Publications by authors named "Qiuyin Cai"

426 Publications

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.

Am J Hum Genet 2022 08;109(8):1366-1387

Division of Genome Science, Department of Precision Medicine, National Institute of Health, Chungbuk, South Korea.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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http://dx.doi.org/10.1016/j.ajhg.2022.06.012DOI Listing
August 2022

Associations of Pre-Diagnostic Serum Levels of Total Bilirubin and Albumin With Lung Cancer Risk: Results From the Southern Community Cohort Study.

Front Oncol 2022 23;12:895479. Epub 2022 Jun 23.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, United States.

Background: Previous studies conducted among European and Asian decedents reported inverse associations of serum total bilirubin and albumin with lung cancer risk. Yet, no study has been conducted among African Americans or low-income European Americans.

Methods: This study included 522 incident lung cancer cases and 979 matched controls nested in the Southern Community Cohort Study, a cohort of predominantly low-income African and European Americans. Serum levels of total bilirubin and albumin, collected up to 11 years prior to case diagnoses, were measured by a clinical chemistry analyzer. Conditional logistic regression models were applied to evaluate the associations of total bilirubin and albumin with lung cancer risk.

Results: Overall, serum levels of total bilirubin (OR = 0.96, 95% CI: 0.66-1.39) were not significantly associated with lung cancer risk. However, higher levels of serum total bilirubin were significantly associated with decreased risk of lung cancer among participants who were diagnosed within two years following sample collection (OR = 0.36, 95% CI: 0.15-0.87) and among former/never smokers (OR = 0.54, 95% CI: 0.32-0.93). Serum levels of albumin were significantly associated with decreased risk of lung cancer overall (OR = 0.70, 95% CI: 0.50-0.98) and among African Americans (OR = 0.62, 95% CI: 0.41-0.96), but not among European Americans.

Conclusion: Our results indicate that in a low-income African American and European American population, serum levels of total bilirubin may be related to lung cancer progression and differ by smoking status. Meanwhile, the association of serum albumin levels with lung cancer risk may differ by race. Further studies are warranted to confirm these results.
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http://dx.doi.org/10.3389/fonc.2022.895479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261263PMC
June 2022

Prospective Proteomic Study Identifies Potential Circulating Protein Biomarkers for Colorectal Cancer Risk.

Cancers (Basel) 2022 Jul 3;14(13). Epub 2022 Jul 3.

Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017, USA.

Background: Proteomics-based technologies are emerging tools used for cancer biomarker discovery. Limited prospective studies have been conducted to evaluate the role of circulating proteins in colorectal cancer (CRC) development.

Methods: A two-stage case-control proteomics study nested in the Shanghai Women's Health Study was conducted. A total of 1104 circulating proteins were measured in the discovery phase, consisting of 100 incident CRC cases and 100 individually matched controls. An additional 60 case-control pairs were selected for validation. Protein profiling at both stages was completed using the Olink platforms. Conditional logistic regression was used to evaluate the associations between circulating proteins and CRC risk. The elastic net method was employed to develop a protein score for CRC risk.

Results: In the discovery set, 27 proteins showed a nominally significant association with CRC risk, among which 22 were positively and 5 were inversely associated. Six of the 27 protein markers were significantly associated with CRC risk in the validation set. In the analysis of pooled discovery and validation sets, odds ratios (ORs) per standard deviation (SD) increase in levels of these proteins were 1.54 (95% confidence interval (CI): 1.15-2.06) for CD79B; 1.71 (95% CI: 1.24-2.34) for DDR1; 2.04 (95% CI: 1.39-3.01) for EFNA4; 1.54 (95% CI: 1.16-2.02) for FLRT2; 2.09 (95% CI: 1.47-2.98) for LTA4H and 1.88 (95% CI: 1.35-2.62) for NCR1. Sensitivity analyses showed consistent associations for all proteins with the exclusion of cases diagnosed within the first two years after the cohort enrollment, except for CD79B. Furthermore, a five-protein score was developed based on the six proteins identified and showed significant associations with CRC risk in both discovery and validation sets (Discovery: OR = 2.46, 95% CI: 1.53-3.95; validation: OR = 4.16, 95% CI: 1.92-8.99).

Conclusions: A panel of five protein markers was identified as potential biomarkers for CRC risk. Our findings provide novel insights into the etiology of CRC and may facilitate the risk assessment of the malignancy.
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http://dx.doi.org/10.3390/cancers14133261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9265260PMC
July 2022

Developing and validating polygenic risk scores for colorectal cancer risk prediction in East Asians.

Int J Cancer 2022 Jun 29. Epub 2022 Jun 29.

Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Several polygenic risk scores (PRSs) have been developed to predict the risk of colorectal cancer (CRC) in European descendants. We used genome-wide association study (GWAS) data from 22 702 cases and 212 486 controls of Asian ancestry to develop PRSs and validated them in two case-control studies (1454 Korean and 1736 Chinese). Eleven PRSs were derived using three approaches: GWAS-identified CRC risk SNPs, CRC risk variants identified through fine-mapping of known risk loci and genome-wide risk prediction algorithms. Logistic regression was used to estimate odds ratios (ORs) and area under the curve (AUC). PRS , a PRS with 115 GWAS-reported risk variants derived from East-Asian data, validated significantly better than PRS derived from European descendants. In the Korea validation set, OR per SD increase of PRS was 1.63 (95% CI = 1.46-1.82; AUC = 0.63), compared with OR of 1.44 (95% CI = 1.29-1.60, AUC = 0.60) for PRS . PRS derived using meta-analysis results of both populations slightly improved the AUC to 0.64. Similar but weaker associations were found in the China validation set. Individuals among the highest 5% of PRS have a 2.52-fold elevated CRC risk compared with the medium (41-60th) risk group and have a 12% to 20% risk of developing CRC by age 85. PRSs constructed using results from fine-mapping and genome-wide algorithms did not perform as well as PRS and PRS in risk prediction, possibly due to a small sample size. Our results indicate that CRC PRSs are promising in predicting CRC risk in East Asians and highlights the importance of using population-specific data to build CRC risk prediction models.
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http://dx.doi.org/10.1002/ijc.34194DOI Listing
June 2022

Absolute Risk of Oropharyngeal Cancer After an HPV16-E6 Serology Test and Potential Implications for Screening: Results From the Human Papillomavirus Cancer Cohort Consortium.

