With the convergence of promising biomarkers for lung cancer risk stratifications, and the increasing need for better eligibility assessment for lung cancer low-dose CT (LDCT) screening, the elephant ...in the room now is whether and how the implementation of biomarker-based lung cancer screening eligibility can be successfully achieved. This brief commentary provides an outline of key considerations for biomarker implementations for LDCT eligibility assessment and possible mitigation strategies. See related article by Jacobsen et al., p. 758.
In order to review the epidemiologic evidence concerning previous lung diseases as risk factors for lung cancer, a meta-analysis and systematic review was conducted.
Relevant studies were identified ...through MEDLINE searches. Using random effects models, summary effects of specific previous conditions were evaluated separately and combined. Stratified analyses were conducted based on smoking status, gender, control sources and continent.
A previous history of COPD, chronic bronchitis or emphysema conferred relative risks (RR) of 2.22 (95% confidence interval (CI): 1.66, 2.97) (from 16 studies), 1.52 (95% CI: 1.25, 1.84) (from 23 studies) and 2.04 (95% CI: 1.72, 2.41) (from 20 studies), respectively, and for all these diseases combined 1.80 (95% CI: 1.60, 2.11) (from 39 studies). The RR of lung cancer for subjects with a previous history of pneumonia was 1.43 (95% CI: 1.22-1.68) (from 22 studies) and for subjects with a previous history of tuberculosis was 1.76 (95% CI=1.49, 2.08), (from 30 studies). Effects were attenuated when restricting analysis to never smokers only for COPD/emphysema/chronic bronchitis (RR=1.22, 0.97-1.53), however remained significant for pneumonia 1.36 (95% CI: 1.10, 1.69) (from 8 studies) and tuberculosis 1.90 (95% CI: 1.45, 2.50) (from 11 studies).
Previous lung diseases are associated with an increased risk of lung cancer with the evidence among never smokers supporting a direct relationship between previous lung diseases and lung cancer.
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.
The use of liquid biopsies for cancer detection and management is rapidly gaining prominence
. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using ...cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations
. By contrast, large-scale epigenetic alterations-which are tissue- and cancer-type specific-are not similarly constrained
and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns.
To investigate the association between cannabis smoking and lung cancer risk, data on 2,159 lung cancer cases and 2,985 controls were pooled from 6 case‐control studies in the US, Canada, UK, and New ...Zealand within the International Lung Cancer Consortium. Study‐specific associations between cannabis smoking and lung cancer were estimated using unconditional logistic regression adjusting for sociodemographic factors, tobacco smoking status and pack‐years; odds‐ratio estimates were pooled using random effects models. Subgroup analyses were done for sex, histology and tobacco smoking status. The shapes of dose‐response associations were examined using restricted cubic spline regression. The overall pooled OR for habitual versus nonhabitual or never users was 0.96 (95% CI: 0.66–1.38). Compared to nonhabitual or never users, the summary OR was 0.88 (95%CI: 0.63–1.24) for individuals who smoked 1 or more joint‐equivalents of cannabis per day and 0.94 (95%CI: 0.67–1.32) for those consumed at least 10 joint‐years. For adenocarcinoma cases the ORs were 1.73 (95%CI: 0.75–4.00) and 1.74 (95%CI: 0.85–3.55), respectively. However, no association was found for the squamous cell carcinoma based on small numbers. Weak associations between cannabis smoking and lung cancer were observed in never tobacco smokers. Spline modeling indicated a weak positive monotonic association between cumulative cannabis use and lung cancer, but precision was low at high exposure levels. Results from our pooled analyses provide little evidence for an increased risk of lung cancer among habitual or long‐term cannabis smokers, although the possibility of potential adverse effect for heavy consumption cannot be excluded.
What's new?
Due to the potential adverse effect of cannabis smoking and its popularity, an investigation of its association with lung cancer risk is essential to help support appropriate regulations as well as health and social policy responses. The analysis presented here included the largest data set on cannabis and lung cancer risk to date. Its non‐linear dose‐response was examined using restricted cubic spline regression, a first in this line of work. Results provide little evidence for an increased risk of lung cancer among habitual or long‐term cannabis smokers, although the possibility of potential adverse effect for heavy consumption cannot be excluded.
Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese ...populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations.
To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up.
We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10
, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; p
=2·02 × 10
). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years.
We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations.
National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.
Inflammation is a facilitating process for multiple cancer types. It is believed to affect cancer development and progression through several etiologic pathways, including increased levels of DNA ...adduct formation, increased angiogenesis, and altered antiapoptotic signaling. This review highlights the application of inflammatory biomarkers in epidemiologic studies and discusses the various cellular mediators of inflammation characterizing the innate immune system response to infection and chronic insult from environmental factors. Included is a review of six classes of inflammation-related biomarkers: cytokines/chemokines, immune-related effectors, acute-phase proteins, reactive oxygen and nitrogen species, prostaglandins and cyclooxygenase-related factors, and mediators such as transcription factors and growth factors. For each of these biomarkers, we provide a brief overview of the etiologic role in the inflammation response and how they have been related to cancer etiology and progression within the literature. We provide a discussion of the common techniques available for quantification of each marker, including strengths, weaknesses, and potential pitfalls. Subsequently, we highlight a few under-studied measures to characterize the inflammatory response and their potential utility in epidemiologic studies of cancer. Finally, we suggest integrative methods for future studies to apply multifaceted approaches to examine the relationship between inflammatory markers and their roles in cancer development.
Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to cancer risk. However, epidemiologic findings have been inconsistent. The authors ...conducted meta-analyses of associations between genes in the base excision repair pathway and cancer risk, focusing on three key genes: 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease (APE1/APEX1), and x-ray repair cross-complementing group 1 (XRCC1). They found increased lung cancer risk among subjects carrying the OGG1 Cys/Cys genotype (odds ratio (OR) = 1.24, 95% confidence interval (CI): 1.01, 1.53), using 3,253 cases and 3,371 controls from seven studies; this is consistent with experimental evidence that this isoform exhibits decreased activity. They found a protective effect of the XRCC1 194Trp allele for tobacco-related cancers (OR = 0.86, 95% CI: 0.77, 0.95), using 4,895 cases and 5,977 controls from 16 studies; this is compatible with evidence of lower mutagen sensitivity for this allele. The XRCC1 399Gln/399Gln genotype was associated with increased risk of tobacco-related cancers among light smokers (OR = 1.38, 95% CI: 0.99, 1.94) but decreased risk among heavy smokers (OR = 0.71, 95% CI: 0.51, 0.99), suggesting effect modification by tobacco smoking. There was no association between cancer risk and the APE1/APEX1 Asp148Glu and XRCC1 Arg280His polymorphisms. Recommendations for future studies include pooling of individual data to facilitate evaluation of multigenic effects and detailed analysis of effect modification by environmental exposure.
Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden ...include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.
Lung cancer is the leading cause of cancer mortality globally. Early detection through risk-based screening can markedly improve prognosis. However, most risk models were developed in North American ...cohorts of smokers, whereas less is known about risk profiles for never-smokers, which represent a growing proportion of lung cancers, particularly in Asian populations.
Based on the China Kadoorie Biobank, a population-based prospective cohort of 512 639 adults with up to 12 years of follow-up, we built Asian Lung Cancer Absolute Risk Models (ALARM) for lung cancer mortality using flexible parametric survival models, separately for never and ever-smokers, accounting for competing risks of mortality. Model performance was evaluated in a 25% hold-out test set using the time-dependent area under the curve and by comparing model-predicted and observed risks for calibration.
Predictors assessed in the never-smoker lung cancer mortality model were demographics, body mass index, lung function, history of emphysema or bronchitis, personal or family history of cancer, passive smoking, and indoor air pollution. The ever-smoker model additionally assessed smoking history. The 5-year areas under the curve in the test set were 0.77 (95% confidence interval = 0.73 to 0.80) and 0.81 (95% confidence interval = 0.79 to 0.84) for ALARM-never-smokers and ALARM-ever smokers, respectively. The maximum 5-year risk for never and ever-smokers was 2.6% and 12.7%, respectively.
This study is among the first to develop risk models specifically for Asian populations separately for never and ever-smokers. Our models accurately identify Asians at high risk of lung cancer death and may identify those with risks exceeding common eligibility thresholds who may benefit from screening.
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