median age of the patients was 67 (42-85 years), there was a median follow-up of 851.5 days and 586 patients died. The univariable analysis showed that 10 of the 101 SNPs were associated with sTIL. Six SNPs were also associated with disease-free survival. A multivariable analysis revealed that sTIL, rs1801131, rs25487, and rs8030672 were independent prognostic markers for ESCC patients. The model combining SNPs, clinical characteristics and sTIL outperformed the model with clinical characteristics alone for predicting outcomes in ESCC patients. CONCLUSION: We discovered 10 SNPs associated with sTIL in ESCC and we built a model of sTIL, SNPs and clinical characteristics with improved prediction of survival in ESCC patients.

A nomogram for screening esophageal squamous cell carcinoma based on environmental risk factors in a high-incidence area of China: a population-based case-control study.

BACKGROUND: Selection of high-risk subjects for endoscopic screening of esophageal squamous cell carcinoma (ESCC) lacks individual predictive tools based on environmental risk factors. METHODS: We performed a large population-based case-control study of 1418 ESCC cases and 1992 controls in a high-risk area of China. Information on potential risk factors was collected via face-to-face interview using an electronic structured questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models, and predictive nomograms were established accordingly. A weighted analysis was further conducted to introduce age into predictive nomograms due to frequency matching study design. RESULTS: Most cases were usually exposed to 4 to 6 risk factors, but most controls were usually exposed to 3 to 5 risk factors. The AUCs of male and female predictive nomograms were 0.75 (95%CI: 0.72, 0.77) and 0.76 (95%CI: 0.73, 0.79), respectively. The weighted analysis adding age in the predictive model improved the AUC in both men and women (0.81 (95%CI: 0.79, 0.84) and 0.88 (95%CI: 0.85, 0.90), respectively). CONCLUSIONS: An easy-to-use preclinical predictive tool is provided to select candidate population with high ESCC risk for endoscopic screening. Its usefulness needs to be further evaluated in future screening practice.

Targeted proteomics-derived biomarker profile develops a multi-protein classifier in liquid biopsies for early detection of esophageal squamous cell carcinoma from a population-based case-control study.

BACKGROUND: Early diagnosis of esophageal squamous cell carcinoma (ESCC) remains a challenge due to the lack of specific blood biomarkers. We aimed to develop a serum multi-protein signature for the early detection of ESCC. METHODS: We selected 70 healthy controls, 30 precancerous patients, 60 stage I patients, 70 stage II patients and 70 stage III/IV ESCC patients from a completed ESCC case-control study in a high-risk area of China. Olink Multiplex Oncology II targeted proteomics panel was used to simultaneously detect the levels of 92 cancer-related proteins in serum using proximity extension assay. RESULTS: We found that 10 upregulated and 13 downregulated protein biomarkers in serum could distinguish the early-stage ESCC from healthy controls, which were validated by the significant dose-response relationships with ESCC pathological progression. Applying least absolute shrinkage and selection operator (LASSO) regression and backward elimination algorithm, ANXA1 (annexin A1), hK8 (kallikrein-8), hK14 (kallikrein-14), VIM (vimentin), and RSPO3 (R-spondin-3) were kept in the final model to discriminate early ESCC cases from healthy controls with an area under curve (AUC) of 0.936 (95% confidence interval: 0.899 ~ 0.973). The average accuracy rates of the five-protein classifier were 0.861 and 0.825 in training and test data by five-fold cross-validation. CONCLUSIONS: Our study suggested that a combination of ANXA1, hK8, hK14, VIM and RSPO3 serum proteins could be considered as a potential tool for screening and early diagnosis of ESCC, especially with the establishment of a three-level hierarchical screening strategy for ESCC control.

Healthy Lifestyle Factors, Cancer Family History, and Gastric Cancer Risk: A Population-Based Case-Control Study in China.