J Clin Oncol 2022 Jun 14:JCO2101785. Epub 2022 Jun 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

Purpose: Seropositivity for the HPV16-E6 oncoprotein is a promising marker for early detection of oropharyngeal cancer (OPC), but the absolute risk of OPC after a positive or negative test is unknown.

Methods: We constructed an OPC risk prediction model that integrates (1) relative odds of OPC for HPV16-E6 serostatus and cigarette smoking from the human papillomavirus (HPV) Cancer Cohort Consortium (HPVC3), (2) US population risk factor data from the National Health Interview Survey, and (3) US sex-specific population rates of OPC and mortality.

Results: The nine HPVC3 cohorts included 365 participants with OPC with up to 10 years between blood draw and diagnosis and 5,794 controls. The estimated 10-year OPC risk for HPV16-E6 seropositive males at age 50 years was 17.4% (95% CI, 12.4 to 28.6) and at age 60 years was 27.1% (95% CI, 19.2 to 45.4). Corresponding 5-year risk estimates were 7.3% and 14.4%, respectively. For HPV16-E6 seropositive females, 10-year risk estimates were 3.6% (95% CI, 2.5 to 5.9) at age 50 years and 5.5% (95% CI, 3.8 to 9.2) at age 60 years and 5-year risk estimates were 1.5% and 2.7%, respectively. Over 30 years, after a seropositive result at age 50 years, an estimated 49.9% of males and 13.3% of females would develop OPC. By contrast, 10-year risks among HPV16-E6 seronegative people were very low, ranging from 0.01% to 0.25% depending on age, sex, and smoking status.

Conclusion: We estimate that a substantial proportion of HPV16-E6 seropositive individuals will develop OPC, with 10-year risks of 17%-27% for males and 4%-6% for females age 50-60 years in the United States. This high level of risk may warrant periodic, minimally invasive surveillance after a positive HPV16-E6 serology test, particularly for males in high-incidence regions. However, an appropriate clinical protocol for surveillance remains to be established.
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http://dx.doi.org/10.1200/JCO.21.01785DOI Listing
June 2022

Tooth Loss and Risk of Lung Cancer among Urban Chinese Adults: A Cohort Study with Meta-Analysis.

Cancers (Basel) 2022 May 14;14(10). Epub 2022 May 14.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Epidemiological evidence on tooth loss and lung cancer risk remains limited, especially for smoking-specific associations. To investigate the association between tooth loss and lung cancer risk by smoking status, we first analyzed data from the Shanghai Men's Health Study ( = 49,868) and the Shanghai Women's Health Study ( = 44,309). Cox regression models were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer risk in relation to tooth loss. We also conducted a meta-analysis to summarize epidemiologic findings to date, incorporating results from the current study and six previously published studies. For 7.3 median follow-up years, 973 incident lung cancer cases (613 men and 360 women) were ascertained. After adjustment for major covariates, tooth loss was associated with an increased risk of lung cancer among men (HR [95% CI] for >10 teeth vs. none = 1.59 [1.21-2.11]) but not among women (0.86 [0.50-1.46]). The positive association was stronger among male current smokers (1.75 [1.26-2.45], -interaction by smoking status = 0.04). In a meta-analysis incorporating 4052 lung cancer cases and 248,126 non-cases, tooth loss was associated with a 1.64-fold increased risk of developing lung cancer (relative risk [RR, 95% CI] for the uppermost with the lowest category = 1.64 [1.44-1.86]). The positive association was more evident among current smokers (1.86 [1.41-2.46]), but no significant associations were found among never or former smokers. Our findings suggest that tooth loss may be associated with an increased risk of lung cancer, and the association could be modified by smoking status.
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http://dx.doi.org/10.3390/cancers14102428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9140069PMC
May 2022

Associations of lung cancer risk with biomarkers of Helicobacter pylori infection.

Carcinogenesis 2022 Jun;43(6):538-546

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.

Helicobacter pylori infection has been suggested to be associated with lung cancer risk. However, information is lacking on whether the association differs by H. pylori antigen. We conducted a nested case-control study within the Southern Community Cohort Study, including 295 incident lung cancer cases and 295 controls. Helicobacter pylori multiplex serology assay was performed to detect antibodies to 15 H. pylori proteins. Conditional logistic regression was used to estimate odds ratios (ORs) and confidence intervals (95% CIs) after adjustment for covariates. Overall H. pylori+ was associated with a non-statistically significant increased risk of lung cancer (OR: 1.29; 95% CI: 0.85-1.95). Significant associations, however, were observed for H. pylori+ VacA+ (OR: 1.64; 95% CI: 1.02-2.62) and H. pylori+ Catalase+ (OR: 1.75; 95% CI: 1.11-2.77). The positive association of H. pylori+ Catalase+ with lung cancer risk was predominantly seen among African Americans (OR: 2.09; 95% CI: 1.11-3.95) but not European Americans (OR: 1.20; 95% CI: 0.56-2.54). Among participants who smoked ≥ 30 pack-years, overall H. pylori+ (OR: 1.85; 95% CI: 1.02-3.35), H. pylori+ CagA+ (OR: 2.77; 95% CI: 1.35-5.70), H. pylori+ VacA+ (OR: 2.53; 95% CI: 1.25-5.13) and H. pylori+ HP1564+ (OR: 2.01; 95% CI: 1.07-3.77) were associated with increased risk of lung cancer. Our study provides novel evidence that associations of H. pylori infection with lung cancer risk differ by H. pylori biomarker, may be more evident among African Americans and may be modified by smoking habits. Furthermore, studies are warranted to confirm our findings.
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http://dx.doi.org/10.1093/carcin/bgac047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234758PMC
June 2022

Lipid peroxidation biomarkers associated with height and obesity measures in the opposite direction in women.

Obesity (Silver Spring) 2022 06 26;30(6):1257-1267. Epub 2022 Apr 26.

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA.

Objective: This study aimed to investigate whether and how lipid peroxidation markers are associated with height and obesity measures.

Methods: In two independent samples of women (Study 1: n = 1,005; Study 2: n = 1,158), systemic levels of lipid peroxidation were assessed by urinary markers F -isoprostanes (F -IsoPs) and its major metabolite (F -IsoP-M), with gas chromatography/negative ion chemical ionization mass spectrometry assays. Anthropometric parameters were directly measured and genetically estimated, and they were used in the primary analysis and in a Mendelian randomization analysis in relation to lipid peroxidation, respectively, with general linear models.

