Publications by authors named "Adonina Tardon"

289 Publications

Vitamin D, pregnancy and caries in children in the INMA-Asturias birth cohort.

BMC Pediatr 2021 09 3;21(1):380. Epub 2021 Sep 3.

Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Instituto de Investigación Sanitaria del Principado de Asturias. ISPA, CIBER de Epidemiología y Salud Pública. Universidad de Oviedo, Asturias, Spain.

Background: Vitamin D is traditionally associated with the metabolism of calcium and phosphorus, a process essential for the mineralization of hard tissue such as bone or tooth. Deficiency of this vitamin is a problem worldwide, however. Given the possibly significant role of Vitamin D in odontogenesis in children, the objective of our study was to determine the influence of vitamin D levels in the blood on dental anomalies in children between 6 and 10 years of age, by means of 25-hydroxy vitamin D tests performed during pregnancy and the first years of life.

Methods: The data analyzed were sourced from data belonging to the INMA-Asturias birth cohort, a prospective cohort study initiated in 2004 as part of the INMA Project. The 25-hydroxy vitamin D (25(OH)D) test was performed with samples from 188 children in the INMA-Asturias birth cohort with a dental examination performed between 6 and 10 years of age. The samples were taken at three stages: in the mother at 12 weeks of gestation, and subsequently in the child at 4 and 8 years of age. Diet, nutritional and oro-dental hygiene habits were also analyzed by means of questionnaires.

Results: The results indicate a significant association between caries and correct or incorrect brushing technique. With incorrect brushing technique, the prevalence of caries was 48.89%, but this dropped to 22.38% with correct brushing technique. An association was also found between tooth decay and frequency of sugar intake. The prevalence of caries was 24.54% with occasional sugar intake, but this rose to 56% with regular sugar intake. On the other hand, levels < 20 ng/ml in both mother and child at 8 years of age would also be risk factors (OR = 2.51(1.01-6.36) and OR = 3.45(1.14-11.01)) for the presence of caries in children. The risk of caries practically tripled where 25(OH) D values were < 20 ng/ml.

Conclusions: Although incorrect brushing technique and regular sugar consumption was found to be the main cause of caries in the children, the low concentrations of vitamin D in the blood of the pregnant mothers may have magnified this correlation, indicating that the monitoring of vitamin D levels during pregnancy should be included in antenatal programmes. It is particularly striking that 50% of the children were deficient in vitamin D at the age of 4, and that dental floss was practically absent from regular cleaning routines.
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http://dx.doi.org/10.1186/s12887-021-02857-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414781PMC
September 2021

Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts.

Eur J Epidemiol 2021 May 28. Epub 2021 May 28.

ISGlobal, Barcelona Institute for Global Health, C. Doctor Aiguader 88, 08003, Barcelona, Spain.

The potential etiological role of early acetaminophen exposure on Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD) is inconclusive. We aimed to study this association in a collaborative study of six European population-based birth/child cohorts. A total of 73,881 mother-child pairs were included in the study. Prenatal and postnatal (up to 18 months) acetaminophen exposure was assessed through maternal questionnaires or interviews. ASC and ADHD symptoms were assessed at 4-12 years of age using validated instruments. Children were classified as having borderline/clinical symptoms using recommended cutoffs for each instrument. Hospital diagnoses were also available in one cohort. Analyses were adjusted for child and maternal characteristics along with indications for acetaminophen use. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. The proportion of children having borderline/clinical symptoms ranged between 0.9 and 12.9% for ASC and between 1.2 and 12.2% for ADHD. Results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have borderline or clinical ASC (OR = 1.19, 95% CI 1.07-1.33) and ADHD symptoms (OR = 1.21, 95% CI 1.07-1.36) compared to non-exposed children. Boys and girls showed higher odds for ASC and ADHD symptoms after prenatal exposure, though these associations were slightly stronger among boys. Postnatal exposure to acetaminophen was not associated with ASC or ADHD symptoms. These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use.
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http://dx.doi.org/10.1007/s10654-021-00754-4DOI Listing
May 2021

A multi-omics study links TNS3 and SEPT7 to long-term former smoking NSCLC survival.

NPJ Precis Oncol 2021 May 17;5(1):39. Epub 2021 May 17.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, 02115, USA.

The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819 at 7p12.3 (P = 3.90 × 10) and rs1143149 at 7p14.2 (P = 9.75 × 10), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819: P = 8.0 × 10; rs1143149: P = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC.
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http://dx.doi.org/10.1038/s41698-021-00182-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128887PMC
May 2021

Prenatal Exposure to Cigarette Smoke and Anogenital Distance at 4 Years in the INMA-Asturias Cohort.

Int J Environ Res Public Health 2021 04 29;18(9). Epub 2021 Apr 29.

Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Monforte de Lemos Avenue 3-5, 28029 Madrid, Spain.

