Somatic mutations of esophageal adenocarcinoma: a comparison between Black and White patients.

Esophageal adenocarcinoma is the most common histological subtype of esophageal cancer in Western countries and shows poor prognosis with rapid growth. EAC is characterized by a strong male predominance and racial disparity. EAC is up to fivefold more common among Whites than Blacks, yet Black patients with EAC have poorer survival rates. The racial disparity remains largely unknown, and there is limited knowledge of mutations in EAC regarding racial disparities. We used whole-exome sequencing to show somatic mutation profiles derived from tumor samples from 18 EAC male patients. We identified three molecular subgroups based on the pre-defined esophageal cancer-specific mutational signatures. Group 1 is associated with age and NTHL1 deficiency-related signatures. Group 2 occurs primarily in Black patients and is associated with signatures related to DNA damage from oxidative stress and NTHL1 deficiency-related signatures. Group 3 is associated with defective homologous recombination-based DNA often caused by BRCA mutation in White patients. We observed significantly mutated race related genes (LCE2B in Black, SDR39U1 in White) were (q-value < 0.1). Our findings underscore the possibility of distinct molecular mutation patterns in EAC among different races. Further studies are needed to validate our findings, which could contribute to precision medicine in EAC.

DNA methylation biomarkers distinguishing early-stage prostate cancer from benign prostatic hyperplasia.

Background: DNA methylation markers are considered robust diagnostic features in various cancer types, as epigenetic marks are commonly altered during cancer progression. Differentiation between benign prostatic hyperplasia (BPH) and early-stage prostate cancer (PCa) is clinically difficult, relying on the information of the patient's symptoms or levels of prostate-specific antigen. Methods: A total of 42 PCa patients and 11 BPH patients were recruited. Genomic DNA was purified from tissues and used for the library preparation of the target-enriched methylome with enzymatic conversion and a Twist 85 Mbp EM-seq panel. Paired-end sequencing (150 bp) was performed using NovaSeq 6000 or NextSeq 550. After quality control, including adapter trimming and de-duplication of raw sequencing data, differential methylation patterns were analyzed between the BPH and PCa groups. Results: We report DNA methylation patterns existing between BPH and PCa. The major finding is that broad hypermethylation occurred at genic loci in PCa tissues as compared to the BPH. Gene ontology analysis suggested that hypermethylation of genic loci involved in chromatin and transcriptional regulation is involved in cancer progression. We also compared PCa tissues with high Gleason scores to tissues with low Gleason scores. The high-Gleason PCa tissues showed hundreds of focal differentially methylated CpG sites corresponding to genes functioning in cancer cell proliferation or metastasis. This suggests that dissecting early-to-advanced-grade cancer stages requires an in-depth analysis of differential methylation at the single CpG site level. Conclusions: Our study reports that enzymatic methylome sequencing data can be used to distinguish PCa from BPH and advanced PCa from early-stage PCa. The stage-specific methylation patterns in this study will be valuable resources for diagnostic purposes as well as further development of liquid biopsy approaches for the early detection of PCa.

Particulate matter exposure during pregnancy increases risk of childhood asthma: modified by gender and NRF2 genotype.

BACKGROUND: Exposure to particulate matter (PM) has been known to develop asthma in children and the oxidative stress-related mechanisms are suggested. For the development of asthma, not only the exposure dose but also the critical window and the risk modifying factors should be evaluated. OBJECTIVE: We investigated whether prenatal exposure to PM10 increases the risk of childhood asthma and evaluated the modifying factors, such as gender and reactive oxidative stress-related gene. METHODS: A general population-based birth cohort, the Panel Study of Korean Children (PSKC), including 1572 mother-baby dyads was analyzed. Children were defined to have asthma at age 7 when a parent reported physician-diagnosed asthma. Exposure to PM10 during pregnancy was estimated by land-use regression models based on national monitoring system. TaqMan method was used for genotyping nuclear factor, erythroid 2-related factor, NRF2 (rs6726395). A logistic Bayesian distributed lag interaction model (BDLIM) was used to evaluate the associations between prenatal PM10 exposure and childhood asthma by gender and NRF2. RESULTS: Exposure to PM10 during pregnancy was associated with the development of asthma (aOR 1.03, 95% CI 1.001.06). Stratifying by gender and NRF2 genotype, exposure to PM10 during 26-28 weeks gestation increased the risk of childhood asthma, especially in boys with NRF2 GG genotype. CONCLUSIONS: A critical window for PM10 exposure on the development of childhood asthma was during 26-28 weeks of gestation, and this was modified by gender and NRF2 genotype.