Results: After adjusting for potential confounders, it was found that measured adult height was inversely associated with levels of F -IsoPs (β = -0.89, p < 0.001) and F -IsoP-M (β = -0.71, p = 0.003), whereas obesity measures were positively associated with F -IsoP-M (β = 1.81, p < 0.001 for BMI; and β = 0.77, p < 0.001 for waist circumference). Results were consistent between the two study samples. The opposite associations were further replicated when using genetically determined measures of height and obesity in the Mendelian randomization analysis. Moreover, analyses mutually adjusted for height and obesity measures suggested that these associations were independent of one another.

Conclusions: This study, for the first time, to our knowledge, reveals that a shared biological process (lipid peroxidation) is associated with both height and obesity measures but in the opposite direction.
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http://dx.doi.org/10.1002/oby.23408DOI Listing
June 2022

The Role of Thoracic Radiation Therapy Dosing in the Treatment of Limited-Stage Small Cell Lung Cancer: A Study Based on the National Cancer Database.

Adv Radiat Oncol 2022 Sep-Oct;7(5):100907. Epub 2022 Feb 3.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.

Purpose: Small cell lung cancer (SCLC) is a highly fatal disease, but its treatment has remained relatively unchanged for decades. Randomized clinical trials evaluating radiation therapy (RT) dosing and fractionation have yielded mixed results on overall survival (OS).

Methods And Materials: We identified 2261 patients with limited-stage (LS) SCLC undergoing definitive RT at 1.5, 1.8, and 2.0 Gy dose per fraction, concurrently with chemotherapy, between 2004 and 2015 within the National Cancer Database. Overall survival (OS) was evaluated using the Kaplan-Meier method, and Cox proportional hazards regression was used to investigate whether there was any survival difference among patients who received hyperfractionated, twice-daily RT at 1.5 Gy per fraction (HF1.5) and once-daily, standard fractionation RT at 1.8 Gy (SF1.8) or 2.0 Gy (SF2.0) per fraction. Subgroup analyses by age, sex, race, time to RT, facility type, and Charlson comorbidity index were also performed.

Results: All stage median OS rates for HF1.5, SF1.8, and SF2.0 Gy groups were 21.6, 18.9, and 19.4 months, respectively (log-rank  = .0079). Multivariate analyses adjusting for demographic factors, socioeconomic status, tumor characteristics, and year of diagnosis showed SF1.8 (hazard ratio [HR] = 1.30, 1.03-1.63) and SF2.0 (HR = 1.20, 1.00-1.45) was associated with worse 1-year survival compared with HF1.5. This association was more evident in stage IIb-stage III than stage I to stage IIa patients. Propensity score-weighted analysis showed similar results. Stratified analyses showed the significant associations were confined to male or black patients, those aged >65 years, with 1 comorbidity, who had waited >60 days to start RT or were treated at an academic medical center.

Conclusions: Analyses of real-world treatment outcome data showed that receiving hyperfractionated, twice-daily RT was associated with improved survival among patients with LS-SCLC compared with standard, once-daily fractionation regimens at 1 year after diagnosis, particularly for subsets of patients. Some associations retained statistical significance 3 years postdiagnosis.
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http://dx.doi.org/10.1016/j.adro.2022.100907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034280PMC
February 2022

Evaluating breast cancer predisposition genes in women of African ancestry.

Genet Med 2022 07 8;24(7):1468-1475. Epub 2022 Apr 8.

Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN. Electronic address:

Purpose: Studies conducted primarily among European ancestry women reported 12 breast cancer predisposition genes. However, etiologic roles of these genes in breast cancer among African ancestry women have been less well-investigated.

Methods: We conducted a case-control study in African American women, which included 1117 breast cancer cases and 2169 cancer-free controls, and a pooled analysis, which included 7096 cases and 8040 controls of African descent. Odds ratios of associations with breast cancer risk were estimated.

Results: Using sequence data, we identified 61 pathogenic variants in 12 breast cancer predisposition genes, including 11 pathogenic variants not yet reported in previous studies. Pooled analysis showed statistically significant associations of breast cancer risk with pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, TP53, NF1, RAD51C, and RAD51D (all P < .05). The associations with BRCA1, PALB2, and RAD51D were stronger for estrogen receptor (ER)-negative than for ER-positive breast cancer (P heterogeneity < .05), whereas the association with CHEK2 was stronger for ER-positive than for ER-negative breast cancer.

Conclusion: Our study confirmed previously identified associations of breast cancer risk with BRCA1, BRCA2, PALB2, ATM, TP53, NF1, and CHEK2 and provided new evidence to extend the associations of breast cancer risk with RAD51C and RAD51D, which was identified previously in European ancestry populations, to African ancestry women.
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http://dx.doi.org/10.1016/j.gim.2022.03.015DOI Listing
July 2022

Findings from the first colorectal cancer screening among 103 542 individuals in Vietnam with systematic review of colorectal cancer screening programs in Asia-Pacific region.

Jpn J Clin Oncol 2022 Jul;52(7):699-707

UPMC Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA.

Background: Colorectal cancer is a leading cancer incidence and cause of death worldwide and in Vietnam. Although screening is considered an effective measure to prevent and control colorectal cancer, there is no such effort in Vietnam.

Methods: Between 01 January 2018 and 31 October 2019, a population-based colorectal cancer screening program was conducted in Hanoi, Vietnam. A health advocacy campaign and follow-up phone calls were used to enroll residents aged ≥40 years old to complete an immunochemical-fecal occult blood testing. Positive immunochemical-fecal occult blood testing was followed by a colonoscopy. We also conducted a systematic review of the colorectal cancer screening programs in the Asia-Pacific region that used similar approach by searching Ovid Medline and PubMed databases.

Results: During study period, 103 542 individuals among 672 742 eligible residents attended the screening of whom 81.5% participants finished immunochemical-fecal occult blood testing test and the positive rate was 6.1%. The coverage rate for immunochemical-fecal occult blood testing test was 11.9%. Among 2278 individuals who underwent colonoscopy, 3.5% were histologically diagnosed with cancer, 17.8% with advanced adenomas, and 23.1% with non-advanced adenomas. Males had significantly higher detection rate of advanced adenomas, cancer or ≥ two polyps/tumor than females (P < 0.0001). The systematic review showed that in two-step modality (i.e. immunochemical-fecal occult blood testing/fecal immunochemical test and colonoscopy), the test positive was from 4.1 to 10.6%. Once colonoscopy was performed subsequently, the rate of cancer among positive participants was from 1.7 to 16.4% and that of advanced adenomas was from 7.1 to 23.1%.

