This review aimed to summarize the up-to-date evidence on non-genetic factors for the development of never smoking lung cancer (NSLC) and to explore reasons behind the conflicting results. Relevant literature was searched in three electronic databases (PubMed, Embase and Web of Science) from 1 January 2000–31 July 2022. Cohort studies that investigated non-genetic risk factors for primary lung cancer in never smokers were included. The effect of non-genetic factors about NSLC were summarized with pooled relative risk (RR) and 95 % confidence intervals (CIs) through meta-analysis or narrative description when unexplained statistical heterogeneity was observed. The Newcastle–Ottawa Scale was used to appraise the methodological quality of included studies. Sixty cohort studies were included, covering population from Asia, Europe and America. Most included studies (42, 70.0 %) were of high methodological quality. Over 50 years old (RR = 5.26), environmental tobacco smoke (Pooled RR = 1.30), Chronic obstructive pulmonary disease (COPD) (RR = 2.67), family history of lung cancer (Pooled RR = 1.83) and higher level of neutrophil-lymphocyte ratio (RR = 1.73) increased the risk of NSLC. Dairy foods consumption (RR = 0.79), isoflavone intake (Pooled RR = 0.65), and riboflavin intake (RR = 0.62) decreased the risk among female population. Inconsistency or unclear definition for never smokers and risk factors could be observed in included studies. Most life behavior factors associated with NSLC can be modified through lifestyle changes. Future cohort studies are suggested to adopt a clearer definition on never smokers and exposure, conducting subgroup analysis when evidence indicating there is heterogeneity between genders, and explore dose-response relationship between the identified factors and NSLC.
- • Eight categories of risk factors associated with NSLC have been summarized.
- • Over 50 years old, environmental tobacco smoke, COPD, family history of lung cancer and higher level of NLR increased the risk of NSLC.
- • Dairy foods consumption, isoflavone and riboflavin intake can decrease the risk among female population.
- • Research on NSLC has mainly focused on Asian without unified definition of exposure.
Lung cancer is one of the most common malignant tumors in the world, ranking as the second most commonly cancer globally in terms of incidence (11.4 %) and top 1 in terms of mortality (18.0 %) . An increasing trend has been observed in lung cancer incidence since 2011 . Despite cigarette smoking has been proved to be the predominant contributor to lung cancer development, the incidence of never smokers lung cancer (NSLC) is also increasing , accounting for approximately 10 %− 25 % of all lung cancer cases . With the increasing of NSLC in the young and/or female population , it is considered to be the seventh leading cause of cancer mortality in the entire population . Consensus has been made to regard NSLC as a distinct disease entity appeared , distinctive genetic subtypes have also been identified for NSLC .
Numerous factors have been reported to be related to NSLC. In addition to genetic factors, identifying modifiable factors can not only guide residents to improve their lifestyles , but also effectively identify potential medium/high risk groups of lung cancer to improve screening efficiency . Based on the available research, generally accepted risk factors included but not limited to exposure to radon, arsenic, asbestos, environmental tobacco smoke, family lung cancer history, menstrual and reproductive factors, mycobacterium tuberculosis and human papillomavirus (HPV) infection . Related protective factors are the intake of fruits, vegetables and physical activity . Other uncertain associations involved inflammatory diseases and diabetes .
Systematic reviews have been conducted to summarize risk factors for NSLC. The majority of them were published on or before 2018, with literature search being carried out on or before June 2017 . However, much new evidence has emerged since then with no systematic review summarizing them. For example, there is a new study published in 2019 showing that diabetes does not increase the risk of NSLC, contradicting to the results of previous studies . Therefore, an updated systematic review is needed to summarize the newly emerged evidence according to related consensus and recommendations . In addition, all previous reviews focused on one risk factor only, did not comprehensively summarize and categorize all these factors, and lacked comparisons between different sex. It may be inconvenient when users of evidence want to evaluate different types of risk factors at the same time.