Smoking by women is associated with adverse pregnancy outcomes such as spontaneous abortion, preterm delivery, low birth weight, infertility, and prolonged time to pregnancy. Anogenital distance (AGD) is a sensitive biomarker of prenatal androgen and antiandrogen exposure. We investigated the effect of smoking and passive smoke exposure during pregnancy on anogenital distance in offspring at 4 years in the INMA-Asturias cohort (Spain). Women were interviewed during pregnancy to collect information on tobacco consumption, and anogenital distance was measured in 381 children: Anoscrotal distance in boys and anofourchetal distance in girls. We also measured maternal urinary cotinine levels at 32 weeks of pregnancy. We constructed linear regression models to analyze the association between prenatal smoke exposure and anogenital distance and adjusted the models by relevant covariates. Reported prenatal smoke exposure was associated with statistically significant increased anogenital index (AGI), both at week 12 of pregnancy (β = 0.31, 95% confidence interval: 0.00, 0.63) and at week 32 of pregnancy (β = 0.31, 95% confidence interval: 0.00, 0.63) in male children, suggesting altered androgenic signaling.
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http://dx.doi.org/10.3390/ijerph18094774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124891PMC
April 2021

Adherence to the Mediterranean Diet in a School Population in the Principality of Asturias (Spain): Relationship with Physical Activity and Body Weight.

Nutrients 2021 Apr 29;13(5). Epub 2021 Apr 29.

Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Roma Avenue s/n, 33001 Oviedo, Spain.

The Mediterranean diet (MD), despite its multiple benefits, presents low levels of adherence among children. Moreover, childhood is a key stage in the acquisition of healthy habits. The aim of this study was to describe adherence to MD in school-age children from Asturias, Spain, and to evaluate the association with weight status and several lifestyle behaviors. A cross-sectional study was conducted on 309 children aged between 8 and 13 years old. The level of adherence to MD was evaluated through the KIDMED questionnaire. Descriptive analysis and logistic regression models were used to analyze the association between adherence to MD and weight status, frequency of out-of-school exercise, frequency of school canteen attendance, and sleep habits. We found that 54.4% of children had optimal adherence to MD and 29.9% of the sample was overweight or obese. Frequency of exercise practice was positively associated with optimal adherence to MD (95% CI: 1.02, 1.33). A positive association was found between some KIDMED items and frequency of out-of-school exercise practice and attendance at the school canteen. This study shows the need for an improvement in the adherence to MD in youth considering the concomitant occurrence of other related healthy behaviors.
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http://dx.doi.org/10.3390/nu13051507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145401PMC
April 2021

Pre and postnatal exposure to mercury and respiratory health in preschool children from the Spanish INMA Birth Cohort Study.

Sci Total Environ 2021 Aug 20;782:146654. Epub 2021 Mar 20.

Epidemiology and Environmental Health Joint Research Unit, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, FISABIO-Public Health, FISABIO-Universitat Jaume I-Universitat de València, Av. Catalunya 21, 46020 Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Av. Monforte de Lemos, 3-5. Pabellón 11, 28029 Madrid, Spain.

Effects of mercury on maturing immune system have been reported, however the association with respiratory and allergy problems during infancy remains unclear. The aim of this study is to evaluate the association between pre and postnatal mercury exposure and respiratory and allergy problems among preschool children and to examine the role of potential modifying factors. Study subjects were children participant in Spanish Childhood and Environment Project (INMA, 2003-2008). We measured total mercury levels in cord blood (n = 1868) and hair at 4 years of age (n = 1347). Respiratory outcomes (wheezing, severe wheezing, chestiness, persistent cough, eczema and otitis) were obtained by questionnaires administered to parents. Associations were investigated by logistic regression adjusted for socio-demographic and lifestyle-related variables in each cohort and subsequent meta-analysis. We tested effect modification by factors related to individual susceptibility, diet and co-exposure with other pollutants. The geometric mean of cord blood and hair total mercury was 8.20 μg/L and 0.97 μg/g, respectively. No statistically significant association between pre or postnatal mercury exposure and respiratory and allergy outcomes was found. Notwithstanding, lower maternal intake of fruits and vegetables increased the risk of some respiratory outcomes due to the prenatal exposure to mercury (p < 0.05). Moreover, an inverse association between prenatal mercury exposure and some respiratory outcomes was observed among children with higher maternal exposure to organocholorine compounds or smoking (p < 0.05). Also, sex and postnatal smoking exposure modulated mercury postnatal effects on persistent cough (p < 0.05). In conclusion, no association between pre and postnatal mercury exposure and respiratory and allergy problems among the whole population at study was found. However, diet and other toxicants could modulate this relation, especially during prenatal period. More research on this topic is warranted due to the limited evidence.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146654DOI Listing
August 2021

Consumption of ultra-processed foods and drinks and colorectal, breast, and prostate cancer.

Clin Nutr 2021 04 27;40(4):1537-1545. Epub 2021 Feb 27.

Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Universidad de Cantabria - IDIVAL, Santander, Spain. Electronic address:

Aims: To study whether the consumption of ultra-processed foods and drinks is associated with breast, colorectal, and prostate cancers.

Methods: Multicentric population-based case-control study (MCC-Spain) conducted in 12 Spanish provinces. Participants were men and women between 20 and 85 years of age with diagnoses of colorectal (n = 1852), breast (n = 1486), or prostate cancer (n = 953), and population-based controls (n = 3543) frequency-matched by age, sex, and region. Dietary intake was collected using a validated food frequency questionnaire. Foods and drinks were categorized according to their degree of processing based on the NOVA classification. Unconditional multivariable logistic regression was used to evaluate the association between ultra-processed food and drink consumption and colorectal, breast, and prostate cancer.

Results: In multiple adjusted models, consumption of ultra-processed foods and drinks was associated with a higher risk of colorectal cancer (OR for a 10% increase in consumption: 1.11; 95% CI 1.04-1.18). The corresponding odds for breast (OR 1.03; 95% CI 0.96-1.11) and prostate cancer (OR 1.02; 95% CI 0.93-1.12) were indicative of no association.

Conclusions: Results of this large population-based case-control study suggest an association between the consumption of ultra-processed foods and drinks and colorectal cancer. Food policy and public health should include a focus on food processing when formulating dietary guidelines.
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http://dx.doi.org/10.1016/j.clnu.2021.02.033DOI Listing
April 2021

A reply to "Lung cancer outcomes: Are BMI and race clinically relevant?"

Lung Cancer 2021 04 26;154:225-226. Epub 2021 Feb 26.

Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1016/j.lungcan.2021.02.019DOI Listing
April 2021

Risk of gastric cancer in the environs of industrial facilities in the MCC-Spain study.

Environ Pollut 2021 Jun 3;278:116854. Epub 2021 Mar 3.

Epidemiology Section, Public Health Division, Department of Health of Madrid, C/San Martín de Porres, 6, 28035, Madrid, Spain; Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública - CIBERESP), Spain. Electronic address:

Background: Gastric cancer is the fifth most frequent tumor worldwide. In Spain, it presents a large geographic variability in incidence, suggesting a possible role of environmental factors in its etiology. Therefore, epidemiologic research focused on environmental exposures is necessary.

Objectives: To assess the association between risk of gastric cancer (by histological type and tumor site) and residential proximity to industrial installations, according to categories of industrial groups and specific pollutants released, in the context of a population-based multicase-control study of incident cancer conducted in Spain (MCC-Spain).

Methods: In this study, 2664 controls and 137 gastric cancer cases from 9 provinces, frequency matched by province of residence, age, and sex were included. Distances from the individuals' residences to the 106 industries located in the study areas were computed. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (from 1 km to 3 km) to industries, adjusting for matching variables and potential confounders.

Results: Overall, no excess risk of gastric cancer was observed in people living close to the industrial installations, with ORs ranging from 0.73 (at ≤2.5 km) to 0.93 (at ≤1.5 km). However, by industrial sector, excess risks (OR; 95%CI) were found near organic chemical industry (3.51; 1.42-8.69 at ≤2 km), inorganic chemical industry (3.33; 1.12-9.85 at ≤2 km), food/beverage sector (2.48; 1.12-5.50 at ≤2 km), and surface treatment using organic solvents (3.59; 1.40-9.22 at ≤3 km). By specific pollutant, a statistically significant excess risk (OR; 95%CI) was found near (≤3 km) industries releasing nonylphenol (6.43; 2.30-17.97) and antimony (4.82; 1.94-12.01).

Conclusions: The results suggest no association between risk of gastric cancer and living in the proximity to the industrial facilities as a whole. However, a few associations were detected near some industrial sectors and installations releasing specific pollutants.
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http://dx.doi.org/10.1016/j.envpol.2021.116854DOI Listing
June 2021

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

PLoS Genet 2021 03 5;17(3):e1009254. Epub 2021 Mar 5.

University of Salzburg, Department of Biosciences and Cancer Cluster Salzburg, Salzburg, Austria.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.
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http://dx.doi.org/10.1371/journal.pgen.1009254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968735PMC
March 2021

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

Genome Med 2021 02 1;13(1):15. Epub 2021 Feb 1.

CIBERONC, Madrid, Spain.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance.

Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants.

Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support.

Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
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http://dx.doi.org/10.1186/s13073-020-00816-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849104PMC
February 2021

The Use of Lower or Higher Than Recommended Doses of Folic Acid Supplements during Pregnancy Is Associated with Child Attentional Dysfunction at 4-5 Years of Age in the INMA Project.

Nutrients 2021 Jan 23;13(2). Epub 2021 Jan 23.

Instituto de Investigación Sanitaria y Biomédica de Alicante, ISABIAL-UMH, 03010 Alicante, Spain.