Conclusion: We showed that the two-step modality is a promising strategy for colorectal cancer screening in Vietnam that might apply to similar settings with limited resources.
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http://dx.doi.org/10.1093/jjco/hyac043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264238PMC
July 2022

Endogenous sex hormones, aromatase activity and lung cancer risk in postmenopausal never-smoking women.

Int J Cancer 2022 Sep 2;151(5):699-707. Epub 2022 Apr 2.

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.

Although reproductive factors have been repeatedly associated with lung cancer risk, no study to date has directly evaluated the relationship with endogenous sex hormones nor with aromatase activity in postmenopausal never-smoking women. A case-control study of 397 incident lung cancer cases and their individually matched controls, nested within the Shanghai Women's Health Study, was conducted among postmenopausal women who were lifetime never smokers. Prediagnostic concentrations of sex hormones was quantitated using LC-MS/MS assays in plasma. The product-substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). Multivariable conditional logistic regression models were used to calculate odds ratios (ORs) for lung cancer. Baseline concentrations of estradiol, free testosterone and IAA were inversely associated with subsequent risk of lung cancer in multivariable-adjusted models. When further adjusted for body mass index, the inverse association with estradiol was attenuated and no longer statistically significant, but the association with free testosterone and IAA remained. In analyses confined to participants having never used menopausal hormone therapy in 376 case-control pairs, the inverse association with free testosterone and IAA was slightly strengthened. OR for the highest vs the lowest quartile of free testosterone was 0.55 (95% CI = 0.34-0.90; P  = .03), and the corresponding OR for IAA was 0.57 (95% CI = 0.34-0.96; P  = .04). Our study, for the first time, suggests that higher levels of circulating free testosterone and estimated aromatase activity may be associated with lower lung cancer risk in postmenopausal never-smoking women.
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http://dx.doi.org/10.1002/ijc.34005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9271581PMC
September 2022

Incorporating Polygenic Risk Scores and Nongenetic Risk Factors for Breast Cancer Risk Prediction Among Asian Women.

JAMA Netw Open 2022 03 1;5(3):e2149030. Epub 2022 Mar 1.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: Polygenic risk scores (PRSs) have shown promise in breast cancer risk prediction; however, limited studies have been conducted among Asian women.

Objective: To develop breast cancer risk prediction models for Asian women incorporating PRSs and nongenetic risk factors.

Design, Setting, And Participants: This diagnostic study included women of Asian ancestry from the Asia Breast Cancer Consortium. PRSs were developed using data from genomewide association studies (GWASs) of breast cancer conducted among 123 041 women with Asian ancestry (including 18 650 women with breast cancer) using 3 approaches: (1) reported PRS for women with European ancestry; (2) breast cancer-associated single-nucleotide variations (SNVs) identified by fine-mapping of GWAS-identified risk loci; and (3) genomewide risk prediction algorithms. A nongenetic risk score (NGRS) was built, including 7 well-established nongenetic risk factors, using data of 416 case participants and 1558 control participants from a prospective cohort study. PRSs were initially validated in an independent data set including 1426 case participants and 1323 control participants and further evaluated, along with the NGRS, in the second data set including 368 case participants and 736 control participants nested within a prospective cohort study.

Main Outcomes And Measures: Logistic regression was used to examine associations of risk scores with breast cancer risk to estimate odds ratios (ORs) with 95% CIs and area under the receiver operating characteristic curve (AUC).

Results: A total of 126 894 women of Asian ancestry were included; 20 444 (16.1%) had breast cancer. The mean (SD) age ranged from 49.1 (10.8) to 54.4 (10.4) years for case participants and 50.6 (9.5) to 54.0 (7.4) years for control participants among studies that provided demographic characteristics. In the prospective cohort, a PRS with 111 SNVs developed using the fine-mapping approach (PRS111) showed a prediction performance comparable with a genomewide PRS that included more than 855 000 SNVs. The OR per SD increase of PRS111 score was 1.67 (95% CI, 1.46-1.92), with an AUC of 0.639 (95% CI, 0.604-0.674). The NGRS had a limited predictive ability (AUC, 0.565; 95% CI, 0.529-0.601). Compared with the average risk group (40th-60th percentile), women in the top 5% of PRS111 and NGRS were at a 3.84-fold (95% CI, 2.30-6.46) and 2.10-fold (95% CI, 1.22-3.62) higher risk of breast cancer, respectively. The prediction model including both PRS111 and NGRS achieved the highest prediction accuracy (AUC, 0.648; 95% CI, 0.613-0.682).

Conclusions And Relevance: In this study, PRSs derived using breast cancer risk-associated SNVs had similar predictive performance in Asian and European women. Including nongenetic risk factors in models further improved prediction accuracy. These findings support the utility of these models in developing personalized screening and prevention strategies.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.49030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8938714PMC
March 2022

Large-scale Integrated Analysis of Genetics and Metabolomic Data Reveals Potential Links Between Lipids and Colorectal Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2022 06;31(6):1216-1226

Cancer Control and Population Sciences, Huntsman Cancer Institute and Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah.

Background: The etiology of colorectal cancer is not fully understood.

Methods: Using genetic variants and metabolomics data including 217 metabolites from the Framingham Heart Study (n = 1,357), we built genetic prediction models for circulating metabolites. Models with prediction R2 > 0.01 (Nmetabolite = 58) were applied to predict levels of metabolites in two large consortia with a combined sample size of approximately 46,300 cases and 59,200 controls of European and approximately 21,700 cases and 47,400 controls of East Asian (EA) descent. Genetically predicted levels of metabolites were evaluated for their associations with colorectal cancer risk in logistic regressions within each racial group, after which the results were combined by meta-analysis.

Results: Of the 58 metabolites tested, 24 metabolites were significantly associated with colorectal cancer risk [Benjamini-Hochberg FDR (BH-FDR) < 0.05] in the European population (ORs ranged from 0.91 to 1.06; P values ranged from 0.02 to 6.4 × 10-8). Twenty one of the 24 associations were replicated in the EA population (ORs ranged from 0.26 to 1.69, BH-FDR < 0.05). In addition, the genetically predicted levels of C16:0 cholesteryl ester was significantly associated with colorectal cancer risk in the EA population only (OREA: 1.94, 95% CI, 1.60-2.36, P = 2.6 × 10-11; OREUR: 1.01, 95% CI, 0.99-1.04, P = 0.3). Nineteen of the 25 metabolites were glycerophospholipids and triacylglycerols (TAG). Eighteen associations exhibited significant heterogeneity between the two racial groups (PEUR-EA-Het < 0.005), which were more strongly associated in the EA population. This integrative study suggested a potential role of lipids, especially certain glycerophospholipids and TAGs, in the etiology of colorectal cancer.

