Elsevier

European Journal of Cancer

Volume 48, Issue 13, September 2012, Pages 1957-1968
European Journal of Cancer

Increased risk of lung cancer in individuals with a family history of the disease: A pooled analysis from the International Lung Cancer Consortium

https://doi.org/10.1016/j.ejca.2012.01.038 Get rights and content

Abstract

Background and methods

Familial aggregation of lung cancer exists after accounting for cigarette smoking. However, the extent to which family history affects risk by smoking status, histology, relative type and ethnicity is not well described. This pooled analysis included 24 case-control studies in the International Lung Cancer Consortium. Each study collected age of onset/interview, gender, race/ethnicity, cigarette smoking, histology and first-degree family history of lung cancer. Data from 24,380 lung cancer cases and 23,305 healthy controls were analysed. Unconditional logistic regression models and generalised estimating equations were used to estimate odds ratios and 95% confidence intervals.

Results

Individuals with a first-degree relative with lung cancer had a 1.51-fold increase in the risk of lung cancer, after adjustment for smoking and other potential confounders (95% CI: 1.39, 1.63). The association was strongest for those with a family history in a sibling, after adjustment (odds ratios (OR) = 1.82, 95% CI: 1.62, 2.05). No modifying effect by histologic type was found. Never smokers showed a lower association with positive familial history of lung cancer (OR = 1.25, 95% CI: 1.03, 1.52), slightly stronger for those with an affected sibling (OR = 1.44, 95% CI: 1.07, 1.93), after adjustment.

Conclusions

The occurrence of lung cancer among never smokers and similar magnitudes of the effect of family history on lung cancer risk across histological types suggests familial aggregation of lung cancer is independent of those risks associated with cigarette smoking. While the role of genetic variation in the aetiology of lung cancer remains to be fully characterised, family history assessment is immediately available and those with a positive history represent a higher risk group.

Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide.1 Current and former smokers are at greatest risk, but lung cancer does occur among non-smokers, with varying rates across countries.2 The association between cigarette smoking and increased risk of lung cancer is now undisputed. Despite this, less than 20% of smokers develop lung cancer, suggesting that the effect of tobacco smoke exposure is modified by other variables, including individual susceptibility.3 The search for a gene or genes associated with susceptibility is still nascent. Genome wide association studies have independently reported chromosomal region 15q24-25.1, which contains nicotinic acetylcholine receptor sub-unit genes, to be associated with increased risk of lung cancer in ever smokers.4, 5, 6 These findings have been replicated among individuals with a family history of lung cancer, and the relative risk of lung cancer associated with markers in this region are much higher for familial cases compared to the relative risk observed among sporadic cases.7 Linkage analysis in families with aggregation of lung cancer also described a region on chromosome 6q23-25 associated with risk of lung cancer.8 The clinical significance of these findings is still unclear. In the meantime, lung cancer risk models using epidemiologic data have been developed, and the most parsimonious models for both ever and never smokers include a family history of cancer variable.9

Developing risk models for lung cancer are vital, given the report from the National Lung Screening Trial (NLST), which suggests that low-dose helical computed tomography (CT) scans may cut deaths from lung cancer by 20%.10 It should be noted these findings were among individuals 55–74 years of age, with a smoking history of 30+ pack years, and should not be extended to other populations.11 A crucial component to a successful screening programme is defining a population at high risk. Until screening protocols have been developed, the main recommendations to reduce the risk of lung cancer remain smoking avoidance, cessation and limiting exposure to known carcinogens (e.g. radon, environmental tobacco smoke).12

Relatives of individuals with lung cancer may be at higher risk of lung cancer than the general population. Various smaller studies have provided evidence that familial aggregation of lung cancer exists after adjusting for the aggregation of cigarette smoking and type of family relatedness.13, 14 In this study, we performed a pooled analysis of data contributed to the International Lung Cancer Consortium (ILCCO), in order to describe in greater detail familial aggregation of lung cancer. Given the large sample size of this analysis, we were able to perform subgroup analyses examining risk by gender, race/ethnicity, histologic type, age at diagnosis and smoking status.

Section snippets

Study population

The ILCCO was established in 2004, with the goal of sharing compatible data from lung cancer epidemiology studies to achieve greater power than from single studies alone. To date, 57 lung cancer studies are included in ILCCO. Further details regarding the aims, guidelines and policies of ILCCO are described in Hung et al.15

To be included in the main analysis of familial aggregation of lung cancer, the following minimum criteria were set. Each study must have collected data regarding the lung

Results

Information regarding family history of cancer in first-degree relatives was available for 24,380 cases and 23,399 controls. Of the 57 studies which have contributed data to ILCCO, 24 studies met inclusion criteria for the analysis. Studies from North America accounted for 54% of the datasets analysed (n = 13), eight were from Europe and three were from Asia and Oceania (Table 1). Population-based controls were ascertained by 11 studies, eight studies employed hospital-based controls, and five

Discussion

The results presented here represent the most comprehensive analysis of the association between family history of lung cancer and lung cancer since the first strong evidence of familial aggregation was reported nearly 50 years ago.17 To date, this is the largest pooled analysis which incorporated a traditional case-control analysis and also used data from individual family members to examine risk adjusted for gender and smoking status of each relative. Individuals with family history in a

Conflict of interest statement

The authors declare no conflicts of interest exist. They do wish to acknowledge the following support:

ILCCO data management is supported by Canadian Cancer Society (CCSRI no. 020214) and Cancer Care Ontario Research Chair Award.

M.L.C.: NIH K07 CA125203-01A2.

A.G.S.: NIH R01CA060691, NIH R01CA87895, NIH N01-PC35145, NIH P30CA22453.

D.C.C.: Grants: NIH (NCI) RO1CA74386 and P50 CA090578.

G.R.: Grant number 2003159 from the Bi-national Israel US Science Foundation (BSF).

H.B. and H.M.: ESTHER study was

Acknowledgements

Drs. Cote, Liu, Etzel and Hung had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

The contributions of the following individuals: Christa Stegmaier, Hartwig Ziegler, Sonja Wolf and Volker Herrmann (ESTHER study) Urvi Mujumdar and Radhai Rastogi (MSKCC), Lynda Forbes, Yvonne Bush, Kelly Montgomery and Angela Wenzlaff (WSU), Dr. Tomas Lynch and Dr. John Wain, (Mass General Hosp), Dr. Kofi Asomaning and Ms.

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