We assessed the association between the use of lower- and higher-than-recommended doses of folic acid supplements (FAs) during pregnancy and attentional function in boys and girls at age of 4-5. We analyzed data from 1329 mother-child pairs from the mother-child cohort INfancia y Medio Ambiente Project (INMA) study. Information on FAs use during pregnancy was collected in personal interviews at weeks 12 and 30, and categorized in <400, 400-999 (recommended dose), and ≥1000 μg/day. Child attentional function was assessed by Conners' Kiddie Continuous Performance Test. Multivariable regression analyses were used to estimate incidence rate ratios (IRR) and beta coefficients with 95% confidence intervals (CI). Compared to recommended FAs doses, the periconceptional use of <400 and ≥1000 μg/day was associated with higher risk of omission errors-IRR = 1.14 (95% CI: 1.01; 1.29) and IRR = 1.16 (95% CI: 1.02; 1.33), respectively. The use of FAs < 400 μg/day and ≥1000 μg/day was significantly associated with deficits of attentional function only in boys. FAs use < 400 μg/day was associated with higher omission errors with IRR = 1.22 and increased hit reaction time (HRT) β = 34.36, and FAs use ≥ 1000 μg/day was associated with increased HRT β = 33.18 and HRT standard error β = 3.31. The periconceptional use of FAs below or above the recommended doses is associated with deficits of attentional function in children at age of 4-5, particularly in boys.
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http://dx.doi.org/10.3390/nu13020327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912326PMC
January 2021

Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model.

Cancer Res 2021 03 20;81(6):1607-1615. Epub 2021 Jan 20.

Institute for Clinical and Translational Research, Baylor Medical College, Houston, Texas.

Lung cancer is the leading cause of cancer-related death globally. An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK Biobank data ( = 335,931). Absolute risk was estimated on the basis of age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial ( = 50,772 participants). The lung cancer ORs for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 [95% confidence interval (CI) = 1.92-3.00; = 1.80 × 10] in the validation set ( = 5.26 × 10). The OR per SD of PRS increase was 1.26 (95% CI = 1.20-1.32; = 9.69 × 10) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status, and family history. Collectively, these results suggest that individual's genetic background may inform the optimal lung cancer LDCT screening strategy. SIGNIFICANCE: Three large-scale datasets reveal that, after accounting for risk factors, an individual's genetics can affect their lung cancer risk trajectory, thus may inform the optimal timing for LDCT screening.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969419PMC
March 2021

Dietary inflammatory index of mothers during pregnancy and Attention Deficit-Hyperactivity Disorder symptoms in the child at preschool age: a prospective investigation in the INMA and RHEA cohorts.

Eur Child Adolesc Psychiatry 2021 Jan 4. Epub 2021 Jan 4.

University of the Basque Country UPV/EHU, Donostia-San Sebastián, Spain.

Inflammation provides a substrate for mechanisms that underlie the association of maternal diet during pregnancy with Attention Deficit-Hyperactivity Disorder (ADHD) symptoms in childhood. However, no previous study has quantified the proinflammatory potential of maternal diet as a risk factor for ADHD. Thus, we evaluated the association of maternal dietary inflammatory index (DII) scores during pregnancy with ADHD symptoms in 4-year-old children born in two Mediterranean regions. We analyzed data from two population-based birth cohort studies-INMA (Environment and Childhood) four subcohorts in Spain (N = 2097), and RHEA study in Crete (Greece) (N = 444). The DII score of maternal diet was calculated based on validated food frequency questionnaires completed during pregnancy (12th and/or 32nd week of gestation). ADHD symptoms were assessed by ADHD-DSM-IV in INMA cohort and by ADHDT test in RHEA cohort, with questionnaires filled-out by teachers and parents, respectively. The associations between maternal DII and ADHD symptoms were analysed using multivariable-adjusted zero-inflated negative binomial regression models in each cohort study separately. Meta-analysis was conducted to combine data across the cohorts for fitting within one model. The DII was significantly higher in RHEA (RHEA = 2.09 [1.94, 2.24]) in comparison to INMA subcohorts (Asturias = - 1.52 [- 1.67, - 1.38]; Gipuzkoa = - 1.48 [- 1.64, - 1.33]; Sabadell = - 0.95 [- 1.07, - 0.83]; Valencia = - 0.76 [- 0.90, - 0.62]). Statistically significant reduced risk of inattention symptomatology (OR = 0.86; CI 95% = 0.77-0.96), hyperactivity symptomatology (OR = 0.82; CI 95% = 0.72-0.92) and total ADHD symptomatology (OR = 0.82; CI 95% = - 0.72 to 0.93) were observed with increased maternal DII in boys. No statistically significant associations were observed in girls between maternal DII and inattention, hyperactivity and total ADHD symptomatology. We found reduced risk of ADHD symptomatology with increased DII only in boys. This relationship requires further exploration in other settings.
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http://dx.doi.org/10.1007/s00787-020-01705-2DOI Listing
January 2021

The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients.

Lung Cancer 2021 02 4;152:58-65. Epub 2020 Dec 4.

Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Introduction: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC).

