Faculty Bibliography

BACKGROUND:Auto-antibodies to tumor suppressor p53 are found in a subset of patients with colorectal cancer. A recent prospective study in the United States has reported a significant 1.8-fold increased odds for colorectal cancer development with prediagnostic seropositivity to p53. In this study, we sought to examine this association in a U.S. colorectal cancer cohort consortium to evaluate the potential utility of p53 auto-antibodies as an early biomarker for colorectal cancer. METHODS:Auto-antibodies to p53 were measured in prediagnostic blood samples of 3,702 incident colorectal cancer cases and 3,702 controls, matched by age, race, and sex, from 9 U.S. prospective cohorts. The association of seropositivity to p53 with colorectal cancer risk, overall and by time between blood draw and diagnosis, was determined by conditional logistic regression. RESULTS:Overall, 5% of controls and 7% of cases were seropositive to p53, resulting in a statistically significant 33% increased colorectal cancer risk [odds ratio (OR), 1.33; 95% confidence interval (CI), 1.09-1.61]. By follow-up time, the association was only significant with colorectal cancer diagnoses within 4 years after blood draw (OR, 2.27; 95% CI, 1.62-3.19), but not thereafter (OR, 0.97; 95% CI, 0.76-1.24). CONCLUSIONS:In this large consortium of prospective cohorts, we found that prediagnostic seropositivity to tumor suppressor p53 was significantly associated with an over 2-fold increased odds of developing colorectal cancer within 4 years after blood draw. IMPACT/CONCLUSIONS:Our finding suggests that p53 seropositivity may not be a useful predictor of long-term colorectal cancer risk; however, it might be considered as a marker to aid in the early diagnosis of colorectal cancer.

Elevated blood pressure in childhood is an important risk factor for hypertension in adulthood. Environmental exposures have been associated with elevated blood pressure over the life course and exposure to mercury (Hg) has been linked to cardiovascular effects in adults. As subclinical vascular changes begin early in life, Hg may play a role in altered blood pressure in children. However, the evidence linking early life Hg exposure to altered blood pressure in childhood has been largely inconsistent. In the ongoing New Hampshire Birth Cohort Study, we investigated prenatal and childhood Hg exposure at multiple time points and associations with blood pressure measurements in 395 young children (mean age 5.5 years, SD 0.4). Hg exposure was measured in children's toenail clippings at age 3 and in urine at age 5-6 years, as well as in maternal toenail samples collected at ∼28 weeks gestation and 6 weeks postpartum, the latter two samples reflecting early prenatal and mid-gestation exposures, respectively. Five measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were averaged for each child using a standardized technique. In covariate-adjusted linear regression analyses, we observed that a 0.1 μg/g increase in child toenail Hg at age 3 or a 0.1 μg/L urine Hg at age 5-6 were individually associated with greater DBP (toenail β: 0.53 mmHg; 95% CI: -0.02, 1.07; urine β: 0.48 mmHg; 95% CI: 0.10, 0.86) and MAP (toenail β: 0.67 mmHg; 95% CI: 0.002, 1.33; urine β: 0.55 mmHg; 95% CI: 0.10, 1.01). Neither early prenatal nor mid-gestation Hg exposure, as measured by maternal toenails, were related to any changes to child BP. Simultaneous inclusion of both child urine Hg and child toenail Hg in models suggested a potentially stronger relationship of urine Hg at age 5-6 with DBP and MAP, as compared to toenail Hg at age 3. Our findings suggest that Hg exposure during childhood is associated with alterations in BP. Childhood may be an important window of opportunity to reduce the impacts of Hg exposure on children's blood pressure, and in turn, long-term health.

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors, and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g. HR per 5kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors. This article is protected by copyright. All rights reserved.

BACKGROUND:Excess body weight is an established cause of postmenopausal breast cancer, but it is unknown if weight loss reduces risk. METHODS:Associations between weight change and risk of breast cancer were examined among women aged ≥50 years in the Pooling Project of Prospective Studies of Diet and Cancer. In 10 cohorts, weight assessed on three surveys was used to examine weight change patterns over approximately 10 years (Interval 1 median= 5.2 years; Interval 2 median = 4.0 years). Sustained weight loss was defined as ≥ 2kg lost in Interval 1 that was not regained in Interval 2. Among 180,885 women, 6,930 invasive breast cancers were identified during follow-up. RESULTS:Compared with women with stable weight (± 2kg), women with sustained weight loss had a lower risk of breast cancer. This risk reduction was linear and specific to women not using postmenopausal hormones (>2-4.5kg lost: Hazard Ratio (HR)= 0.82, 95% confidence interval (CI): 0.70-0.96; >4.5-<9kg lost: HR = 0.75, 95% CI: 0.63-0.90; ≥9kg lost: HR = 0.68, 95% CI: 0.50-0.93). Women who lost ≥9kg and gained some (but not all) of it back were also at a lower risk of breast cancer. Other patterns of weight loss and gain over the two intervals had a similar risk of breast cancer to women with stable weight. CONCLUSIONS:These results suggest that sustained weight loss, even modest amounts, is associated with lower breast cancer risk for women aged ≥50 years. Breast cancer prevention may be a strong weight loss motivator for the two-thirds of American women who are overweight or obese.