Prenatal PM2.5 affects atopic dermatitis depending on maternal anxiety and gender: COCOA study.

BACKGROUND: The prevalence of atopic dermatitis (AD) is increasing worldwide. Prenatal particulate matter with an aerodynamic diameter <2.5 µm (PM2.5) and maternal anxiety during pregnancy has been suggested as a potential causes of AD. This study investigated the effects of prenatal PM2.5 and maternal anxiety on AD and identified the critical period of PM2.5 exposure for AD in infants. METHODS: This study included 802 children from the COCOA birth cohort study with follow-up data at 1 year of age. PM2.5 was estimated by land-use regression models and prenatal anxiety was measured with a questionnaire. AD was diagnosed by doctor at 1 year of age. Logistic regression analysis and Bayesian distributed lag interaction models were applied. RESULTS: Higher PM2.5 during the first trimester of pregnancy, higher prenatal maternal anxiety, and male gender were associated with AD at 1 year of age (adjusted odds ratio [aOR] and 95% confidence interval [CI]: 1.86 [1.08-3.19], 1.58 [1.01-2.47], and 1.54 [1.01-2.36], respectively). Higher PM2.5 during the first trimester and higher maternal anxiety during pregnancy showed an additive effect on the risk of AD (aOR: 3.13; 95% CI: 1.56-6.28). Among boys exposed to higher maternal anxiety during pregnancy, gestational weeks 5-8 were the critical period of PM2.5 exposure for the development of AD. CONCLUSIONS: Higher PM2.5 exposure during gestational weeks 5-8 increased the probability of AD in infancy, especially in boys with higher maternal anxiety. Avoiding PM2.5 exposure and maternal anxiety from the first trimester may prevent infant AD.

Prenatal PM2.5 exposure and vitamin D-associated early persistent atopic dermatitis via placental methylation.

BACKGROUND: The effects of prenatal particulate matter with an aerodynamic diameter ranging from 0.1 µm to 2.5 µm (PM2.5) and vitamin D on atopic dermatitis (AD) phenotypes have not been evaluated. DNA methylation and cord blood (CB) vitamin D could represent a plausible link between prenatal PM2.5 exposure and AD in an offspring. OBJECTIVE: To determine the critical windows of prenatal PM2.5 exposure on the AD phenotypes, if vitamin D modulated these effects, and if placental DNA methylation mediated these effects on AD in offspring. METHODS: Mother-child pairs were enrolled from the birth cohort of the Cohort for Childhood Origin of Asthma and allergic diseases (COCOA) study. PM2.5 was estimated by land-use regression models, and CB vitamin D was measured by chemiluminescence immunoassay. AD was identified by the parental report of a physician's diagnosis. We defined the following 4 AD phenotypes according to onset age (by the age of 2 years) and persistence (by the age of 3 years): early-onset transient and persistent, late onset, and never. Logistic regression analysis and Bayesian distributed lag interaction model were used. DNA methylation microarray was analyzed using an Infinium Human Methylation EPIC BeadChip (Illumina, San Diego, California) in placenta. RESULTS: PM2.5 exposure during the first trimester of pregnancy, especially during 6 to 7 weeks of gestation, was associated with early-onset persistent AD. This effect increased in children with low CB vitamin D, especially in those with PM2.5 exposure during 3 to 7 weeks of gestation. AHRR (cg16371648), DPP10 (cg19211931), and HLADRB1 (cg10632894) were hypomethylated in children with AD with high PM2.5 and low CB vitamin D. CONCLUSION: Higher PM2.5 during the first trimester of pregnancy and low CB vitamin D affected early-onset persistent AD, and the most sensitive window was 6 to 7 weeks of gestation. Placental DNA methylation mediated this effect.