Methods: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses.

Results: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; p = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (p = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (p<0.001) and obese categories (p = 0.004) relative to the normal-BMI category, when compared to male ever-smokers.

Conclusion: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.
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http://dx.doi.org/10.1016/j.lungcan.2020.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042597PMC
February 2021

Lung cancer risk in painters: results from the SYNERGY pooled case-control study consortium.

Occup Environ Med 2021 04 28;78(4):269-278. Epub 2020 Oct 28.

Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.

Objectives: We evaluated the risk of lung cancer associated with ever working as a painter, duration of employment and type of painter by histological subtype as well as joint effects with smoking, within the SYNERGY project.

Methods: Data were pooled from 16 participating case-control studies conducted internationally. Detailed individual occupational and smoking histories were available for 19 369 lung cancer cases (684 ever employed as painters) and 23 674 age-matched and sex-matched controls (532 painters). Multivariable unconditional logistic regression models were adjusted for age, sex, centre, cigarette pack-years, time-since-smoking cessation and lifetime work in other jobs that entailed exposure to lung carcinogens.

Results: Ever having worked as a painter was associated with an increased risk of lung cancer in men (OR 1.30; 95% CI 1.13 to 1.50). The association was strongest for construction and repair painters and the risk was elevated for all histological subtypes, although more evident for small cell and squamous cell lung cancer than for adenocarcinoma and large cell carcinoma. There was evidence of interaction on the additive scale between smoking and employment as a painter (relative excess risk due to interaction >0).

Conclusions: Our results by type/industry of painter may aid future identification of causative agents or exposure scenarios to develop evidence-based practices for reducing harmful exposures in painters.
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http://dx.doi.org/10.1136/oemed-2020-106770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958079PMC
April 2021

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Genet Epidemiol 2021 02 14;45(1):99-114. Epub 2020 Sep 14.

Faculty of Medical Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1β pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.
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http://dx.doi.org/10.1002/gepi.22358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855632PMC
February 2021

Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization.

Int J Cancer 2021 03 23;148(5):1077-1086. Epub 2020 Sep 23.

The National Institute of Occupational Health (STAMI), Oslo, Norway.

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (OR = 1.28, 95% CI = 1.06-1.55, P = .011), and an inverse effect on lung adenocarcinoma (OR = 0.86, 95% CI = 0.77-0.96, P = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (OR = 1.19, 95% CI = 1.01-1.40, P = .036), but this effect disappeared after adjustment of smoking (OR = 1.02, 95% CI = 0.90-1.16, P = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.
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http://dx.doi.org/10.1002/ijc.33292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845289PMC
March 2021

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma.

Front Med 2021 Apr 5;15(2):275-291. Epub 2020 Sep 5.

National Institute of Occupational Health (STAMI), Oslo, Pb 5330, Norway.

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
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http://dx.doi.org/10.1007/s11684-020-0779-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374896PMC
April 2021

Residential proximity to industrial pollution sources and colorectal cancer risk: A multicase-control study (MCC-Spain).

Environ Int 2020 11 19;144:106055. Epub 2020 Aug 19.

Cancer and Environmental Epidemiology Unit, Department of Epidemiology and Chronic Diseases, National Center for Epidemiology, Carlos III Institute of Health, Avda. Monforte de Lemos 5, 28029 Madrid, Spain; Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública - CIBERESP), Av. de Monforte de Lemos 3-5, 28029 Madrid, Spain. Electronic address:

Background: Colorectal cancer is the third most frequent tumor in males and the second in females worldwide. In Spain, it is an important and growing health problem, and epidemiologic research focused on potential risk factors, such as environmental exposures, is necessary.

Objectives: To analyze the association between colorectal cancer risk and residential proximity to industries, according to pollution discharge route, industrial groups, categories of carcinogens and other toxic substances, and specific pollutants released, in the context of a population-based multicase-control study of incident cancer carried out in Spain (MCC-Spain).

Methods: MCC-Spain included 557 colorectal cancer cases and 2948 controls in 11 provinces, frequency matched by sex, age, and region of residence. Distances were computed from subjects' residences to each of the 134 industries located in the study area. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (from 1 km to 3 km) to industrial facilities, adjusting for matching variables and other confounders.

Results: Excess risk (OR; 95%CI) of colorectal cancer was detected near industries overall for all distances analyzed, from 1 km (2.03; 1.44-2.87) to 3 km (1.26; 1.00-1.59). In general, industries releasing pollutants to air showed higher excess risks than facilities releasing pollution to water. By industrial sector, excess risk (OR; 95%CI) was found near (≤3 km) production of metals (2.66; 1.77-4.00), surface treatment of metals (1.48; 1.08-2.02), glass and mineral fibers (2.06; 1.39-3.07), organic chemical industry (4.80; 3.20-7.20), inorganic chemical industry (6.74; 4.38-10.36), food/beverage sector (3.34; 2.38-4.68), and surface treatment using organic solvents (6.16; 4.06-9.36). By pollutants, the main excess risks (OR; 95%CI) were found near (≤3 km) industries releasing nonylphenol (9.19; 5.91-14.28), antimony (5.30; 3.45-8.15), naphthalene (3.11; 2.16-4.49), organotin compounds (2.64; 1.76-3.98), manganese (2.53; 1.63-3.93), dichloromethane (2.52; 1.74-3.66), and vanadium (2.49; 1.59-3.91).