Conclusions: This study identified potential novel risk biomarkers for colorectal cancer by integrating genetics and circulating metabolomics data.

Impact: The identified metabolites could be developed into new tools for risk assessment of colorectal cancer in both European and EA populations.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-1008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354799PMC
June 2022

Association of Fruit, Vegetable, and Animal Food Intakes with Breast Cancer Risk Overall and by Molecular Subtype among Vietnamese Women.

Cancer Epidemiol Biomarkers Prev 2022 05;31(5):1026-1035

Vanderbilt Epidemiology Center, Division of Epidemiology, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Evidence on associations between dietary intake and risk of breast cancer subtypes is limited and inconsistent. We evaluated associations of fruit, vegetable, meat, and fish consumption with risk of breast cancer overall and by molecular subtype in the Vietnamese Breast Cancer Study (VBCS).

Method: VBCS includes 476 incident breast cancer cases and 454 age-matched controls. Dietary habits over the past 5 years were assessed by in-person interviews using a validated food frequency questionnaire. Associations of food groups with breast cancer were evaluated via logistic regression for overall and molecular subtype with adjustment for age, education, income, family history of cancer, menopausal status, body mass index, exercise, total energy intake, and other potential dietary confounders. Odds ratio (OR) was used to approximate relative risk.

Results: High fruit intake was inversely associated with breast cancer risk, with adjusted ORs [95% confidence intervals (CI)] of 0.67 (95% CI, 0.47-0.95) and 0.41 (95% CI, 0.27-0.61) for second and third tertiles versus first tertile, respectively (Ptrend < 0.001). This association was stronger for triple-negative than other subtypes (Pheterogeneity < 0.001). High intake of freshwater fish was inversely associated with overall breast cancer (ORT3vsT1 = 0.63; 95% CI, 0.42-0.95; Ptrend = 0.03). An inverse association was observed between HER2-enriched subtype and red and organ meat intake (ORT3vsT1 = 0.40; 95% CI, 0.17-0.93; Ptrend = 0.04; Pheterogeneity = 0.50).

Conclusions: High intakes of fruit and freshwater fish were associated with reduced breast cancer risk; association for the former was stronger for triple-negative subtype.

Impact: Our findings suggest high intakes of fruit and freshwater fish may reduce breast cancer risk among Vietnamese women.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-1085DOI Listing
May 2022

The putative oncogenic role of WDTC1 in colorectal cancer.

Carcinogenesis 2022 Jun;43(6):594-600

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.

Microsatellite instability (MSI) is detected in approximately 15% of colorectal cancers (CRCs). WD40 and tetratricopeptide repeats 1 (WDTC1) is frequently mutated in MSI CRC, indicating that it may contribute to CRC development. However, the functional evidence of the role of WDTC1 in CRC development remains unknown. Herein, we conducted in vitro assays to examine the function of WDTC1 using knockdown experiments in three CRC cell lines, SW480, CACO2, and LoVo. We provided strong evidence that silencing WDTC1 significantly suppressed cell proliferation, migration, and invasion consistently in all three CRC cell lines. To evaluate the potential role of WDTC1 in regulating CRC-related genes, we conducted RNA sequencing after 24 and 48 h in SW480 cells after treating WDTC1-siRNA and its vehicle control cells. Differential gene expression analysis identified 44 (42 downregulated and 2 upregulated) and 16 (all downregulated) genes, at time points of 24 and 48 h, respectively, whereas 15 downregulated genes were commonly detected at both time points. The ingenuity pathways analysis suggested that the most significant enrichments associated with cancer function and upstream regulator ATM/ATR were observed for these commonly observed genes. We further verified differential gene expression of eight cancer-related genes, ARHGEF12, GSTP1, FNDC3A, TMTC3, RTN4, RRM2, UHMK1, and PTPRF, using RT-PCR in all three cell lines. Our findings provided additional insight into the oncogenic role of WDTC1 in CRC development.
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http://dx.doi.org/10.1093/carcin/bgac027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234762PMC
June 2022

Quality of dietary carbohydrate is more important than its quantity in lipid peroxidation.

Am J Clin Nutr 2022 Jul;116(1):189-196

Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: High glycemic index (GI) diets have been linked to elevated risk of cardiometabolic diseases. One possible underlying mechanism comes from high GI diet's potential to promote lipid peroxidation.

Objectives: We aim to evaluate whether and to what extent dietary carbohydrate quality and quantity are associated with systemic levels of lipid peroxidation in females.

Methods: In this cross-sectional analysis of 2163 middle-aged women, a subset of the Shanghai Women's Health Study, we measured lipid peroxidation biomarkers F2-isoprostanes (F2-IsoPs) and its metabolite, 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M), in urine. The quality of carbohydrate was defined by dietary GI, assessed using a validated FFQ via in-person interviews. A multivariable linear regression model with restricted cubic spline functions was used to evaluate the association of measured biomarkers with carbohydrate intake and dietary GI.

Results: After adjustment for potential confounding factors such as cigarette smoking, BMI, and comorbidities, among others, we found that F2-IsoP-M concentrations were positively associated with both carbohydrate intake and dietary GI. Carbohydrate intake and dietary GI were weakly correlated (r = 0.12). When further mutually adjusted for the 2 factors, the positive association with F2-IsoP-M remained statistically significant for GI (P = 0.004) but not for carbohydrate intake (P = 0.50). Compared with those in the 10th percentile of dietary GI, fold increases (95% CI) in F2-IsoP-M concentrations for those in the 30th, 50th, 70th, and 90th percentiles were 1.03 (1.00, 1.07), 1.06 (1.01, 1.10), 1.09 (1.03, 1.14), and 1.13 (1.05, 1.21), respectively. Moreover, there appeared a threshold regarding the association between dietary GI and F2-IsoP-M concentrations, with the dose-effect slope of GI being 2.3 times greater when GI was ≥75 relative to GI <75.