Background: We aimed to explore the relationship between lifestyle factors, cancer family history, and gastric cancer risk. Methods: We examined the association between lifestyle factors, cancer family history, and gastric cancer risk based on a population-based case-control study in Taixing, China, with 870 cases and 1928 controls. A lifestyle score was constructed considering body shape, smoking, alcohol drinking, tooth brushing habit, and food storage method. Unconditional logistic regression models were used to calculate odd ratios (ORs) and 95% confidence intervals (CIs). Results: Compared with participants with a lifestyle score of 0, subjects with a lifestyle score of 1 (OR 0.59, 95%CI 0.43-0.83), 2 (OR 0.42, 95%CI 0.30-0.59), 3 (OR 0.29, 95%CI 0.20-0.41), 4 (OR 0.20, 95%CI 0.13-0.32), or 5 (OR 0.10, 95%CI 0.04-0.22) had a lower risk of gastric cancer (P for trend < 0.001). Overall, 34% of gastric cancer cases (95%CI 27-41%) can be attributed to non-compliance with ≥3 healthy lifestyle. Family history of early-onset cancer is closely related to the occurrence of gastric cancer, with an OR ranging from 1.77 to 3.27. Regardless of family history, a good lifestyle is associated with a reduced risk of gastric cancer, with an OR value between 0.38 and 0.70. Conclusions: The early-onset cancer family history is closely related to the occurrence of gastric cancer and a good lifestyle is associated with a reduced risk of gastric cancer regardless of family history. Our results provide a basis for identifying and providing behavior guidance of high-risk groups of gastric cancer.

Non-invasive early detection of cancer four years before conventional diagnosis using a blood test.

Early detection has the potential to reduce cancer mortality, but an effective screening test must demonstrate asymptomatic cancer detection years before conventional diagnosis in a longitudinal study. In the Taizhou Longitudinal Study (TZL), 123,115 healthy subjects provided plasma samples for long-term storage and were then monitored for cancer occurrence. Here we report the preliminary results of PanSeer, a noninvasive blood test based on circulating tumor DNA methylation, on TZL plasma samples from 605 asymptomatic individuals, 191 of whom were later diagnosed with stomach, esophageal, colorectal, lung or liver cancer within four years of blood draw. We also assay plasma samples from an additional 223 cancer patients, plus 200 primary tumor and normal tissues. We show that PanSeer detects five common types of cancer in 88% (95% CI: 80-93%) of post-diagnosis patients with a specificity of 96% (95% CI: 93-98%), We also demonstrate that PanSeer detects cancer in 95% (95% CI: 89-98%) of asymptomatic individuals who were later diagnosed, though future longitudinal studies are required to confirm this result. These results demonstrate that cancer can be non-invasively detected up to four years before current standard of care.

Associations Between Gastric Atrophy and Its Interaction With Poor Oral Health and the Risk for Esophageal Squamous Cell Carcinoma in a High-Risk Region of China: A Population-Based Case-Control Study.

Previous findings concerning gastric atrophy as a potential risk factor for esophageal squamous cell carcinoma (ESCC) have been inconsistent. We aimed to test whether gastric atrophy and, further, its interaction with poor oral health elevated the risk of ESCC in a high-risk region of China. Our population-based case-control study in Taixing, China (2010-2014), recruited cases from local hospitals and the local cancer registry. Controls were selected randomly from the local population registry. Ultimately, 1,210 cases and 1,978 controls answered questionnaires and provided blood samples for assay of pepsinogens. Unconditional logistic regression models were used to estimate odds ratios and 95% confidence intervals. Gastric atrophy (defined as a serum level of pepsinogen I of <55 µg/L) was associated with an increased risk for ESCC (odds ratio = 1.61; 95% confidence interval: 1.33, 1.96), even after full adjustment for potential confounding factors. In addition, suggestion of an additive interaction between gastric atrophy and poor oral health was observed (relative excess risk due to interaction = 1.28, 95% confidence interval: 0.39, 2.18). We conclude that gastric atrophy appears to be a risk factor for ESCC in a high-risk region of China, and there is a suggested additive interaction with poor oral health that increases this risk even further.