Conclusions: Our results support the hypothesis that residing in the proximity of industries may be a risk factor for colorectal cancer.
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http://dx.doi.org/10.1016/j.envint.2020.106055DOI Listing
November 2020

Association of Lifestyle Factors and Neuropsychological Development of 4-Year-Old Children.

Int J Environ Res Public Health 2020 08 5;17(16). Epub 2020 Aug 5.

ISGlobal, Instituto de Salud Global de Barcelona-Campus MAR, 08003 Barcelona, Spain.

Background: We aimed to assess how lifestyle factors such as diet, sleep, screen viewing, and physical activity, individually, as well as in a combined score, were associated with neuropsychological development in pre-school age children.

Methods: We conducted a cross-sectional study in 1650 children of 4 years of age, from the Environment and Childhood Project (INMA) population-based birth cohorts in four regions of Spain. Children were classified per a childhood healthy lifestyle score (CHLS) with a range of 0 to 4 that included eating in concordance with the Mediterranean diet (1 point); reaching recommended sleep time (1 point); watching a maximum recommended screen time (1 point); and being physically active (1 point). The McCarthy Scales of Children's Abilities (MSCA) were used to test neuropsychological development. Multi-adjusted linear regression models were created to assess the association with the lifestyle factors individually and as a combined score.

Results: CHLS was not associated with MSCA general cognitive score (1-point increment = -0.5, 95% CI: -1.2, 0.2). Analyzed by separate lifestyle factors, physical activity had a significant negative association with MSCA score and less TV/screen time had a negative association with MSCA score.

Conclusion: In this cross-sectional study, a combined score of lifestyle factors is not related to neuropsychological development at pre-school age.
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http://dx.doi.org/10.3390/ijerph17165668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459714PMC
August 2020

Occupational Exposure to Pesticides and Chronic Lymphocytic Leukaemia in the MCC-Spain Study.

Int J Environ Res Public Health 2020 07 17;17(14). Epub 2020 Jul 17.

Cancer Epidemiology Research Programme, Institut Català d'Oncologia (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.

We aimed to study the association between occupational exposure to pesticides and chronic lymphocytic leukemia (CLL) in Spain. Occupational exposure to pesticides (four insecticides, four herbicides and two fungicides) was evaluated using a job-exposure matrix for the Spanish population (MatEmESp) among 302 CLL cases and 1567 population controls in five regions of Spain, 2010-2013. Cumulative exposure scores (CES) were obtained by summing across the exposed jobs the product of prevalence, intensity and duration of exposure to each active substance. Principal components analysis (PCA) and logistic regression models adjusted for age, sex, region, education and occupational exposure to solvents were used. Around 20% of controls and 29% of cases were exposed to one or more pesticides. Compared to non-exposed, subjects in the highest tertile (3rd tertile) of CES of insecticides, herbicides, fungicides were more likely to have CLL [OR (95% CI), P-trend; 2.10 (1.38; 3.19), 0.002; 1.77 (1.12; 2.80), 0.12; and 1.67 (1.06; 2.64), 0.10, respectively). Following PCA, the first component (PC1, explaining 70% of the variation) equally led by seven active substances (the insecticide pyrethrin, all herbicides, all fungicides) was associated with a 26% higher odds of having CLL for 1-standard deviation increase in PC1 (95% CI: 1.14 to 1.40). These results confirm previous associations between CLL and exposure to pesticides and provide additional evidence by application groups and active substance. However, more research is needed to disentangle independent effects of individual active substances.
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http://dx.doi.org/10.3390/ijerph17145174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400560PMC
July 2020

Genetic Determinants of Lung Cancer Prognosis in Never Smokers: A Pooled Analysis in the International Lung Cancer Consortium.

Cancer Epidemiol Biomarkers Prev 2020 10 22;29(10):1983-1992. Epub 2020 Jul 22.

Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.

Background: Lung cancer remains the leading cause of cancer death worldwide, with 15% to 20% occurring in never smokers. To assess genetic determinants for prognosis among never smokers, we conducted a genome-wide investigation in the International Lung Cancer Consortium (ILCCO).

Methods: Genomic and clinical data from 1,569 never-smoking patients with lung cancer of European ancestry from 10 ILCCO studies were included. HRs and 95% confidence intervals of overall survival were estimated. We assessed whether the associations were mediated through mRNA expression-based 1,553 normal lung tissues from the lung expression quantitative trait loci (eQTL) dataset and Genotype-Tissue Expression (GTEx). For cross-ethnicity generalization, we assessed the associations in a Japanese study ( = 887).

