Summary Height is a highly heritable, classic polygenic trait with ∼700 common associated variants identified so far through genome-wide association studies. Here, we report 83 height-associated coding variants with lower minor allele frequencies (range of 0.1-4.8%) and effects of up to 2 cm/allele (e.g. in IHH, STC2, AR and CRISPLD2), >10 times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (+1-2 cm/allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates (e.g. ADAMTS3, IL11RA, NOX4) and pathways (e.g. proteoglycan/glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate to large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, non-coding variants from which pinpointing causal genes remains challenging. Here, we combined data from 718,734 individuals to discover rare and low-frequency (MAF<5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which eight in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2, ZNF169) newly implicated in human obesity, two (MC4R, KSR2) previously observed in extreme obesity, and two variants in GIPR. Effect sizes of rare variants are ~10 times larger than of common variants, with the largest effect observed in carriers of an MC4R stop-codon (p.Tyr35Ter, MAF=0.01%), weighing ~7kg more than non-carriers. Pathway analyses confirmed enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically-supported therapeutic targets to treat obesity.

Objectives/Hypothesis Literature examining long-term survival in head and neck squamous cell carcinoma (HNSCC) with human papillomavirus (HPV) status is lacking. We compare 10-year overall survival (OS) rates for cases to population-based controls. Study Design Prospective cohort study. Methods Cases surviving 5 years postdiagnosis were identified from the Carolina Head and Neck Cancer Study. We examined 10-year survival by site, stage, p16, and treatment using Kaplan-Meier and Cox proportional hazard models. Cases were compared to age-matched, noncancer controls with stratification by p16 and smoking status. Results Ten-year OS for HNSCC is less than controls. In 581 cases, OS differed between sites with p16+ oropharynx having the most favorable prognosis (87%), followed by oral cavity (69%), larynx (67%), p16− oropharynx (56%), and hypopharynx (51%). Initial stage, but not treatment, also impacted OS. When compared to controls matched on smoking status, the hazard ratio (HR) for death in p16+ oropharynx cases was 1.5 (95% confidence interval [CI]: 0.7–3.1) for smokers and 2.4 (95% CI: 0.7–8.8) for nonsmokers. Similarly, HR for death in non–HPV-associated HNSCC was 2.2 (95% CI: 1.7–3.0) for smokers and 2.4 (95% CI: 1.4–4.9) for nonsmokers. Conclusions OS for HNSCC cases continues to decrease 5 years posttreatment, even after stratification by p16 and smoking status. Site, stage, smoking, and p16 status are significant factors. These data provide important prognostic information for HNSCC. Level of Evidence 2

Introduction Poor oral health has emerged as a risk factor for squamous cell carcinoma of the head and neck (HNSCC) but its impact on survival has not been examined. We sought to estimate the impact of oral health indicators on survival in a population-based HNSCC cohort. Materials and Methods Cases (n=1381) and age-, sex- and race-matched controls (n=1396) were participants in the Carolina Head and Neck Cancer Epidemiologic Study (CHANCE). Vital status was determined via linkage with the National Death Index. Survival was considered at 5 years post-diagnosis or study-enrollment for controls. Oral health was assessed using self-reported indicators including frequency of routine dental exams and tooth brushing. We used Kaplan-Meyer analyses and Cox regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results Routine dental visits during the preceding 10 years were associated with decreased mortality risk (>10 visits: HR=0.6, 95% CI=0.4–0.8) after adjusting for confounders. This effect was most pronounced for oral cavity cancer—(e.g., >10 visits: HR=0.4, 95% CI=0.2–0.9). Dental visits were also positively associated with survival among controls. No other routine health screening (e.g., eye exams) was associated with survival. Conclusion We found significant associations between markers of oral health and survival among both HNSCC cases and controls. This association was most pronounced for sites closer to the dentition. Oral health may have a direct effect on tumor biology due to the associated immune or inflammatory response. It may also represent a proxy for wellness or unmeasured social determinants of health.

