Showing papers by "Andy R Ness published in 2019"

Shared heritability and functional enrichment across six solid cancers

Abstract: Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Investigating the effects of lycopene and green tea on the metabolome of men at risk of prostate cancer: The ProDiet randomised controlled trial

Abstract: Lycopene and green tea consumption have been observationally associated with reduced prostate cancer risk, but the underlying mechanisms have not been fully elucidated. We investigated the effect of factorial randomisation to a 6-month lycopene and green tea dietary advice or supplementation intervention on 159 serum metabolite measures in 128 men with raised PSA levels (but prostate cancer-free), analysed by intention-to-treat. The causal effects of metabolites modified by the intervention on prostate cancer risk were then assessed by Mendelian randomisation, using summary statistics from 44,825 prostate cancer cases and 27,904 controls. The systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R2 = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [β (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (β: -0.62; -1.03, -0.02; p = 0.004), pyruvate (β: -0.56; -0.95, -0.16; p = 0.006) and docosahexaenoic acid (β: -0.50; -085, -0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (β: -0.65; -1.04, -0.26; p = 0.001 and β: -0.59; -1.01, -0.18; p = 0.006). A genetically instrumented SD increase in pyruvate increased the odds of prostate cancer by 1.29 (1.03, 1.62; p = 0.027). An intervention to increase lycopene intake altered the serum metabolome of men at risk of prostate cancer. Lycopene lowered levels of pyruvate, which our Mendelian randomisation analysis suggests may be causally related to reduced prostate cancer risk.

Association between Comorbidity and Survival in Head and Neck Cancer: Results from Head and Neck 5000

Abstract: Background People with head and neck cancer have higher comorbidity levels but it remains unclear if pretreatment comorbidity is an independent prognosticator in head and neck cancer. Methods Survival analyses were performed using data from participants in a UK multicentre cohort study with cancers of the oral cavity (n = 668), oropharynx (n = 1074), and larynx (n = 530). Survival analyses were incrementally adjusted for age, sex, marital status, income, education, stage, alcohol, and smoking. Results After adjusting for demographic, clinical, and behavioral confounders, higher baseline comorbidity was associated with reduced overall survival (mild comorbidity HR = 1.4, 95% CI = 1.1, 1.7; moderate comorbidity HR = 1.7, 95% CI = 1.3, 2.2; severe comorbidity HR = 2.8, 95% CI = 1.9, 4.; P-trend Conclusions Our findings suggest that comorbidity is an independent prognosticator for overall survival in head and neck cancer. Comorbid illnesses should be considered in the assessment and treatment planning of people with head and neck cancer.

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

Abstract: L.K. is a fellow in the Canadian Institutes of Health Research (CIHR) Strategic Training in Advanced Genetic Epidemiology (STAGE) programme and is supported by the CIHR Doctoral Research Award from the Frederick Banting and Charles Best Canada Graduate Scholarships (GSD-137441). Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by the National Institutes of Health (U19-CA148127, CA148127S1). Genotyping for the TRICL-ILCCO OncoArray was supported by in-kind genotyping at Centre for Inherited Disease Research (CIDR) (26820120008i-0–6800068-1). Genotyping for the Head and Neck Cancer OncoArray performed at CIDR was funded by the US National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780–0. CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03–0365 and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02–67 and FICYT IB09–133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Publica. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health (NIH)/National Cancer Institute (NCI): UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989 (PI Doherty). The Liverpool Lung Project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578 and CA074386. The Multiethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464 and CA148127. The work performed in MSH-PMH study was supported by the Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997) and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. Dr Melinda Aldrich is supported by the by NIH/National Cancer Institute 5K07CA172294. The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Kentucky Lung Cancer Research Initiative (KLCRI) was supported by the Department of Defense (Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program) under award number: 10153006 (W81XWH-11–1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The research undertaken by M.D.T., L.V.W. and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). The Tampa study was funded by Public Health Service grants P01-CA68384 and R01-DE13158 from the National Institutes of Health. The University of Pittsburgh head and neck cancer case–control study is supported by US National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP; grants 04/12054–9 and 10/51168–0). The authors thank all the members of the GENCAPO team. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707–10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The Alcohol-Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission’s fifth framework programme (QLK1– 2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) awards IG 2011 10491 and IG 2013 14220 to S.B. and by Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97–0222), with additional funding from Fondo para la Investigacion Cientifica y Tecnologica (Argentina) and the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (01/01768–2). The IARC Central Europe study was supported by the European Commission’s INCO-COPERNICUS Program (IC15-CT98–0332), US NIH/National Cancer Institute grant CA92039 and World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662 and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG SANCO) and the International Agency for Research on Cancer.

