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The independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation. Alcohol and smoking are both associated with oral/oropharyngeal cancer risk, but independent effects are unclear given their relatedness. Here, the authors use multivariable Mendelian randomization to show that both alcohol and smoking are independently causal for oral/oropharyngeal cancer.

Background The relationship between germline genetic variation and breast cancer survival is largely unknown, especially in understudied minority populations who often have poorer survival. Genome-wide association studies (GWAS) have interrogated breast cancer survival but often are underpowered due to subtype heterogeneity and clinical covariates and detect loci in non-coding regions that are difficult to interpret. Transcriptome-wide association studies (TWAS) show increased power in detecting functionally relevant loci by leveraging expression quantitative trait loci (eQTLs) from external reference panels in relevant tissues. However, ancestry- or race-specific reference panels may be needed to draw correct inference in ancestrally diverse cohorts. Such panels for breast cancer are lacking. Results We provide a framework for TWAS for breast cancer in diverse populations, using data from the Carolina Breast Cancer Study (CBCS), a population-based cohort that oversampled black women. We perform eQTL analysis for 406 breast cancer-related genes to train race-stratified predictive models of tumor expression from germline genotypes. Using these models, we impute expression in independent data from CBCS and TCGA, accounting for sampling variability in assessing performance. These models are not applicable across race, and their predictive performance varies across tumor subtype. Within CBCS ( N  = 3,828), at a false discovery-adjusted significance of 0.10 and stratifying for race, we identify associations in black women near AURKA , CAPN13 , PIK3CA , and SERPINB5 via TWAS that are underpowered in GWAS. Conclusions We show that carefully implemented and thoroughly validated TWAS is an efficient approach for understanding the genetics underpinning breast cancer outcomes in diverse populations.

Background Young-onset breast cancer (<40 years) is associated with worse prognosis and higher mortality. Breast cancer risk factors may contribute to distinct tumor biology and distinct age at onset, but understanding of these relationships has been hampered by limited representation of young women in epidemiologic studies and may be confounded by menopausal status. Methods We examined tumor characteristics and epidemiologic risk factors associated with premenopausal women’s and young women’s breast cancer in phases I–III of the Carolina Breast Cancer Study (5309 cases, 2022 control subjects). Unconditional logistic regression was used to assess heterogeneity by age (<40 vs. ≥40 years) and menopausal status. Results In both premenopausal and postmenopausal strata, younger women had more aggressive disease, including higher stage, hormone receptor-negative, disease as well as increased frequency of basal-like subtypes, lymph node positivity, and larger tumors. Higher waist-to-hip ratio was associated with reduced breast cancer risk among young women but with elevated risk among older women. Parity was associated with increased risk among young women and reduced risk among older women, while breastfeeding was more strongly protective for young women. Longer time since last birth was protective for older women but not for young women. In comparison, when we stratified by age, menopausal status was not associated with distinct risk factor or tumor characteristic profiles, except for progesterone receptor status, which was more commonly positive among premenopausal women. Conclusions Age is a key predictor of breast cancer biologic and etiologic heterogeneity and may be a stronger determinant of heterogeneity than menopausal status. Young women’s breast cancer appears to be etiologically and biologically distinct from that among older women.

BACKGROUND:Few studies have examined the impact of lifestyle patterns on survival following breast cancer. We aimed to identify distinct lifestyle patterns based on five behavior/dietary exposures among a population-based sample of women diagnosed with breast cancer and to examine their association with subsequent survival. METHODS:In the Carolina Breast Cancer Study Phases I/II, we interviewed 1,808 women 20–74 years of age following diagnosis of invasive breast cancer. We determined vital status using the National Death Index (717 deaths, 427 from breast cancer; median follow-up 13.56 years). We assessed lifestyle patterns using a latent class analysis based on five behavioral and dietary exposurescurrent versus never/former smokers; low versus high vegetable and fruit intake; high and low/moderate, versus no alcohol consumption; and no and low/moderate, versus high regular physical activity. We used Cox regression to estimate covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality, and cause-specific and subdistribution HRs for breast cancer–specific mortality within 5 years and 13 years postdiagnosis conditional on 5-year survival. RESULTS:We identified three distinct lifestyle patternshealthy behavior and diet (n = 916); healthy behavior and unhealthy diet (n = 624); and unhealthy behavior and diet (n = 268). The unhealthy (vs. healthy) behavior and diet pattern was associated with a 13-year conditional all-cause mortality HR of 1.4 (95% CI = 1.1, 1.9) and with 13-year conditional breast cancer–specific and subdistribution HRs of 1.2 (95% CI = 0.79, 1.9) and 1.2 (95% CI = 0.77, 1.8), respectively. CONCLUSIONS:Behavioral and dietary patterns can be used to identify lifestyle patterns that influence survival patterns following breast cancer diagnosis.

