Methylation-derived Neutrophil-to-Lymphocyte Ratio and Lung Cancer Risk in Heavy Smokers

Our plain-English summary of Methylation-derived Neutrophil-to-Lymphocyte Ratio and Lung Cancer Risk in Heavy Smokers, by L. Grieshober, S. Graw, M.J. Barnett, et al (Cancer Prevention Research, 2018).

The study

• Authors: L. Grieshober, S. Graw, M.J. Barnett, M.D. Thornquist, G.E. Goodman, C. Chen, D.C. Koestler, C.J. Marsit, J.A. Doherty
• Journal: Cancer Prevention Research
• Published: 2018;11(11):727-734
• Type of article: Randomized trial
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The neutrophil-to-lymphocyte ratio (NLR) is a biomarker that indicates systemic inflammation and can be estimated using array-based DNA methylation data as methylation-derived NLR (mdNLR). We assessed the relationship between prediagnosis mdNLR and lung cancer risk in a nested case-control study in the β-Carotene and Retinol Efficacy Trial (CARET) of individuals at high risk for lung cancer due to heavy smoking or substantial occupational asbestos exposure. We matched 319 incident lung cancer cases to controls based on age at blood draw, smoking, sex, race, asbestos, enrollment year, and time at risk. We computed mdNLR using the ratio of predicted granulocyte and lymphocyte proportions derived from DNA methylation signatures in whole blood collected prior to diagnosis (median 4.4 years in cases). Mean mdNLR was higher in cases than controls (2.06 vs. 1.86, P = 0.03). Conditional logistic regression models adjusted for potential confounders revealed a 21% increased risk of lung cancer per unit increase in mdNLR [OR 1.21; 95% confidence interval (CI) 1.01-1.45]. A 30% increased risk of non-small cell lung cancer (NSCLC) was observed for each unit increase in mdNLR (n = 240 pairs; OR 1.30, 95% CI, 1.03-1.63), and there was no statistically significant association between mdNLR and small-cell lung cancer risk. The mdNLR-NSCLC association was most pronounced in those with asbestos exposure (n = 42 male pairs; OR 3.39; 95% CI, 1.32-8.67). A better understanding of the role of mdNLR in lung cancer etiology may improve prevention and detection of lung cancer. Cancer Prev Res; 11(11); 727-34. ©2018 AACR.

©2018 American Association for Cancer Research.

In plain English

This nested case-control study used stored blood from CARET, a trial of heavy smokers that also enrolled men with occupational asbestos exposure who smoked. The authors matched 319 people who later developed lung cancer to 319 who did not, on factors including age, sex, smoking status and history of occupational asbestos exposure. Using DNA methylation in blood drawn before diagnosis (a median of 4.4 years earlier in cases), they estimated an inflammation marker called the methylation-derived neutrophil-to-lymphocyte ratio (mdNLR). Mean mdNLR was 2.06 in cases and 1.86 in controls (p=0.03). Each one-unit rise in mdNLR was associated with higher odds of lung cancer (odds ratio 1.21, 95% CI 1.01 to 1.44) and of non-small cell lung cancer (1.30, 1.03 to 1.63). The association with small cell lung cancer was not statistically significant. The strongest association was among asbestos-exposed participants, all of them men: 2.13 (1.12 to 4.05) for all lung cancers and 3.39 (1.32 to 8.67) for non-small cell lung cancer. The authors concluded that higher mdNLR is associated with increased lung cancer risk in heavy smokers. They noted small subgroups, possibly limited generalizability, and no external replication.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Nested case-control study (1:1 matched) within a randomized chemoprevention trial, analysed with conditional logistic regression
• Who was studied: 319 incident lung cancer cases (240 non-small cell, 68 small cell, 11 unknown type) and 319 matched controls from the US multicenter CARET trial. The trial enrolled heavy smokers aged 50-69 and men aged 45-69 with occupational asbestos exposure who were current or former heavy smokers. Blood was collected between 1994 and 1997, and endpoints were collected from 1985 to 2005. Participants were about 64 years old at blood draw; 97% were white, 66% male, and 65% current smokers.
• Exposure: The main exposure was the methylation-derived neutrophil-to-lymphocyte ratio (mdNLR), estimated from DNA methylation in whole blood collected before diagnosis. All participants were heavy smokers. Occupational asbestos exposure was a matching factor and a subgroup. The article does not describe fiber types, jobs or asbestos doses.
• Main results:
  • Mean mdNLR was 1.86 (SD 0.90) in controls versus 2.06 (SD 1.31) in cases, p=0.03
  • All lung cancers, adjusted for age, pack years, cigarettes per day and BMI: each unit increase in mdNLR was associated with a 21% increased risk (OR 1.21, 95% CI 1.01-1.44)
  • Non-small cell lung cancer (240 pairs): OR 1.30 (95% CI 1.03-1.63) per unit increase in mdNLR
  • Small cell lung cancer (68 pairs): no statistically significant association (Table 2: OR 1.06, 95% CI 0.77-1.47). The authors said this may reflect the smaller sample size.
  • Participants with a history of asbestos exposure: OR 2.13 (95% CI 1.12-4.05) for all lung cancers. Participants without asbestos exposure: OR 1.09 (0.90-1.32) (Table 2).
  • Asbestos-exposed participants, non-small cell lung cancer (42 male pairs): OR 3.39 (95% CI 1.32-8.67). Non-exposed participants: OR 1.15 (0.92-1.45) (Table 2).
  • All asbestos-exposed workers in the study were male. Non-small cell lung cancer associations were similar for men (OR 1.15, 0.88-1.51) and women (OR 1.22, 0.75-1.98) without asbestos exposure, so the authors attributed the stronger association in men to the asbestos-exposed subset.
  • Other subgroups: males OR 1.30 (1.04-1.63) and active intervention arm OR 1.70 (1.12-2.58) for all lung cancers. Associations were similar but no longer statistically significant within strata of smoking status or time at risk.
• The authors' conclusion: The authors concluded that elevated pre-diagnosis mdNLR is associated with an increased risk of lung cancer in heavy smokers at high risk. They suggested that NLR may convey information about lung cancer risk and causes, especially among those with a history of asbestos exposure.
• Limitations the authors state:
  • The sample consisted only of heavy smokers who chose to join the CARET trial, so results may have limited generalizability
  • Small subgroup sizes may have limited statistical power
  • No direct blood-cell-count (cytological) NLR measurements were available
  • Results have not been replicated in an external data set

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Biomarker, Inflammation, nested case-control study, Asbestos Exposure, confidence interval, Non-Small Cell Lung Cancer, Etiology.

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