Dietary restriction during the treatment of cancer: results of a systematic scoping review.

Abstract: Diets that restrict energy or macronutrient intake (e.g. fasting/ketogenic diets (KDs)) may selectively protect non-tumour cells during cancer treatment. Previous reviews have focused on a subset of dietary restrictions (DR) or have not performed systematic searches. We conducted a systematic scoping review of DR at the time of cancer treatment. MEDLINE, Embase, CINAHL, AMED and Web of Science databases were searched for studies of adults undergoing DR alongside treatment for cancer. Search results were screened against inclusion/exclusion criteria. Data from included studies were extracted by two independent reviewers. Results were summarised narratively. Twenty-three independent studies (34 articles), with small sample sizes, met the inclusion criteria. Four categories were identified: KDs (10 studies), fasting (4 studies), protein restriction (5 studies) and combined interventions (4 studies). Diets were tolerated well, however adherence was variable, particularly for KDs. Biomarker analysis in KDs and fasting resulted in the expected increase in ketones or reduction in insulin-like growth factors, respectively, however they did not reduce glucose. Future research with adequately powered studies is required to test the effects of each DR intervention on treatment toxicities and outcomes. Further research into improving adherence to DR may improve the feasibility of larger trials.

Validation and characterisation of a DNA methylation alcohol biomarker across the life course.

Abstract: Recently, an alcohol predictor was developed using DNA methylation at 144 CpG sites (DNAm-Alc) as a biomarker for improved clinical or epidemiologic assessment of alcohol-related ill health. We validate the performance and characterise the drivers of this DNAm-Alc for the first time in independent populations. In N = 1049 parents from the Avon Longitudinal Study of Parents and Children (ALSPAC) Accessible Resource for Integrated Epigenomic Studies (ARIES) at midlife, we found DNAm-Alc explained 7.6% of the variation in alcohol intake, roughly half of what had been reported previously, and interestingly explained a larger 9.8% of Alcohol Use Disorders Identification Test (AUDIT) score, a scale of alcohol use disorder. Explanatory capacity in participants from the offspring generation of ARIES measured during adolescence was much lower. However, DNAm-Alc explained 14.3% of the variation in replication using the Head and Neck 5000 (HN5000) clinical cohort that had higher average alcohol consumption. To investigate whether this relationship was being driven by genetic and/or earlier environment confounding, we examined how earlier versus concurrent DNAm-Alc measures predicted AUDIT scores. In both ARIES parental and offspring generations, we observed associations between AUDIT and concurrent, but not earlier DNAm-Alc, suggesting independence from genetic and stable environmental contributions. The stronger relationship between DNAm-Alcs and AUDIT in parents at midlife compared to adolescents despite similar levels of consumption suggests that DNAm-Alc likely reflects long-term patterns of alcohol abuse. Such biomarkers may have potential applications for biomonitoring and risk prediction, especially in cases where reporting bias is a concern.

Closer to the Truth on National Fistula Prevalence After Unilateral Complete Cleft Lip and Palate Repair? The Cleft Care UK Study.

Abstract: Objectives:To (1) determine the prevalence of nonperialveolar palatal fistula up to age 5 following repair of unilateral cleft lip and palate (UCLP) in the United Kingdom, (2) examine the associati...

Associations between physical activity and asthma, eczema and obesity in children aged 12-16: an observational cohort study.