Results: One locus at 13q22.2 was associated with lung adenocarcinoma survival at genome-wide level, with carriers of rs12875562-T allele exhibiting poor prognosis [HR = 1.71 (1.41-2.07), = 3.60 × 10], and altered mRNA expression of in lung tissue (GTEx, = 9.40 × 10; Lung eQTL dataset, = 0.003). Furthermore, 2 of 11 independent loci that reached the suggestive significance level ( < 10) were significant eQTL affecting mRNA expression of nearby genes in lung tissues, including at 1p36.13 and at 9q34.3. One locus encoding at 4p14 showed associations in both European [HR = 0.50 (0.38-0.66), = 6.92 × 10] and Japanese populations [HR = 0.79 (0.67-0.94), = 0.007].

Conclusions: Based on the largest genomic investigation on the lung cancer prognosis of never smokers to date, we observed that lung cancer prognosis is affected by inherited genetic variants.

Impact: We identified one locus near at genome-wide level and several potential prognostic genes with -effect on mRNA expression. Further functional genomics work is required to understand their role in tumor progression.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541720PMC
October 2020

Association between pre/perinatal exposure to POPs and children's anogenital distance at age 4 years: A study from the INMA-Asturias cohort.

Int J Hyg Environ Health 2020 08 16;229:113563. Epub 2020 Jun 16.

Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Monforte de Lemos Avenue, 3-5, 28029, Madrid, Spain; Unit of Molecular Cancer Epidemiology, University Institute of Oncology of the Principality of Asturias (IUOPA), Department of Medicine, University of Oviedo, Julian Clavería Street s/n, 33006, Oviedo, Asturias, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Roma Avenue s/n. 33001, Oviedo, Asturias, Spain.

Background: Prenatal exposure to endocrine-disrupting chemicals may impair genital development and alter reproductive tract anatomy. Anogenital distance (AGD) is a useful biomarker of exposure to chemicals that act as endocrine disruptors. We evaluated associations between prenatal and perinatal exposure to several persistent organic pollutants (POPs) and AGD in 4-year-old children.

Methods: Data were drawn from the INMA-Asturias cohort. Pediatricians measured the anofourchetal distance in female children and anoscrotal distance in male children. The anogenital index (AGI) was defined as the AGD divided by the child's weight at age of examination. We measured the levels of two hexachlorocyclohexane isomers, hexachlorobenzene, dichlorodiphenyltrichloroethane (DDT) and its metabolites, six polychlorinated biphenyl (PCB) congeners, and six polybrominated diphenyl ether (PBDE) congeners in maternal serum at 12 gestational weeks (n = 155) and in cord blood serum (n = 229). Anthropometric and parental sociodemographic variables were collected via face-to-face interviews. Linear regression models were used to evaluate the relationship between exposure to POPs and AGI, adjusted for confounders and stratified by sex.

Results: In male children, we found inverse associations between AGI and maternal concentrations of PCB-138 (ß = -0.041, 95% confidence interval [CI]: -0.074, -0.008, second tertile), PCB-153 (ß = -0.052, 95% CI: -0.085, -0.020, second tertile), PCB-180 ß = -0.065, 95% CI: -0.096, -0.035, second tertile; ß = -0.042, 95% CI: -0.073, -0.011, third tertile), PBDE-209 (ß = -0.031, 95% CI: -0.058, -0.006), cord serum concentrations of PCB-153 (ß = -0.029, 95% CI: -0.059, -0.000, second tertile; ß = -0.047, 95% CI: -0.085, -0.008, third tertile), and PCB-180 (ß = -0.041, 95% CI: -0.078, -0.005, third tertile). In female children, AGI was positively associated with maternal serum concentrations of PCB-101 (ß = 0.039, 95% CI: 0.002, 0.076, second tertile), and higher cord serum levels of 4,4'-DDT (ß = 0.032, 95% CI: 0.003, 0.061, third tertile) and 4,4'-DDE (ß = 0.040, 95% CI: 0.011, 0.069, third tertile).

Conclusions: Our findings provide evidence of associations between specific POPs and AGI in boys and girls aged 4 years, and suggest that pre/perinatal exposure to POPs has a feminizing effect in males and a masculinizing effect in females.
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http://dx.doi.org/10.1016/j.ijheh.2020.113563DOI Listing
August 2020

Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses.

Gut 2021 02 14;70(2):319-329. Epub 2020 May 14.

National Cancer Registry Ireland, Cork, Ireland.

Objectives: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI).

Design: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis.

Results: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (OR=1.08, 95% CI: 0.86 to 1.29, OR=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55).

Conclusion: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.
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http://dx.doi.org/10.1136/gutjnl-2019-319990DOI Listing
February 2021

Protein-altering germline mutations implicate novel genes related to lung cancer development.

Nat Commun 2020 05 11;11(1):2220. Epub 2020 May 11.