Thyroid cancer risks among medical radiation workers in South Korea, 1996-2015.

BACKGROUND: Thyroid cancer rates, especially among children, are known to be increased by radiation exposure. However, little is known about the impact of chronic low-dose radiation exposure on thyroid cancer risk in adulthood. This study examined radiation effects on thyroid cancer rates as well as an overall evaluation of thyroid cancer risk among medical radiation workers. METHODS: Data on all diagnostic medical radiation workers enrolled in the national dosimetry registry between 1996 and 2011 were linked with the cancer registry data through 2015. Standardized incidence ratios (SIRs) were used to compare the observed cancer incidence rates in this population to those for the general population while internal comparisons were used to estimate relative risks (RRs) for occupational history and excess relative risks (ERRs) were used to quantify the radiation dose-response relationship. RESULTS: Overall, 827 thyroid cancer cases were reported among 93,922 medical radiation workers. Thyroid cancer SIRs were significantly higher than expected for both men (SIR 1.72, 95% confidence interval [CI] 1.53 to 1.91) and women (SIR 1.18, 95% CI 1.08 to 1.28). However, RRs for thyroid cancer by job title and duration of employment showed no particular pattern among diagnostic medical radiation workers. There were no indications of a significant dose effect on thyroid cancer rates for either men (ERR/100 mGy 0.07, 95% CI -0.38 to 0.53) or women (ERR/100 mGy -0.13, 95% CI -0.49 to 0.23). The findings were similar for different job titles or when limited to workers employed for at least one year. CONCLUSIONS: While thyroid cancer incidence rates among Korean medical radiation workers were somewhat higher than those in the general population, there was no significant evidence that this increase was associated with occupational radiation dose. Additional follow-up together with consideration of other risk factors should provide useful information on thyroid cancer rates in this cohort.

Assessment of thyroid cancer risk associated with radiation dose from personal diagnostic examinations in a cohort study of US radiologic technologists, followed 1983-2014.

OBJECTIVE: To assess whether personal medical diagnostic procedures over life, but particularly those associated with exposure in adulthood, were associated with increased thyroid cancer risk. DESIGN: Participants from the US Radiologic Technologists Study, a large, prospective cohort, were followed from the date of first mailed questionnaire survey completed during 1983-1989 to the earliest date of self-reported diagnosis of thyroid cancer or of any other cancer than non-melanoma skin cancer (NMSC) in any of three subsequent questionnaires up to the last in 2012-2014. SETTING: US nationwide, occupational cohort. PARTICIPANTS: US radiologic technologists with exclusion of: those who reported a previous cancer apart from NMSC on the first questionnaire; those who reported a cancer with an unknown date of diagnosis on any of the questionnaires; and those who did not respond to both the first questionnaire and at least one subsequent questionnaire. PRIMARY OUTCOME MEASURE: We used Cox proportional hazards models with age as timescale to compute HRs and 95% CI for thyroid cancer in relation to cumulative 5-year lagged diagnostic thyroid dose. RESULTS: There were 414 self-reported thyroid cancers (n=275 papillary) in a cohort of 76 415 persons. Cumulative thyroid dose was non-significantly positively associated with total (excess relative risk/Gy=2.29 (95% CI -0.91 to 7.01, p=0.19)) and papillary thyroid cancer (excess relative risk/Gy=4.15 (95% CI -0.39, 11.27, p=0.08)) risk. These associations were not modified by age at, or time since, exposure and were independent of occupational exposure. CONCLUSION: Our study provides weak evidence that thyroid dose from diagnostic radiation procedures over the whole of life, in particular associated with exposure in adulthood, influences adult thyroid cancer risk.

Thyroid Radiation Dose to Patients from Diagnostic Radiology Procedures over Eight Decades: 1930-2010.