Abstract: Objectives To compare the physical activity of adolescents with three common long-term conditions (asthma, eczema and obesity) with adolescents without these conditions. Design Cross-sectional and longitudinal analyses of adolescents at ages 12, 14 and 16 in a large UK cohort study. Setting The Avon Longitudinal Study of Parents and Children. Participants 6473 adolescents with complete accelerometer data at at least one time point. Methods Mean minutes of moderate to vigorous intensity physical activity (MVPA) and sedentary time per day were derived from accelerometer-based measurements at ages 12, 14 and 16. Obesity was defined at each time point from height and weight measurements. Parents reported doctor-assessed asthma or eczema. Cross-sectional and longitudinal regression models examined any differences in MVPA or sedentary time for adolescents with asthma, eczema or obesity compared with those without. Results In longitudinal models, boys engaged in an average of 69.7 (95% CI 67.6 to 71.7) min MVPA at age 12, declining by 3.1 (95% CI 2.6 to 3.6) min/year while girls’ average MVPA was 47.5 (95% CI 46.1 to 48.9) min at age 12, declining by 1.8 (95% CI 1.5 to 2.1) min/year. There was no strong evidence of differences in physical activity patterns of those with and without asthma or eczema. Obese boys engaged in 11.1 (95% CI 8.7 to 13.6) fewer minutes of MVPA, and obese girls in 5.0 (95% CI 3.3 to 6.8) fewer minutes than their non-obese counterparts. Cross-sectional models showed comparable findings. Conclusions Mean minutes of MVPA per day did not differ between adolescents with asthma or eczema and those without, but obese adolescents engaged in fewer minutes of MVPA. Findings reinforce the need for strategies to help obese adolescents be more active but suggest no need to develop bespoke physical activity strategies for adolescents with mild asthma or eczema.

Publisher Correction: Shared heritability and functional enrichment across six solid cancers.

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Squamous cell carcinoma of the nasal cavity: A descriptive analysis of cases from the head and neck 5000 study

Abstract: Objectives This paper aims to provide contemporary epidemiological data on squamous cell carcinoma (SCC) of the nasal cavity, which represents a rare type of head and neck cancer. Design, Setting & Participants A descriptive analysis of people with nasal cavity SCC treated with curative intent from the Head and Neck 5000 study; a multicentre clinical cohort study of people from the UK with head and neck cancer. People with tumours of the nasopharynx, paranasal sinuses and other sub‐sites of the head and neck were excluded. Main outcome measures Demographic data and treatment details are presented for all participants. The main outcomes were overall survival and survival according to categories of characteristics (eg, smoker vs non‐smoker); these were explored using Kaplan‐Meier plots. Results Thirty people with nasal cavity SCC were included in the study, of which most were male (67%) and current or ex‐smokers (70%). The majority (70%) presented with early‐stage (T1/2, N0) tumours. Cervical lymph node metastases at presentation were rare, occurring in only one person. Nine people died during the follow‐up period (30%). Worse survival outcomes were seen in people with moderate or severe co‐morbidities. Conclusions This paper provides epidemiological data on nasal cavity SCC in the UK. Patterns of disease and survival outcomes are described, identifying high‐risk groups. Further studies should explore whether primary treatment modality alters survival.

Dietary behaviors and survival in people with head and neck cancer: Results from Head and Neck 5000

Abstract: Background The association between diet and head and neck cancer (HNC) survival is unclear. Methods Cox proportional hazard models measured the association between fruit, vegetable, and deep-fried food intake and HNC overall survival adjusting for clinical, social and lifestyle variables including smoking, alcohol, and HPV status. Results Fruit and vegetable intake and improved survival were associated in minimally adjusted analyses. Following adjustment for smoking and alcohol consumption (fully adjusted analyses), the association with survival disappeared for fruit (HR 0.91, 95% CI 0.67, 1.23; P for trend = .55) and attenuated for vegetables (HR 0.79, 95% CI 0.61, 1.03; P for trend = .04). We observed no association between survival and deep-fried food intake in minimally adjusted or fully adjusted analyses (HR 0.88 95% CI 0.72, 1.07; P for trend = .13). Conclusions Vegetable intake and HNC survival are modestly associated. There is some confounding by tobacco and alcohol consumption.

Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer

Abstract: Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conduct epigenome-wide association studies (EWAS) of these factors and ~3-year survival using Illumina Methylation EPIC blood DNA methylation profiles from 409 individuals in the Head and Neck 5000 (HN5000) study. CpG site associations below our multiple-testing threshold (PBonferroni

Is There a Correlation Between Nasolabial Appearance and Dentoalveolar Relationships in Patients With Repaired Unilateral Cleft Lip and Palate

Abstract: Objective:To determine whether a relationship exists between the aesthetic scores given to photographic records of the nasolabial region of patients with repaired unilateral cleft lip and palate (U...