Conclusions: This study provides evidence that the quality of dietary carbohydrate may be more important than the quantity of the intake with regard to systemic lipid peroxidation.
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http://dx.doi.org/10.1093/ajcn/nqac047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9257472PMC
July 2022

Association Between Long-Term Regular Exercise and Gut Microbiota Among Middle-Aged and Older Urban Chinese.

Int J Sport Nutr Exerc Metab 2022 05 25;32(3):144-152. Epub 2022 Jan 25.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN,USA.

Increasing evidence has suggested that physical activity may modulate gut microbiome composition. We investigated associations of long-term regular exercise with gut microbiota among middle-aged and older urban Chinese individuals. Gut microbiota was assessed using 16S ribosomal ribonucleic acid gene sequencing of stool samples from 2,151 participants from the Shanghai Women's Health Study and Shanghai Men's Health Study. Participants were free of cancer, diabetes, and cardiovascular diseases at the time of stool sample collection. Physical activity was assessed in repeat surveys between 1996 and 2015 using validated questionnaires. Regular exercise was defined as any type of leisure-time physical activity with a standard metabolic equivalent score >3.0. Stool samples were collected using the 95% ethanol method between 2015 and 2018 with an average of 3.0 years (SD = 0.9) after the latest exposure assessment. General linear regression and permutational multivariate analysis of variance were carried out to evaluate associations of microbial α- and β-diversity with regular exercise participation. Logistic regression and linear regression models were used to evaluate the prevalence and relative abundance of individual taxa in association with regular exercise. Regular exercise was significantly associated with β-diversity (Bray-Curtis and Jaccard dissimilarities, both false discovery rates = 0.03%, 0.12% and 0.09% variance explained, respectively) but not with α-diversity. Relative abundance of genus Ruminococcus was significantly lower among regular exercisers compared with nonexercisers (median relative abundance: 0.64% vs. 0.81%, false discovery rate <0.10). Further studies are needed to validate the findings from this study and evaluate health benefits of regular exercise on gut microbiota.
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http://dx.doi.org/10.1123/ijsnem.2021-0065DOI Listing
May 2022

TBX1 functions as a putative oncogene of breast cancer through promoting cell cycle progression.

Carcinogenesis 2022 02;43(1):12-20

Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

We have previously identified a genetic variant, rs34331122 in the 22q11.21 locus, as being associated with breast cancer risk in a genome-wide association study. This novel variant is located in the intronic region of the T-box transcription factor 1 (TBX1) gene. Cis-expression quantitative trait loci analysis showed that expression of TBX1 was regulated by the rs34331122 variant. In the current study, we investigated biological functions and potential molecular mechanisms of TBX1 in breast cancer. We found that TBX1 expression was significantly higher in breast cancer tumor tissues than adjacent normal breast tissues and increased with tumor stage (P < 0.05). We further knocked-down TBX1 gene expression in three breast cancer cell lines, MDA-MB-231, MCF-7 and T47D, using small interfering RNAs and examined consequential changes on cell oncogenicity and gene expression. TBX1 knock-down significantly inhibited breast cancer cell proliferation, colony formation, migration and invasion. RNA sequencing and flow cytometry analysis revealed that TBX1 knock-down in breast cancer cells induced cell cycle arrest in the G1 phase through disrupting expression of genes involved in the cell cycle pathway. Furthermore, survival analysis using the online Kaplan-Meier Plotter suggested that higher TBX1 expression was associated with worse outcomes in breast cancer patients, especially for estrogen receptor-positive breast cancer, with HRs (95% CIs) for overall survival (OS) and distant metastasis free survival (DMFS) of 1.5 (1.05-2.15) and 1.55 (1.10-2.18), respectively. In conclusion, our results suggest that the TBX1 gene may act as a putative oncogene of breast cancer through regulating expressions of cell cycle-related genes.
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http://dx.doi.org/10.1093/carcin/bgab111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8832409PMC
February 2022

Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps.

Cell 2021 12 14;184(26):6262-6280.e26. Epub 2021 Dec 14.

Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.
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http://dx.doi.org/10.1016/j.cell.2021.11.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8941949PMC
December 2021

The power of genetic diversity in genome-wide association studies of lipids.

Nature 2021 12 9;600(7890):675-679. Epub 2021 Dec 9.

Department of Clinical Biochemistry, Landspitali-National University Hospital of Iceland, Reykjavik, Iceland.

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels, heart disease remains the leading cause of death worldwide. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine, we anticipate that increased diversity of participants will lead to more accurate and equitable application of polygenic scores in clinical practice.
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http://dx.doi.org/10.1038/s41586-021-04064-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730582PMC
December 2021

Potential Microbiological Risk Factors Associated With Periodontitis and Periodontal Health Disparities.

Front Cell Infect Microbiol 2021 17;11:789919. Epub 2021 Nov 17.

School of Dentistry, Meharry Medical College, Nashville, TN, United States.

Periodontitis disproportionately affects different racial and ethnic populations. In this study, we used qPCR to determine and compare oral microbial profiles in dental plaque samples from 191 periodontitis patients of different ethnic/racial backgrounds. We also obtained the periodontal parameters of these patients retrospectively using axiUm and performed statistical analysis using SAS 9.4. We found that in this patient cohort, neighborhood median incomes were significantly higher among Caucasians Americans (CAs) than among African Americans (AAs) and Hispanic Americans (HAs). Levels of total bacteria and , a keystone periodontal pathogen, were not evenly distributed among the three groups. We confirmed our previous findings that reduces virulence potential and likely serves as a beneficial bacterium. We also showed the ratio of to to be significantly higher in CAs than in HAs and AAs. Our results suggest that higher levels of and lower ratios of to may contribute to periodontal health disparities.
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http://dx.doi.org/10.3389/fcimb.2021.789919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8637773PMC
January 2022

The oral microbiome in relation to pancreatic cancer risk in African Americans.

Br J Cancer 2022 02 30;126(2):287-296. Epub 2021 Oct 30.

Slone Epidemiology Center, Boston University, Boston, MA, USA.

Background: African Americans have the highest pancreatic cancer incidence of any racial/ethnic group in the United States. The oral microbiome was associated with pancreatic cancer risk in a recent study, but no such studies have been conducted in African Americans. Poor oral health, which can be a cause or effect of microbial populations, was associated with an increased risk of pancreatic cancer in a single study of African Americans.