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10) and replication (adjusted OR = 2.93, P = 2.22 × 10) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
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http://dx.doi.org/10.1038/s41467-020-15905-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214407PMC
May 2020

Diesel Engine Exhaust Exposure, Smoking, and Lung Cancer Subtype Risks. A Pooled Exposure-Response Analysis of 14 Case-Control Studies.

Am J Respir Crit Care Med 2020 08;202(3):402-411

Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin and ll Centro di Riferimento per l'Epidemiologia e la Prevenzione Oncologica in Piemonte (CPO-Piemonte), Torino, Italy.

Although the carcinogenicity of diesel engine exhaust has been demonstrated in multiple studies, little is known regarding exposure-response relationships associated with different exposure subgroups and different lung cancer subtypes. We expanded on a previous pooled case-control analysis on diesel engine exhaust and lung cancer by including three additional studies and quantitative exposure assessment to evaluate lung cancer and subtype risks associated with occupational exposure to diesel exhaust characterized by elemental carbon (EC) concentrations. We used a quantitative EC job-exposure matrix for exposure assessment. Unconditional logistic regression models were used to calculate lung cancer odds ratios and 95% confidence intervals (CIs) associated with various metrics of EC exposure. Lung cancer excess lifetime risks (ELR) were calculated using life tables accounting for all-cause mortality. Additional stratified analyses by smoking history and lung cancer subtypes were performed in men. Our study included 16,901 lung cancer cases and 20,965 control subjects. In men, exposure response between EC and lung cancer was observed: odds ratios ranged from 1.09 (95% CI, 1.00-1.18) to 1.41 (95% CI, 1.30-1.52) for the lowest and highest cumulative exposure groups, respectively. EC-exposed men had elevated risks in all lung cancer subtypes investigated; associations were strongest for squamous and small cell carcinomas and weaker for adenocarcinoma. EC lung cancer exposure response was observed in men regardless of smoking history, including in never-smokers. ELR associated with 45 years of EC exposure at 50, 20, and 1 μg/m were 3.0%, 0.99%, and 0.04%, respectively, for both sexes combined. We observed a consistent exposure-response relationship between EC exposure and lung cancer in men. Reduction of workplace EC levels to background environmental levels will further reduce lung cancer ELR in exposed workers.
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http://dx.doi.org/10.1164/rccm.201911-2101OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465091PMC
August 2020

Respirable Crystalline Silica Exposure, Smoking, and Lung Cancer Subtype Risks. A Pooled Analysis of Case-Control Studies.

Am J Respir Crit Care Med 2020 08;202(3):412-421

The M. Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.

Millions of workers around the world are exposed to respirable crystalline silica. Although silica is a confirmed human lung carcinogen, little is known regarding the cancer risks associated with low levels of exposure and risks by cancer subtype. However, little is known regarding the disease risks associated with low levels of exposure and risks by cancer subtype. We aimed to address current knowledge gaps in lung cancer risks associated with low levels of occupational silica exposure and the joint effects of smoking and silica exposure on lung cancer risks. Subjects from 14 case-control studies from Europe and Canada with detailed smoking and occupational histories were pooled. A quantitative job-exposure matrix was used to estimate silica exposure by occupation, time period, and geographical region. Logistic regression models were used to estimate exposure-disease associations and the joint effects of silica exposure and smoking on risk of lung cancer. Stratified analyses by smoking history and cancer subtypes were also performed. Our study included 16,901 cases and 20,965 control subjects. Lung cancer odds ratios ranged from 1.15 (95% confidence interval, 1.04-1.27) to 1.45 (95% confidence interval, 1.31-1.60) for groups with the lowest and highest cumulative exposure, respectively. Increasing cumulative silica exposure was associated ( trend < 0.01) with increasing lung cancer risks in nonsilicotics and in current, former, and never-smokers. Increasing exposure was also associated ( trend ≤ 0.01) with increasing risks of lung adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. Supermultiplicative interaction of silica exposure and smoking was observed on overall lung cancer risks; superadditive effects were observed in risks of lung cancer and all three included subtypes. Silica exposure is associated with lung cancer at low exposure levels. An exposure-response relationship was robust and present regardless of smoking, silicosis status, and cancer subtype.
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http://dx.doi.org/10.1164/rccm.201910-1926OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465090PMC
August 2020

Association Analysis of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls.

Cancer Epidemiol Biomarkers Prev 2020 07 10;29(7):1423-1429. Epub 2020 Apr 10.

National Institute of Occupational Health (STAMI), Oslo, Norway.

Background: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.

Methods: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project.

Results: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery ( < 0.001) and validation ( < 0.05) stages. Among these loci, rs78062588 in (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, = 1.65 × 10). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele ( in 1q21.3) was associated with elevated somatic copy number of (OR = 1.16, = 0.02). In lung adenocarcinomas, rs1611182 ( in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, = 1.76 × 10).

Conclusions: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility.

Impact: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120681PMC
July 2020
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