Cancer diagnosis in first-degree relatives and non-small cell lung cancer risk: Results from a multi-centre case–control study in Europe

Abstract

Because aggregation of cancers at different sites can occur in families, cancer could be considered as a broad phenotype with shared genetic factors. Here, we report results from a multi-centre case–control study of non-small cell lung cancer (NSCLC), with particular emphasis on a history of cancer in first-degree relatives and the risk of lung cancer. From 2002 to 2006, 733 NSCLC patients treated surgically were recruited in 8 European countries and matched to 1312 controls, by centre, sex and age. We used multivariate conditional logistic regression models to test the association between a history of cancer in first-degree relatives and risk of NSCLC. A family history of lung cancer was associated with an odds ratio (OR) for early-onset (54 years or younger) NSCLC of 4.72 (95% confidence interval [CI] = 1.02–21.90). A family history of gastric cancer was associated with an OR for NSCLC of 1.82 (95% CI = 1.08–3.06) and for late-onset (55 years or older) NSCLC of 2.92 (95% CI = 1.10–7.75). Our findings provide further evidence of a familial predisposition to lung cancer and support the hypothesis that family history is a significant risk factor for the disease. Because of the inherent potential for bias in familial case–control study design, cautious interpretation is warranted.

Introduction

Lung cancer is the most common cancer in the world with 1.3 million new cases diagnosed every year. The highest rates of lung cancer are found in Europe and Northern America.¹ Although lung cancer is largely attributable to cigarette smoking, the disease also has an important heritable component. Numerous studies have found an increased risk of lung cancer in individuals who have a first-degree relative with the disease. Familial clustering can also occur between cancers at different sites, suggesting that cancer could be considered a broad phenotype with shared genetic factors.² For instance, it has been reported that oestrogen-related genes may serve as a link between a maternal history of breast cancer and an increased risk of lung cancer.3, 4, 5

In 1963, Tokuhata and Lilienfeld⁶ provided the first epidemiologic evidence of familial aggregation of lung cancer, suggesting the interaction of genes, shared environment and common lifestyle factors in the aetiology of the disease. Since then, researchers have compared the concordance of lung cancer between monozygotic and dizygotic pairs of twins to quantify the extent to which an observed familial pattern is due to genetic or shared environmental factors.⁷ The largest of these studies suggested a limited heritability of lung carcinoma, though none of the studies had statistically significant findings.⁸ More recently, population-based studies in Iceland demonstrated that a familial factor for lung cancer extended beyond the nuclear family, strongly suggesting a genetic predisposition to the disease.2, [7] Major lung cancer susceptibility loci have since been mapped to chromosome 15q25,9, 10, 11, 12, 13 6p21¹² and 5p15,12, 13 further indicating that genetic factors play a role in an individual’s susceptibility to lung cancer. However, the genetic variants the studies identified explain only a small part of the heritable risk, thus implying the presence of other genetic factors that increase the risk for lung cancer.

Because interactions with the environment can substantially modify genetic effects, epidemiological studies of familial aggregation play an important role in elucidating the interplay between genes and the environment. Using the results from a multi-centre case–control study of non-small cell lung cancer (NSCLC) in Europe we investigated the association between a family history of cancer and lung cancer risk, taking into account environmental factors, tobacco use and family size.