Methods: We prospectively investigated the oral microbiome in relation to pancreatic cancer risk among 122 African-American pancreatic cancer cases and 354 controls. DNA was extracted from oral wash samples for metagenomic shotgun sequencing. Alpha and beta diversity of the microbial profiles were calculated. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between microbes and pancreatic cancer risk.

Results: No associations were observed with alpha or beta diversity, and no individual microbial taxa were differentially abundant between cases and control, after accounting for multiple comparisons. Among never smokers, there were elevated ORs for known oral pathogens: Porphyromonas gingivalis (OR = 1.69, 95% CI: 0.80-3.56), Prevotella intermedia (OR = 1.40, 95% CI: 0.69-2.85), and Tannerella forsythia (OR = 1.36, 95% CI: 0.66-2.77).

Conclusions: Previously reported associations between oral taxa and pancreatic cancer were not present in this African-American population overall.
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http://dx.doi.org/10.1038/s41416-021-01578-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770575PMC
February 2022

Sex-Specific Associations between Gut Microbiome and Non-Alcoholic Fatty Liver Disease among Urban Chinese Adults.

Microorganisms 2021 Oct 8;9(10). Epub 2021 Oct 8.

Department of Medicine, Division of Epidemiology, Vanderbilt University Medical Center, Suite 600, Nashville, TN 37232, USA.

Non-alcoholic fatty liver disease (NAFLD) has been linked to altered gut microbiome; however, evidence from large population-based studies is limited. We compared gut microbiome profiles of 188 male and 233 female NAFLD cases with 571 male and 567 female controls from two longitudinal studies of urban Chinese adults. History of NAFLD was assessed during surveys administered in 2004-2017. Microbiota were assessed using 16S rRNA sequencing of stool samples collected in 2015-2018. Associations of NAFLD with microbiome diversity and composition were evaluated by generalized linear or logistic regression models. Compared with controls, male cases had lower microbial α-diversity, higher abundance of genera and and species, lower abundance of genus , and lower prevalence of taxa including order (all < 0.05). In contrast, female cases had higher α-diversity, higher abundance of genus and a family of order , lower abundance of and species, and higher prevalence of . Significant NAFLD-sex interactions were found for α-diversity and above taxa (all false discovery rate < 0.1). In conclusion, we observed sex-specific gut microbiome features related to history of NAFLD. Further studies are needed to validate our findings and evaluate the health effects of NAFLD-related gut microbiota.
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http://dx.doi.org/10.3390/microorganisms9102118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537656PMC
October 2021

Phytoestrogens and lung cancer risk: a nested case-control study in never-smoking Chinese women.

Am J Clin Nutr 2022 03;115(3):643-651

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.

Background: Since several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development.

Objective: The aim was to prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking women.

Methods: We conducted a nested case-control study within a population-based prospective cohort study of women. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking women after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in conditional logistic regression models.

Results: After adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking women, with the OR for the second quartile vs. the lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and P-nonlinearity = 0.006). A similar association was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third, and fourth quartiles compared with the lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41, 0.86), respectively. The inverse association reached a plateau beyond the second quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk.

Conclusions: This study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking women.
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http://dx.doi.org/10.1093/ajcn/nqab358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895217PMC
March 2022

Prospective study of oral microbiome and gastric cancer risk among Asian, African American and European American populations.

Int J Cancer 2022 03 5;150(6):916-927. Epub 2021 Nov 5.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Colonization of specific bacteria in the human mouth was reported to be associated with gastric cancer risk. However, previous studies were limited by retrospective study designs and low taxonomic resolutions. We performed a prospective case-control study nested within three cohorts to investigate the relationship between oral microbiome and gastric cancer risk. Shotgun metagenomic sequencing was employed to characterize the microbiome in prediagnostic buccal samples from 165 cases and 323 matched controls. Associations of overall microbial richness and abundance of microbial taxa, gene families and metabolic pathways with gastric cancer risk were evaluated via conditional logistic regression. Analyses were performed within each cohort, and results were combined by meta-analyses. We found that overall microbial richness was associated with decreased gastric cancer risk, with an odds ratio (OR) per standard deviation (SD) increase in Simpson's reciprocal index of 0.77 (95% confidence interval [CI] = 0.61-0.99). Nine taxa, 38 gene families and six pathways also showed associations with gastric cancer risk at P < .05. Neisseria mucosa and Prevotella pleuritidis were enriched, while Mycoplasma orale and Eubacterium yurii were depleted among cases with ORs and 95% CIs per SD increase in centered log-ratio transformed taxa abundance of 1.31 (1.03-1.67), 1.26 (1.00-1.57), 0.74 (0.59-0.94) and 0.80 (0.65-0.98), respectively. The top two gene families (P = 3.75 × 10 and 3.91 × 10 ) and pathways (P = 1.75 × 10 and 1.53 × 10 ) associated with gastric cancer were related to the decreased risk and are involved in hexitol metabolism. Our study supports the hypothesis that oral microbiota may play a role in gastric cancer etiology.
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http://dx.doi.org/10.1002/ijc.33847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982516PMC
March 2022

Integrating Genome and Methylome Data to Identify Candidate DNA Methylation Biomarkers for Pancreatic Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2021 11 8;30(11):2079-2087. Epub 2021 Sep 8.

Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii.

Background: The role of methylation in pancreatic cancer risk remains unclear. We integrated genome and methylome data to identify CpG sites (CpG) with the genetically predicted methylation to be associated with pancreatic cancer risk. We also studied gene expression to understand the identified associations.

Methods: Using genetic data and white blood cell methylation data from 1,595 subjects of European descent, we built genetic models to predict DNA methylation levels. After internal and external validation, we applied prediction models with satisfactory performance to the genetic data of 8,280 pancreatic cancer cases and 6,728 controls of European ancestry to investigate the associations of predicted methylation with pancreatic cancer risk. For associated CpGs, we compared their measured levels in pancreatic tumor versus benign tissue.

Results: We identified 45 CpGs at nine loci showing an association with pancreatic cancer risk, including 15 CpGs showing an association independent from identified risk variants. We observed significant correlations between predicted methylation of 16 of the 45 CpGs and predicted expression of eight adjacent genes, of which six genes showed associations with pancreatic cancer risk. Of the 45 CpGs, we were able to compare measured methylation of 16 in pancreatic tumor versus benign pancreatic tissue. Of them, six showed differentiated methylation.