BACKGROUND:In almost all countries, incidence rates of liver cancer are 100-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of liver cancer cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with liver cancer risk, overall and by histology, by leveraging resources from five prospective cohorts. METHODS:hormone value (approximate doubling of circulating concentration) and liver cancer were calculated using multivariable-adjusted conditional logistic regression. RESULTS:A doubling in the concentration of 4-androstenedione was associated with a 50% decreased liver cancer risk (OR=0.50,95%CI=0.30-0.82), while SHBG was associated with a 31% increased risk (OR=1.31,95%CI=1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR=1.40,95%CI=1.05-1.89), but not HCC (OR=1.12,95%CI=0.81-1.54). CONCLUSIONS:This study provides the first evidence that higher levels of 4-androstenedione may be associated with lower, and SHBG with higher, liver cancer risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease liver cancer risk. Indeed, estradiol may be associated with an increased ICC risk.

INTRODUCTION/BACKGROUND:Epidemiological studies that investigate alterations in the gut microbial composition associated with smoking are lacking. This study examined the composition of the gut microbiome in smokers compared with non-smokers. METHODS:Stool samples were collected in a cross-sectional study of 249 participants selected from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Microbial DNA was extracted from the fecal samples and sequenced by 16S rRNA gene sequencing. The associations of smoking status and intensity of smoking with the relative abundance or the absence and presence of individual bacterial taxon from phylum to genus levels were examined. RESULTS:The relative abundance of bacterial taxa along the Erysipelotrichi-to-Catenibacterium lineage was significantly higher in current smokers compared to never smokers. The odds ratio comparing the mean relative abundance in current smokers with that in never smokers was 1.91 (95% confidence interval [CI] = 1.36 to 2.69) for the genus Catenibacterium and 1.89 (95% CI = 1.39 to 2.56) for the family Erysipelotrichaceae, the order Erysipelotrichale, and the class Erysipelotrichi ((FDR-adjusted p-values = 0.0008 to 0.01). A dose-response association was observed for each of these bacterial taxa. The presence of Alphaproteobacteria was significantly greater comparing current with never smokers (OR = 4.85, FDR-adjusted p-values = 0.04). CONCLUSIONS:Our data in a Bangladeshi population are consistent with evidence of an association between smoking status and dosage with change in the gut bacterial composition. IMPLICATIONS/CONCLUSIONS:This study for the first time examined the relationship between smoking and the gut microbiome composition. The data suggest that smoking status may play an important role in the composition of the gut microbiome, especially among individuals with higher levels of tobacco exposure.

BACKGROUND:Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC. METHODS:We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases). RESULTS:Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors. CONCLUSIONS:This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

BACKGROUND:There is concern about the potential of an increased risk related to medications that act on the renin-angiotensin-aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2). METHODS:We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference. RESULTS:Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive. CONCLUSIONS:We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.

Gastric cancer represents one of the leading causes of cancer deaths worldwide. Helicobacter pylori (H. pylori) infection is the strongest risk factor associated with gastric cancer. Due to new molecular techniques allowing greater identification of stomach microbes, investigators are beginning to examine the role that bacteria other than H. pylori play in gastric cancer development. Recently, researchers have investigated how the composition of the gastric microbiota varies among individuals with various stages of gastric disease. Specific microbes residing in the stomach have been preferentially associated with gastric cancer patients compared to individuals with a healthy gastric mucosa. Studies conducted on the insulin-gastrin (INS-GAS) transgenic mouse model have provided additional insight into the association between the gastric microbiota and gastric cancer. The purpose of this article is to review the current state of literature on the relationship between the gastric microbiota and gastric cancer based on clinical studies performed to date.

BACKGROUND:Studies demonstrate that children with type 1 diabetes may not be meeting exercise recommendations. This, coupled with the lack of data on the determinants of exercise promotion in youth, may indicate a need for additional focus on exercise guidelines and promotion in youth with type 1 diabetes. OBJECTIVE:The objective of this study is to understand provider perspectives regarding exercise promotion in children with type 1 diabetes. SUBJECTS AND METHODS/METHODS:An online survey regarding perspectives on exercise was emailed to Pediatric Endocrine Society members. RESULTS:Of the 84 respondents, 85.5% believe counseling regarding exercise recommendations is a priority. However, 87.8% did not identify Office of Disease Prevention and Health Promotion (ODPHP) guidelines correctly and 79.3% did not identify American Diabetes Association (ADA) guidelines correctly. Providers who exercised regularly (p = 0.009) and providers who identified ODPHP guidelines correctly (p = 0.004) were more likely to identify ADA guidelines correctly. Providers who identified ADA guidelines correctly were 4.21 times (OR 4.21; 95% CI 1.30-13.7) more likely to make good recommendations and those who discussed recommendations at diagnosis were 6.10 times (OR 6.10; 95% CI 1.76-21.2) more likely to make good recommendations. CONCLUSION/CONCLUSIONS:To our knowledge, this study is the first to investigate provider perspectives of exercise promotion in children with type 1 diabetes. We found provider recommendations were not consistent with ADA exercise guidelines and most providers were not fully aware of the recommendations. Future research should address increasing provider education regarding exercise guidelines and developing exercise promotion tools. This article is protected by copyright. All rights reserved.