Development and validation of a multivariable risk prediction model for head and neck cancer using the UK Biobank.

Head and neck cancer (HNC) is the eighth most common cancer in the UK, with over 12,000 new cases every year. The incidence of HNC is predicted to increase by 33% by 2035. Risk modelling produces personalised risk estimates for specific diseases, which can be used to inform education, screening programmes and recruitment to clinical trials.

Protein-altering germline mutations implicate novel genes related to lung cancer development.

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.

Long non-coding RNA dysregulation is a frequent event in non-small cell lung carcinoma pathogenesis.

Background: Long non-coding RNAs compose an important level of epigenetic regulation in normal physiology and disease. Despite the plethora of publications of lncRNAs in human cancer, the landscape is still unclear.

Methods: Microarray analysis in 44 NSCLC paired specimens was followed by qPCR-based validation in 29 (technical) and 38 (independent) tissue pairs.

Highly aggressive undifferentiated small round blue cell tumor of foot with unique SMARCA1, KAT6A and NAV3 mutations.

Malignancies characterized histologically by high-grade monotonous small round blue cells (SRBCs) belong to a heterogeneous group of neoplasms often referred to as Ewing family of tumors. The most common molecular confirmation of these neoplasms is by fusions between EWSR1 gene on chromosome 22 and the ETS family of transcription factors, including FLI1 gene (11q24) and the ERG (21q22), that are implicated in the development of different tissues as well as cancer progression. In this article, we present a case of highly aggressive extraskeletal SRBC tumor involving the foot of a 24-year-old male with sole molecular findings of mutations in KAT6A, NAV3 and SMARCA1 genes with high expression of soft tissue markers (COL1A1, COL1A2, COL3A1) and MYC mRNA.

Evaluation of a health service adopting proactive approach to reduce high risk of lung cancer: The Liverpool Healthy Lung Programme.

Objectives: This Liverpool Healthy Lung Programme is a response to high rates of lung cancer and respiratory diseases locally and aims to diagnose lung cancer at an earlier stage by proactive approach to those at high risk of lung cancer. The objective of this study is to evaluate the programme in terms of its likely effect on mortality from lung cancer and its delivery to deprived populations.

Methods: Persons aged 58-75 years, with a history of smoking or a diagnosis of chronic obstructive pulmonary disease (COPD) according to general practice records were invited for lung health check in a community health hub setting.

DPP-4 Inhibitor Dose Selection According to Manufacturer Specifications: A Contemporary Experience From UK General Practice.

Recently, 2 dipeptidyl peptidase-4 (DPP-4) inhibitors, sitagliptin and saxagliptin, adjusted dosing specification from creatinine clearance to glomerular filtration rate, more typically reported in routine laboratory tests. This cross-sectional study examines all DPP-4 inhibitor initiations that require dose adjustment and the dose selection using data from UK general practice. Results indicate that 34% of patients taking a nonlinagliptin DPP-4 inhibitor were given a higher dose and 11% a lower dose than specified in the Summary of Product Characteristics.

Probability of cancer in lung nodules using sequential volumetric screening up to 12 months: the UKLS trial.

Background: Estimation of the clinical probability of malignancy in patients with pulmonary nodules will facilitate early diagnosis, determine optimum patient management strategies and reduce overall costs.

Methods: Data from the UK Lung Cancer Screening trial were analysed. Multivariable logistic regression models were used to identify independent predictors and to develop a parsimonious model to estimate the probability of lung cancer in lung nodules detected at baseline and at 3-month and 12-month repeat screening.

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development.

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study.

Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis.

Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear.

Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses.

Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population.

Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population.

Common Polymorphisms in Relation to Survival among Small Cell Lung Cancer Patients: A Multicenter Study from the International Lung Cancer Consortium.

DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients.

Age at menopause and hormone replacement therapy as risk factors for head and neck and oesophageal cancer (Review).