This study summarizes and compares estimates of radiation absorbed dose to the thyroid gland for typical patients who underwent diagnostic radiology examinations in the years from 1930 to 2010. The authors estimated the thyroid dose for common examinations, including radiography, mammography, dental radiography, fluoroscopy, nuclear medicine, and computed tomography (CT). For the most part, a clear downward trend in thyroid dose over time for each procedure was observed. Historically, the highest thyroid doses came from the nuclear medicine thyroid scans in the 1960s (630 mGy), full-mouth series dental radiography (390 mGy) in the early years of the use of x rays in dentistry (1930s), and the barium swallow (esophagram) fluoroscopic exam also in the 1930s (140 mGy). Thyroid uptake nuclear medicine examinations and pancreatic scans also gave relatively high doses to the thyroid (64 mGy and 21 mGy, respectively, in the 1960s). In the 21st century, the highest thyroid doses still result from nuclear medicine thyroid scans (130 mGy), but high thyroid doses are also associated with chest/abdomen/pelvis CT scans (18 and 19 mGy for males and females, respectively). Thyroid doses from CT scans did not exhibit the same downward trend as observed for other examinations. The largest thyroid doses from conventional radiography came from cervical spine and skull examinations. Thyroid doses from mammography (which began in the 1960s) were generally a fraction of 1 mGy. The highest average doses to the thyroid from mammography were about 0.42 mGy, with modestly larger doses associated with imaging of breasts with large compressed thicknesses. Thyroid doses from dental radiographic procedures have decreased markedly throughout the decades, from an average of 390 mGy for a full-mouth series in the 1930s to an average of 0.31 mGy today. Upper GI series fluoroscopy examinations resulted in up to two orders of magnitude lower thyroid doses than the barium swallow. There are considerable uncertainties associated with the presented doses, particularly for characterizing exposures of individual identified patients. Nonetheless, the tabulations provide the only comprehensive report on the estimation of typical radiation doses to the thyroid gland from medical diagnostic procedures over eight decades (1930-2010). These data can serve as a resource for epidemiologic studies that evaluate the late health effects of radiation exposure associated with diagnostic radiologic examinations.

Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013.

Importance: Thyroid cancer incidence has increased substantially in the United States over the last 4 decades, driven largely by increases in papillary thyroid cancer. It is unclear whether the increasing incidence of papillary thyroid cancer has been related to thyroid cancer mortality trends. Objective: To compare trends in thyroid cancer incidence and mortality by tumor characteristics at diagnosis. Design, Setting, and Participants: Trends in thyroid cancer incidence and incidence-based mortality rates were evaluated using data from the Surveillance, Epidemiology, and End Results-9 (SEER-9) cancer registry program, and annual percent change in rates was calculated using log-linear regression. Exposure: Tumor characteristics. Main Outcomes and Measures: Annual percent changes in age-adjusted thyroid cancer incidence and incidence-based mortality rates by histologic type and SEER stage for cases diagnosed during 1974-2013. Results: Among 77 276 patients (mean [SD] age at diagnosis, 48 [16] years; 58 213 [75%] women) diagnosed with thyroid cancer from 1974-2013, papillary thyroid cancer was the most common histologic type (64 625 cases), and 2371 deaths from thyroid cancer occurred during 1994-2013. Thyroid cancer incidence increased, on average, 3.6% per year (95% CI, 3.2%-3.9%) during 1974-2013 (from 4.56 per 100 000 person-years in 1974-1977 to 14.42 per 100 000 person-years in 2010-2013), primarily related to increases in papillary thyroid cancer (annual percent change, 4.4% [95% CI, 4.0%-4.7%]). Papillary thyroid cancer incidence increased for all SEER stages at diagnosis (4.6% per year for localized, 4.3% per year for regional, 2.4% per year for distant, 1.8% per year for unknown). During 1994-2013, incidence-based mortality increased 1.1% per year (95% CI, 0.6%-1.6%) (from 0.40 per 100 000 person-years in 1994-1997 to 0.46 per 100 000 person-years in 2010-2013) overall and 2.9% per year (95% CI, 1.1%-4.7%) for SEER distant stage papillary thyroid cancer. Conclusions and Relevance: Among patients in the United States diagnosed with thyroid cancer from 1974-2013, the overall incidence of thyroid cancer increased 3% annually, with increases in the incidence rate and thyroid cancer mortality rate for advanced-stage papillary thyroid cancer. These findings are consistent with a true increase in the occurrence of thyroid cancer in the United States.