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Objective To comprehensively examine the prognostic significance of extranodal extension (ENE) in human papillomavirus–positive oropharyngeal squamous cell carcinoma (HPV‐positive OPSCC). Methods Retrospective cohort of cases diagnosed with HPV‐positive OPSCC from 2010 to 2015 in the National Cancer Database. Inclusion of all OPSCC HPV‐positive cases with appropriate International Classification of Diseases‐0‐3 codes that received surgery with a neck dissection. Univariate and multivariable analyses were conducted. Hazard ratios (HR) for the independent effects of ENE and N stage on overall survival were estimated by Cox proportional hazards regression. Results Cases that were ENE‐negative had the highest 5‐year survival (92.6%; 95% confidence interval [CI]: 90.5%–94.7%). ENE‐positive cases had the lowest 5‐year survival (84.0%; 95% CI: 80.7%−87.4%). After adjusting for confounding variables, ENE‐positivity was associated with almost twice the hazard of death (HR = 1.90; 95% CI: 1.35–2.67) compared to ENE‐negative cases. Nodal (N) category 1, ENE‐positive status was associated with an increased risk of death (HR = 1.88; 95% CI: 1.26–2.80) compared with N1, ENE‐negative status. Compared to N1/ENE‐negative cases, N2/ENE‐positive cases had the poorest survival (HR: 2.93; 95% CI: 1.94–4.43). Both microscopic and macroscopic ENE were associated with worse outcomes compared to node‐positive/ENE‐negative status. Conclusion The implementation of the American Joint Committee on Cancer 8th edition staging system provides a much‐improved framework to develop and discuss treatment plans for HPV‐positive OPSCC. We feel that careful consideration should be given to the importance of ENE in patients with HPV‐positive OPSCC. Level of Evidence 4 Laryngoscope, 130:939–945, 2020

Objectives To explore whether HPV-related biomarkers predict oropharyngeal squamous cell cancer (OPSCC) survival similarly across different global regions, and to explore their prognostic utility among non-oropharyngeal (non-OP) head and neck cancers. Methods Data from 1362 head and neck SCC (HNSCC) diagnosed 2002-2011 was used from epidemiologic studies in: Brazil (GENCAPO study, n=388), U.S. (CHANCE study, n=472), and Europe (ARCAGE study, n=502). Tumors were centrally tested for p16INK4a and HPV16 DNA (by PCR). Risk of mortality was examined using Cox proportional hazard models. Results There were 517 OPSCC and 845 non-OP HNSCC. Cases were primarily male (81%), ever smokers (91%), with median age of 58 years and median follow-up of 3.1 years (IQR=1.4- 5.9). Among OPSCC, the risk of mortality was significantly lower among 184 HPV-related (i.e., p16+/HPV16+) compared to 333 HPV-unrelated (p16− and/or HPV16−) cases (HR=0.25, 95%CI=0.18- 0.34). Mortality was reduced among HPV-related OPSCC cases from the U.S., Europe, and Brazil (each p≤0.01) and after adjustment, remained significantly reduced (aHR=0.34, 95%CI=0.24- 0.49). Among non-OP HNSCC, neither p16 (aHR=0.83, 95%CI=0.60-1.14), HPV16 DNA (aHR=1.20, 95%CI=0.89-1.63), or p16+/HPV16+ (aHR=0.59, 95%CI=0.32-1.08) was a significantly predictor of mortality. When interaction was tested, the effect of HPV16/p16 was significantly different in OPSCC than non-OP HNSCC (p-interaction=0.02). Conclusion HPV-related OPSCCs had similar survival benefits across these three regions. Prognostic utility of HPV among non-OP HNSCC is limited so tumor HPV/p16 testing should not be routinely done among non-OP HNSCC.

Background Indicators of poor oral health, including smoking, have been associated with increased risk of head and neck squamous cell carcinoma, especially oropharyngeal carcinoma (OPSCC), yet few studies have examined whether this association is modified by HPV-status. Methods We used interview and tumor HPV-status data from a large population-based case-control study, the Carolina Head and Neck Cancer Study (CHANCE), to estimate the association between oral health indicators and smoking among 102 HPV-positive and 145 HPV-negative OPSCC cases and 1396 controls. HPV-status was determined by immunohistochemistry of p16INK4a expression. Unconditional multinomial logistic regression was used to estimate odds ratios (OR) for all oral health indictors adjusting for important covariates. Results Routine dental exams were associated with decreased risk of both HPV-negative [OR: 0.52; 95% confidence interval (CI): 0.35-0.76] and HPV-positive OPSCC (OR: 0.55; 95% CI: 0.36-.86). Tooth mobility (a proxy for periodontal disease) increased the risk of HPV-negative (OR: 1.70; 95% CI: 1.18-2.43) slightly more than HPV-positive OPSCC (OR: 1.45; 95% CI: 0.95-2.20). Ten or more pack-years of cigarette smoking was strongly associated with increased risk of HPV-negative OPSCC (OR: 4.26; 95% CI: 2.85-6.37) and less so with HPV-positive OPSCC (OR: 1.62; 95% CI: 1.10-2.38). Conclusions While HPV-positive and HPV-negative HNSCC differ significantly with respect to etiology and tumorigenesis, our findings suggest a similar pattern of association between poor oral health, frequency of dental examinations, and both HPV-positive and HPV-negative OPSCC. Future research is required to elucidate interactions between poor oral health, tobacco use, and HPV in the development of OPSCC.