A feasibility randomised controlled trial of short-term fasting prior to CAPOX chemotherapy for stage 2/3 colorectal cancer: SWiFT protocol.

Abstract: Capecitabine and oxaliplatin (CAPOX) chemotherapy is a standard treatment for stage 2/3 colorectal cancer. Treatment is associated with dose-limiting toxicities such as neutropenia, vomiting, diarrhoea, and stomatitis. Short-term fasting prior to chemotherapy may help protect normal cells from the toxic effects of chemotherapy by allowing them to conserve energy for maintenance and repair. However, there is a lack of evidence to support the efficacy of short-term fasting in protecting against chemotherapy-related toxicities in humans, and it is not known whether people due to undergo chemotherapy will be willing and able to follow a short-term fast. Preliminary data confirming this is feasible are required before adequately powered trials can be designed and conducted. The short-term, water only, fasting trial (SWiFT) is a two-armed feasibility randomised controlled trial, aiming to recruit 30 people scheduled to begin routine treatment with CAPOX chemotherapy for stage 2/3 colorectal cancer. Participants will be randomly allocated, in a 1:1 ratio, to either a 36-h fast or standard dietary advice prior to chemotherapy administration for the first 3 cycles of chemotherapy. The primary outcome measures will assess the feasibility of the trial and include: adherence to intervention, recruitment, retention, and data completion rates as well as the acceptability of the intervention which will be qualitatively assessed. The secondary outcome measures aim to provide further information on possible outcomes of interest for a definitive trial and include side effects of chemotherapy, quality of life, markers of cellular metabolism and inflammation, appetite, and sarcopenia. It is not known whether it is possible to recruit to a trial of short-term fasting in this population, or whether participants would be able to adhere to the intervention. Therefore, we aim to test the feasibility of a pre-chemotherapy, 36-h, water-only fast in people receiving CAPOX chemotherapy for stage 2/3 colorectal cancer. This trial has been registered with the ISRCTN Registry. Trial registration no: ISRCTN17994717. Date of registration: 23 October 2018. URL: http://www.isrctn.com/ISRCTN17994717

Validation and characterization of a DNA methylation alcohol biomarker across the life course

Abstract: Recently, an alcohol predictor was developed using DNA methylation at 144 CpG sites (DNAm-Alc) as a biomarker for improved clinical or epidemiologic assessment of alcohol-related ill health. We validate the performance and characterize the drivers of this DNAm-Alc for the first time in independent populations. In N=1,049 parents from the Avon Longitudinal Study of Parents and Children (ALSPAC) Accessible Resource for Integrated Epigenomic Studies (ARIES) at midlife, we found DNAm-Alc explained 7.6% of the variation in alcohol intake, roughly half of what had been reported previously, and interestingly explained a larger 9.8% of AUDIT score, a scale of alcohol use disorder. Explanatory capacity in participants from the offspring generation of ARIES measured during adolescence was much lower. However, DNAm-Alc explained 14.3% of the variation in replication using the Head and Neck 5000 (HN5000) clinical cohort that had higher average alcohol consumption. To investigate whether this relationship was being driven by genetic and/or earlier environment confounding we examined how earlier vs. concurrent DNAm-Alc measures predicted AUDIT scores. In both ARIES parental and offspring generations, we observed associations between AUDIT and concurrent, but not earlier DNAm-Alc, suggesting independence from genetic and stable environmental contributions. The stronger relationship between DNAm-Alcs and AUDIT in parents at midlife compared to adolescents despite similar levels of consumption suggests that DNAm-Alc likely reflects long-term patterns of alcohol abuse. Such biomarkers may have potential applications for biomonitoring and risk prediction, especially in cases where reporting bias is a concern.

Outcome Measures in UCLP: The Modified 5-Year-Olds'-Index-Development and Reliability.

Abstract: Objective:Can we reliably discriminate severity within the existing categories of the 5-Year-Olds’ Index?Design:Retrospective method comparison and development study.Setting:School of Oral and Dent...