Changing Patterns in the Performance of Fluoroscopically Guided Interventional Procedures and Adherence to Radiation Safety Practices in a U.S. Cohort of Radiologic Technologists.

OBJECTIVE: Information is limited on changes over time in the types of fluoroscopically guided interventional procedures performed and associated radiation safety practices used by radiologic technologists. MATERIALS AND METHODS: Our study included 12,571 U.S. radiologic technologists who were certified for at least 2 years in 1926-1982 and who reported in a 2012-2013 survey that they ever performed or assisted with fluoroscopically guided interventional procedures. They completed a mailed questionnaire in 2013-2014 describing their detailed work practices for 21 fluoroscopically guided interventional procedures and associated radiation safety practices from the 1950s through 2009. RESULTS: Overall, the proportion of technologists who reported working with therapeutic fluoroscopically guided interventional procedures, including percutaneous coronary interventions, increased over time, whereas the proportion of technologists who worked with diagnostic fluoroscopically guided interventional procedures, including diagnostic cardiovascular catheterization and neuroangiographic procedures, decreased. We also observed substantial increases in the median number of times per month that technologists worked with diagnostic cardiovascular catheterizations and percutaneous coronary interventions. In each time period, most technologists reported consistently (≥ 75% of work time) wearing radiation monitoring badges and lead aprons during fluoroscopically guided interventional procedures. However, fewer than 50% of the technologists reported consistent use of thyroid shields, lead glasses, and room shields during fluoroscopically guided interventional procedures, even in more recent time periods. CONCLUSION: This study provides a detailed historical assessment of fluoroscopically guided interventional procedures performed and radiation safety practices used by radiologic technologists from the 1950s through 2009. Results can be used in conjunction with badge dose data to estimate organ radiation dose for studies of radiation-related health risks in radiologic technologists who have worked with fluoroscopically guided interventional procedures.

Historical Patterns in the Types of Procedures Performed and Radiation Safety Practices Used in Nuclear Medicine From 1945-2009.

The authors evaluated historical patterns in the types of procedures performed in diagnostic and therapeutic nuclear medicine and the associated radiation safety practices used from 1945-2009 in a sample of U.S. radiologic technologists. In 2013-2014, 4,406 participants from the U.S. Radiologic Technologists (USRT) Study who previously reported working with medical radionuclides completed a detailed survey inquiring about the performance of 23 diagnostic and therapeutic radionuclide procedures and the use of radiation safety practices when performing radionuclide procedure-related tasks during five time periods: 1945-1964, 1965-1979, 1980-1989, 1990-1999, and 2000-2009. An overall increase in the proportion of technologists who performed specific diagnostic or therapeutic procedures was observed across the five time periods. Between 1945-1964 and 2000-2009, the median frequency of diagnostic procedures performed substantially increased (from 5 wk to 30 wk), attributable mainly to an increasing frequency of cardiac and non-brain PET scans, while the median frequency of therapeutic procedures performed modestly decreased (from 4 mo to 3 mo). Also a notable increase was observed in the use of most radiation safety practices from 1945-1964 to 2000-2009 (e.g., use of lead-shielded vials during diagnostic radiopharmaceutical preparation increased from 56 to 96%), although lead apron use dramatically decreased (e.g., during diagnostic imaging procedures, from 81 to 7%). These data describe historical practices in nuclear medicine and can be used to support studies of health risks for nuclear medicine technologists.

Maternal exposure to radiographic exams and major structural birth defects.