There were ~986,000 cases of head and neck cancer (HNC) and oesophageal cancer diagnosed worldwide in 2012. The incidence of these types of cancer is much higher in males than females, although this disparity decreases in the elderly population, suggesting a role for hormones as a risk factor. This systematic review investigates the potential role of female hormones [age at menopause and use of hormone replacement therapy (HRT)] as risk factors for HNC/oesophageal squamous cell carcinoma (SCC).

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci.

Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study.

Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer.

Methods And Findings: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls.

mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer.

Deregulation of mitotic spindle genes has been reported to contribute to the development and progression of malignant tumours. The aim of the present study was to explore the association between the expression profiles of Aurora kinases (, and ), cytoskeleton-associated protein 5 (), discs large-associated protein 5 (), kinesin-like protein 11 (), microtubule nucleation factor (), monopolar spindle 1 kinase (), and β-tubulins () and () genes and clinicopathological characteristics in human non-small cell lung carcinoma (NSCLC). Reverse transcription-quantitative polymerase chain reaction-based RNA gene expression profiles of 132 NSCLC and 44 adjacent wild-type tissues were generated, and Cox's proportional hazard regression was used to examine associations.

Risk assessment in relation to the detection of small pulmonary nodules.

The National Lung Cancer Screening trial (NLST) demonstrated that individuals assigned to the LDCT screening arm had a 20% lower mortality than those who were assigned to the conventional chest radiography. The NLST was thoroughly analyzed by the US Preventive Task Force on CT Screening and they recommended that lung cancer screening should be implemented. A number of other countries have also recommended implementation, whilst others are awaiting the outcome of the NELSON Trial.

Aurora B expression modulates paclitaxel response in non-small cell lung cancer.

Background: Taxanes are mitotic poisons widely used in the treatment of non-small cell lung cancer (NSCLC), however, little is known about potential molecular modulators of response to these compounds. Aurora B (AURKB) is a critical regulator of the mitotic spindle assembly, previously shown overexpressed in NSCLC. Here we investigated the hypothesis that AURKB expression modulates the efficacy of taxanes in NSCLC cells.

Utilizing Lung Cancer Risk Prediction Models to Promote Smoking Cessation: Two Randomized Controlled Trials.

Purpose: The current project sought to examine whether delivery of lung cancer risk projections (calculated using the Liverpool Lung Project [LLP] risk model) predicted follow-up smoking status.

Design: Two single-blinded randomized controlled trials.

Setting: Stop Smoking Services in Liverpool (United Kingdom).

The causal relevance of body mass index in different histological types of lung cancer: A Mendelian randomization study.

Body mass index (BMI) is inversely associated with lung cancer risk in observational studies, even though it increases the risk of several other cancers, which could indicate confounding by tobacco smoking or reverse causality. We used the two-sample Mendelian randomization (MR) approach to circumvent these limitations of observational epidemiology by constructing a genetic instrument for BMI, based on results from the GIANT consortium, which was evaluated in relation to lung cancer risk using GWAS results on 16,572 lung cancer cases and 21,480 controls. Results were stratified by histological subtype, smoking status and sex.

Incorporating epistasis interaction of genetic susceptibility single nucleotide polymorphisms in a lung cancer risk prediction model.

Incorporation of genetic variants such as single nucleotide polymorphisms (SNPs) into risk prediction models may account for a substantial fraction of attributable disease risk. Genetic data, from 2385 subjects recruited into the Liverpool Lung Project (LLP) between 2000 and 2008, consisting of 20 SNPs independently validated in a candidate-gene discovery study was used. Multifactor dimensionality reduction (MDR) and random forest (RF) were used to explore evidence of epistasis among 20 replicated SNPs.

Associated Links Among Smoking, Chronic Obstructive Pulmonary Disease, and Small Cell Lung Cancer: A Pooled Analysis in the International Lung Cancer Consortium.

Background: The high relapse and mortality rate of small-cell lung cancer (SCLC) fuels the need for epidemiologic study to aid in its prevention.

Methods: We included 24 studies from the ILCCO collaboration. Random-effects panel logistic regression and cubic spline regression were used to estimate the effects of smoking behaviors on SCLC risk and explore their non-linearity.