PurposeThe association between diet quality, captured by the Mediterranean Diet Score (MDS), and mortality was studied among 1184 individuals diagnosed with head and neck cancer (HNC) who reflected on the year preceding diagnosis about their usual diet using National Cancer Institute’s Diet History Questionnaire (DHQ).MethodsIntakes of nine dietary components were scored and summed to construct the MDS (sample: median = 4; range (0–9); lower MDS reflected poorer diet quality; 5-year survival probability = 0.62). Cox regression estimated 5-year hazard ratios (HR) and 95% confidence intervals (95CI) for all-cause mortality and for HNC-specific death for contrasts of MDS quintiles. Effect measure modification (EMM) by tumor features [human papillomavirus (HPV) positivity; anatomic site] and sociodemographic behavioral factors [race, body mass index (BMI), smoking, alcohol consumption] was explored.ResultsThe 5-year [HR (95CI); P-trend] for all-cause mortality and HNC-specific mortality for highest versus lowest MDS quintile contrasts were [0.51 (0.33, 0.80); 0.014] and [0.43 (0.22, 0.85); 0.004], respectively. A unit increase in MDS adherence resulted in a 15% reduction of the 5-year HR for HNC-specific death for tumors located at the oral cavity [HR (95CI): 0.85 (0.75, 0.96)]. Poor diet quality (MDS ≤ 4) interacted with lower BMI (kg/m2 < 25) and separately with ever-using alcohol to produce 5-year HRs for all-cause and HNC-specific mortality that were statistically significantly larger than the sum of the individual HRs representing each combination (Poor diet quality + lower BMI; Poor diet quality + ever-using alcohol).ConclusionGreater adherence to a Mediterranean diet pattern prior to HNC diagnosis may reduce post-diagnosis mortality.

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented.

Endometrial cancer is the most common gynecologic cancer in the US. Endometrial cancer survivors may experience changes in microbiome due to cancer treatment and other factors. The human microbiome plays a crucial role in maintaining the proper functioning of the body. A more diverse microbiome often indicates a healthier gut environment, while lower vaginal microbiome diversity, specifically a Lactobacillus-dominant vagitype, is associated with more favorable health outcomes. The objectives of this pilot study were to evaluate potential variation in stool and vaginal microbiome communities and to assess the feasibility and acceptability of self-sampling among endometrial cancer survivors. Endometrial cancer survivors (N = 50) enrolled in the Carolina Endometrial Cancer Study, a cohort of women diagnosed with endometrial cancer, were mailed Genotek vaginal swab and stool self-collection kits. Self-reported questionnaires assessed information on survivors' demographics, sexual and bowel function, and perspectives on the self-sampling processes. Tumor characteristics and cancer treatment information were assessed from medical records. Microbiota profiles were characterized by bacteria 16S rRNA amplicon sequencing. Overall, 48 vaginal swabs and 47 stool samples were obtained. Alpha (Shannon p = 0.04) and beta (Bray-Curtis p = 0.004) diversity of vaginal microbiome samples varied by cancer treatment, with higher microbial diversity after chemotherapy or radiation compared to surgery alone. In the surgery only group, 63% of samples were Lactobacillus-dominant compared to 17% among the chemotherapy or radiation group. Stool microbiome diversity did not vary by cancer treatment status. No statistically significant differences in alpha or beta diversity were observed in either vaginal or stool microbiome communities across racial subgroups or by sexual or bowel function. Self-collection of stool and vaginal microbiome samples is feasible and acceptable in cancer survivors. Our results suggest that radiation and chemotherapy for endometrial cancer may decrease the abundance of beneficial Lactobacillus and increase less favorable vaginal microbial diversity among endometrial cancer survivors.