BACKGROUND: An increasing number of radiologic exams are performed in the United States, but very few studies have examined the effects of maternal exposure to radiologic exams during the periconceptional period and birth defects. OBJECTIVES: To assess the association between maternal exposure to radiologic exams during the periconceptional period and 19 categories of birth defects using a large population-based study of birth defects. METHODS: We studied 27,809 case mothers and 10,200 control mothers who participated in the National Birth Defects Prevention Study and delivered between 1997 and 2009. Maternal exposure to radiologic exams that delivered ionizing radiation to the urinary tract, lumbar spine, abdomen, or pelvis were identified based on the mother's report of type of radiologic exams, organ or body part scanned and the month during which the exam occurred RESULTS: Overall, 0.9% of mothers reported exposure to one of these types of radiographic exams during the periconceptional period. We observed significant associations between maternal exposure during the first trimester and isolated Dandy-Walker malformation (odds ratio = 7.7; 95% confidence interval, 1.8-33) and isolated d-transposition of the great arteries (odds ratio = 3.8; 95% confidence interval, 1.4-10.3). However, the result for isolated Dandy-Walker malformation was based on only two exposed cases. CONCLUSION: These results should be interpreted cautiously because multiple statistical tests were conducted and measurements of exposure were based on maternal report. However, our results may be useful for generating hypotheses for future studies. Birth Defects Research (Part A) 106:563-572, 2016. © 2016 Wiley Periodicals, Inc.

Maternal occupational exposure to ionizing radiation and major structural birth defects.

BACKGROUND: Ionizing radiation (IR) is known to be carcinogenic and mutagenic, but little is known about the association between maternal occupational exposure to IR and birth defects. METHODS: We studied 38,009 mothers who participated in the National Birth Defects Prevention Study and delivered between 1997 and 2009. We assessed odds ratios [ORs] for the association between maternal occupations with potential exposure to IR and 39 birth defects. RESULTS: We observed significant odds ratios (ORs) for isolated hydrocephaly (adjusted OR [AOR], 2.1; 95% confidence interval [CI], 1.1-4.2), isolated anotia/microtia (AOR, 2.0; 95% CI, 1.0-4.0), isolated colonic atresia (crude OR, 7.5; 95% CI, 2.5-22.3), isolated omphalocele (AOR, 2.3; 95% CI, 1.1-4.6) and isolated anencephaly (crude OR, 0.23; 95% CI, 0.06-0.94). We also observed a nonsignificant OR for birth defects in aggregate (AOR, 2.0; 95% CI, 0.9-4.6) among mothers with potential occupational exposure to fluoroscopy. CONCLUSION: We assessed 39 birth defects, observing that maternal occupations with potential exposure to IR were associated with a significantly increased risk for 4 birth defects and a significantly protected risk for 1 birth defect. These results should be interpreted cautiously because our measurement of exposure is qualitative, some of these associations may be due to occupational exposures that are correlated with IR and some may be due to chance. However, these findings serve as the first evaluation of these relationships in a large study and may be useful for generating hypotheses for future studies.

Maternal exposure to brominated flame retardants and infant Apgar scores.

Brominated flame retardants (BFRs) and other persistent organic pollutants have been associated with adverse health outcomes in humans and may be particularly toxic to the developing fetus. We investigated the association between in utero polybrominated biphenyl (PBB) and polychlorinated biphenyl (PCB) exposures and infant Apgar scores in a cohort of Michigan residents exposed to PBB through contaminated food after an industrial accident. PBB and PCB concentrations were measured in serum at the time the women were enrolled in the cohort. PBB concentrations were also estimated at the time of conception for each pregnancy using a validated elimination model. Apgar scores, a universal measure of infant health at birth, measured at 1 and 5min, were taken from birth certificates for 613 offspring born to 330 women. Maternal PCB concentrations at enrollment were not associated with below-median Apgar scores in this cohort. However, maternal PBB exposure was associated with a dose-related increase in the odds of a below-median Apgar score at 1min and 5min. Among infants whose mothers had an estimated PBB at conception above the limit of detection of 1 part per billion (ppb) to <2.5ppb, the odds ratio=2.32 (95% CI: 1.22-4.40); for those with PBB⩾2.5ppb the OR=2.62 (95% CI: 1.38-4.96; test for trend p<0.01). Likewise, the odds of a below-median 5min Apgar score increased with higher maternal PBB at conception. It remains critical that future studies examine possible relationships between in utero exposures to brominated compounds and adverse health outcomes.