Conclusions: We identified methylation biomarker candidates associated with pancreatic cancer using genetic instruments and added additional insights into the role of methylation in regulating gene expression in pancreatic cancer development.

Impact: A comprehensive study using genetic instruments identifies 45 CpG sites at nine genomic loci for pancreatic cancer risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568683PMC
November 2021

Discovery of structural deletions in breast cancer predisposition genes using whole genome sequencing data from > 2000 women of African-ancestry.

Hum Genet 2021 Oct 27;140(10):1449-1457. Epub 2021 Aug 27.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, TN, 37203-1738, Nashville, USA.

Single germline nucleotide pathogenic variants have been identified in 12 breast cancer predisposition genes, but structural deletions in these genes remain poorly characterized. We conducted in-depth whole genome sequencing (WGS) in genomic DNA samples obtained from 1340 invasive breast cancer cases and 675 controls of African ancestry. We identified 25 deletions in the intragenic regions of ten established breast cancer predisposition genes based on a consensus call from six state-of-the-art SV callers. Overall, no significant case-control difference was found in the frequency of these deletions. However, 1.0% of cases and 0.3% of controls carried any of the eight putative protein-truncating rare deletions located in BRCA1, BRCA2, CDH1, TP53, NF1, RAD51D, RAD51C and CHEK2, resulting in an odds ratio (OR) of 3.29 (95% CI 0.74-30.16). We also identified a low-frequency deletion in NF1 associated with breast cancer risk (OR 1.93, 95% CI 1.14-3.42). In addition, we detected 56 deletions, including six putative protein-truncating deletions, in suspected breast predisposition genes. This is the first large study to systematically search for structural deletions in breast cancer predisposition genes. Many of the deletions, particularly those resulting in protein truncations, are likely to be pathogenic. Results from this study, if confirmed in future large-scale studies, could have significant implications for genetic testing for this common cancer.
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http://dx.doi.org/10.1007/s00439-021-02342-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9109261PMC
October 2021

Association of oral microbiota with lung cancer risk in a low-income population in the Southeastern USA.

Cancer Causes Control 2021 Dec 25;32(12):1423-1432. Epub 2021 Aug 25.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, TN, USA.

Purpose: Oral microbiome plays an important role in oral health and systemic diseases, including cancer. We aimed to prospectively investigate the association of oral microbiome with lung cancer risk.

Methods: We analyzed 156 incident lung cancer cases (73 European Americans and 83 African Americans) and 156 individually matched controls nested within the Southern Community Cohort Study. Oral microbiota were assessed using 16S rRNA gene sequencing in pre-diagnostic mouth rinse samples. Paired t test and the permutational multivariate analysis of variance test were used to evaluate lung cancer risk association with alpha diversity or beta diversity, respectively. Conditional logistic regression models were used to evaluate the association of individual bacterial abundance or prevalence with lung cancer risk.

Results: No significant differences were observed for alpha or beta diversity between lung cancer cases and controls. Abundance of families Lachnospiraceae_[XIV], Peptostreptococcaceae_[XI], and Erysipelotrichaceae and species Parvimonas micra was associated with decreased lung cancer risk, with odds ratios (ORs) and 95% confidence intervals (CIs) of 0.76 (0.59-0.98), 0.80 (0.66-0.97), 0.81 (0.67-0.99), and 0.83 (0.71-0.98), respectively (all p < 0.05). Prevalence of five pre-defined oral pathogens were not significantly associated with overall lung cancer risk. Prevalence of genus Bacteroidetes_[G-5] and species Alloprevotella sp._oral_taxon_912, Capnocytophaga sputigena, Lactococcus lactis, Peptoniphilaceae_[G-1] sp._oral_taxon_113, Leptotrichia sp._oral_taxon_225, and Fretibacterium fastidiosum was associated with decreased lung cancer risk, with ORs and 95% CIs of 0.55 (0.30-1.00), 0.36 (0.17-0.73), 0.53 (0.31-0.92), 0.43 (0.21-0.88), 0.43 (0.19-0.94), 0.57 (0.34-0.99), and 0.54 (0.31-0.94), respectively (all p < 0.05). Species L. sp._oral_taxon_225 was significantly associated with decreased lung cancer risk in African Americans (OR [95% CIs] 0.28 [0.12-0.66]; p = 0.00012).

Conclusion: Results from this study suggest that oral microbiota may play a role in the development of lung cancer.
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http://dx.doi.org/10.1007/s10552-021-01490-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541916PMC
December 2021

Association between body mass index and colorectal adenomas: Findings from a case-control study in Vietnam.

Int J Cancer 2021 12 9;149(11):1898-1909. Epub 2021 Sep 9.

Vietnam Colorectal Cancer and Polyps Research Program, Vinmec Healthcare System, Hanoi, Vietnam.

Colorectal cancer is a leading cancer worldwide and in Vietnam. Adenomas (adenomatous polyps) is an important precursor of colorectal cancer. There is currently no study to determine the modifiable risk factors for colorectal adenomas, including body mass index (BMI) in Vietnam. We conducted an individually matched case-control study of 1149 colorectal adenomas and 1145 controls in a large-scale colorectal screening program involving 103 542 individuals aged 40-75 years old in Hanoi, Vietnam. Conditional logistic regression was used to evaluate the association between BMI and colorectal adenomas prevalence, after controlling for potential confounders. Overall, comparing to normal weight (ie, 18.5-22.9 kg/m ), underweight (ie, BMI < 18.5) was associated with a non-statistically significant increased prevalence of colorectal adenomas (odd ratio [OR] = 1.29 and 95% confident interval [CI]: 0.88-1.87). This association became significant among male (OR = 1.98, 95% CI: 1.20-3.27), male who were ever smokers (OR = 2.59, 95% CI: 1.33-5.03), nonregular exercise (OR = 2.44, 95% CI: 1.26-4.73) and individuals with cardiometabolic disorders (OR = 3.46, 95% CI: 1.19-10.00). The association between underweight and colorectal adenomas did not vary by smoking status, drinking status, family history of cancer, adenomas types or cardiometabolic disorders. No association was observed among obese individuals (BMI ≥ 25). In the population with low prevalence of obesity, we found that the association between BMI and colorectal adenomas followed a reversed J-shape that underweight was associated with increased prevalence. Further studies are, therefore, warranted to replicate our results and to investigate the biologic mechanism the effect of underweight on colorectal adenomas prevalence.
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http://dx.doi.org/10.1002/ijc.33757DOI Listing
December 2021
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