Selection pressure due to exposure to infectious pathogens endemic to Africa may explain distinct genetic variations in immune response genes. However, the impact of those genetic variations on human immunity remains understudied, especially within the context of modern lifestyles and living environments, which are drastically different from early humans in sub Saharan Africa. There are few data on population differences in constitutional immune environment, where genetic ancestry and environment are likely two primary sources of variation. In a study integrating genetic, molecular and epidemiologic data, we examined population differences in plasma levels of 14 cytokines involved in innate and adaptive immunity, including those implicated in chronic inflammation, and possible contributing factors to such differences, in 914 AA and 855 EA women. We observed significant differences in 7 cytokines, including higher plasma levels of CCL2, CCL11, IL4 and IL10 in EAs and higher levels of IL1RA and IFNα2 in AAs. Analyses of a wide range of demographic and lifestyle factors showed significant impact, with age, education level, obesity, smoking, and alcohol intake, accounting for some, but not all, observed population differences for the cytokines examined. Levels of two pro-inflammatory chemokines, CCL2 and CCL11, were strongly associated with percent of African ancestry among AAs. Through admixture mapping, the signal was pinpointed to local ancestry at 1q23, with fine-mapping analysis refined to the Duffy-null allele of rs2814778. In AA women, this variant was a major determinant of systemic levels of CCL2 (p = 1.1e-58) and CCL11 (p = 2.2e-110), accounting for 19% and 40% of the phenotypic variance, respectively. Our data reveal strong ancestral footprints in inflammatory chemokine regulation. The Duffy-null allele may indicate a loss of the buffering function for chemokine levels. The substantial immune differences by ancestry may have broad implications to health disparities between AA and EA populations.

Prior studies of squamous cell carcinoma of the head and neck (SCCHN) have explored the effect of socioeconomic status (SES) as an independent risk factor; however, none have investigated the interaction of known risk factors with SES. We examined this using the North Carolina Head and Neck Cancer Epidemiology Study, a population-based case–control study. Incident cases of SCCHN from North Carolina between 2002 and 2006 (n = 1,153) were identified and age, sex, and race-matched controls (n = 1,267) were selected from driver license records. SES measures included household income, educational attainment, and health insurance. Logistic regression was used to estimate adjusted odds ratios (OR) and 95 % confidence intervals (CI). Current smoking was more strongly associated with SCCHN among those households making < $ 20,000/year [OR 5.11 (3.61–6.61)] compared to household incomes > $ 50,000/year [OR 2.47 (1.69–3.25); p interaction < 0.001]. Current drinking was more strongly associated with SCCHN in household incomes < $ 20,000 [OR 2.91 (2.05–3.78)] compared to > $50,000/year [1.28 (0.97–1.58); p interaction < 0.001]. Current drinkers with less than high school education or income < $20,000 had nearly threefold odds of never-drinkers in the same SES category [OR 2.91 (2.05–3.78); 2.09 (1.39–2.78), respectively]. Our results suggest that the relationship of smoking and alcohol use may be stronger among those of lower SES.

Background Toxic metals including arsenic, cadmium, manganese, and lead are known human developmental toxicants that are able to cross the placental barrier from mother to fetus. In this population-based study, we assess the association between metal concentrations in private well water and birth defect prevalence in North Carolina. Methods A semi-ecologic study was conducted including 20,151 infants born between 2003 and 2008 with selected birth defects (cases) identified by the North Carolina Birth Defects Monitoring Program, and 668,381 non-malformed infants (controls). Maternal residences at delivery and over 10,000 well locations measured for metals by the North Carolina Division of Public Health were geocoded. The average level of each metal was calculated among wells sampled within North Carolina census tracts. Individual exposure was assigned as the average metal level of the census tract that contained the geocoded maternal residence. Prevalence ratios (PR) with 95% confidence intervals (CI) were calculated to estimate the association between the prevalence of birth defects in the highest category (≥90 th percentile) of average census tract metal levels and compared to the lowest category (≤50 th percentile). Results Statewide, private well metal levels exceeded the EPA Maximum Contaminant Level (MCL) or secondary MCL for arsenic, cadmium, manganese, and lead in 2.4, 0.1, 20.5, and 3.1 percent of wells tested. Elevated manganese levels were statistically significantly associated with a higher prevalence of conotruncal heart defects (PR: 1.6 95% CI: 1.1-2.5). Conclusions These findings suggest an ecologic association between higher manganese concentrations in drinking water and the prevalence of conotruncal heart defects.