Increased risk of cancer among relatives of patients with lung cancer in China

Inasmuch as some 22 per cent of all persons die of cancers affecting various anatomic sites, the random occurrence of cancer among several members of a nuclear family would be usual [1]. However, when cancers occur among members in several generations of the same family, chance itself may not be sufficient to account for that occurrence. An increased familial risk for cancer and particularly lung cancer has been demonstrated among relatives of lung cancer patients [2–6]. However, the precise genetic characteristics which influence lung cancer susceptibility are not known. Many studies of families may be used to attempt to disentangle the effects of shared environmental risk factors and genetic factors [7–9].

However, these conclusions do not address the occasionally observed increased frequency of cancers of several sites in combination, such as those of the breast, brain, bone, liver, adrenal cortex, blood, and/or lymphatics[2]. Warthin[10] was the first to describe a large kindred having a remarkable high incidence of cancers at various sites. Pedigree analysis of several large families with multiple cancers across several generations led Lynch and Krush[11] to propose a new genetic entity, later called "cancer family syndrome". In general, those studies showed that the familial occurrence of cancer tends to deviate from the Possion distribution, in that more families than expected by chance have two or more affected, closely related members. However, these high-risk families were selected for study because of their high frequency of cancer cases. Because the laws of probability can not preclude the probability that these cancer families merely represent a chance occurrence, some investigators have questioned genetic susceptibility as a basis for familial aggregation of cancers at various sites.

To explore whether familial aggregation of cancer represents a random or specific event, we conducted a retrospective case-control study of families. The lung cancer patient (proband) was used to identify a case family and the proband's spouse was used to identify a control family in rural regions of Anhui, China.

In our study, 800 eligible probands were identified. These families were only included in the data set once (if there are more than one cases in a family, the earliest case diagnosed was selected as the proband). An average of 2.6 and 2.9 interviews (contacts) were made to complete information on each of these proband and spouse families, respectively. The largest proportion of the contacts was through siblings, followed closely by spouses. Less than 17 per cent of the contacts were from adult offspring and surviving parents. The distributions of reported cancer in relatives by source of contacts were not significantly different between proband and spouse families. Information on complete two-generation pedigrees was obtained for 800 case families and 800 control families. The remaining families of probands and spouses were excluded from the analysis because of: inadequate information in names, addresses, incomplete data on each individual in the pedigree (2.8 per cent), or refusals to participate (4.2 per cent). The resulting sample includes 4,453 case family members and 4,378 control family members.

A total of 390 case family members(8.76 per cent) and 212 control family members (4.84 per cent) were reported to have cancer (only primary malignancy counted). 36(9.2 per cent) and 22 (10.4 per cent) were living cancer cases in the case and control groups, respectively. Of the cancer deaths reported in the death certificates, 92.8 per cent were detected by interview. Analogously, 94.2 per cent of the noncancer deaths were reported. There were no significant differences in age at death or age of living family members with cancer between the two study groups.

In this study, we attempted to control for as many environmental risk factors as possible for both the probands and their relatives in order to understand better the cause of the observed family aggregation. These data demonstrate an increase risk of non-lung cancer and lung cancer specifically among first-degree relatives of lung cancer probands, and support the hypothesis that genetic factors play a role in the etiology of lung cancer. Tokuhata and Lilienfeld[2] provided the first epidemiologic evidence to support the hypothesis was provided, and reported a significantly increased risk of respiration cancer among relatives of lung cancer patients compared to age-, race-, and sex-matched controls. The risk for cancer in general, however, was not increased. The present authors[3] recently reports similar findings. Lynch et al.[5, 15] reported on the familial risk of cancer in relatives of lung cancer probands and probands with other smoking-related cancers (i.e. bladder, pancreas, oral cavity). They found no increased risk for lung cancer when considered separately. However, the risk for cancers of all anatomic sites was significantly increased among the relatives of lung cancer probands (p < 0.001). This increased risk was not evident for relatives of probands with other smoking-associated cancers, nor were the cancers themselves smoking-related. The authors conclude that the data are consistent with the hypothesis of an underlying susceptibility to malignancy in these families. Unlike Lynch et al.[5], the present study again reports an increased risk for lung cancer, and also notes an increased risk for cancer at several anatomic sites in relatives of lung cancer probands. Even after excluding persons with lung cancer and controlling for the assessed environmental exposures, a statistically significant excess risk of cancer was evident.

Our findings also suggest that female relatives (especially mothers) of lung cancer cases are at higher risk for lung cancer than male relatives. Previous studies have indicated that having a first-degree relative with lung cancer was significantly associated with lung cancer among non-smokers[3, 6, 16–18]. Why the apparently stronger association between lung cancer and lung cancer history in female relatives are unknown. Since certain smoky coal exposure and cooking habits have been implicated as an important risk factor for lung cancer among Chinese women[19]. Genetic factors might influence the susceptibility to environmental carcingens. Excess of 10 carcinogenic chemicals were identified in cooking and smoky coal fume and these shown to interact with one another[20, 21] and these possible effects need to be evaluated further.

Findings of familial aggregation and statistical evidence for a major gene [22–24] have led to the search for high-penetrant, rare, single genes for lung cancer and low-penetrant, high-frequency, susceptibility genes for lung cancer[25]. Some of the most widely and recently studied polymorphic loci coding for phase I and II enzymes involved in the activation and conjugation of carcinogen are cytochrome P4501A1 (CYP1A1), glutathione S-transferase M1 (GSTM1), myeloperoxidase (MPO), and NAD(P)H: quinone oxidoreductase (NQO1)[25]. These genes encoding enzymes that are associated with carcinogen metabolism and DNA repair have been the focus of research into possible susceptibility genes for lung cancer and othe cancer. Furthermore, the recent findings show that the homozygous GSTP1 Ile105Val genetype was significantly under-represented in NSCLC compared with controls especially in females, and neither GSTM1 nor MPO genotypes affected the overall risk of NSCLC, and the MPO and CYP1A1 risk genotypes interacted to increase overall risk of NSCLC[26]. Multiple genes of modest effect interact to confer genomic-based susceptibility to lung cancer. It has been hypothesized that differences in susceptibility to carcinogens result from an individual's ability to form genotoxic intermediates, to detoxify these intermediates, and to repair damaged DNA. Polymorphisms in genes coding for the enzymes that drive these processes are likely candidate susceptibility genes. They could not only increase the lung cancer risk but also affect the risk of other cancers. Identifying and testing specific markers using a linkage analysis to confirm the gene involved in the development and progression of lung cancer, particularly to explore the interaction of gene-gene and gene-environment, should be a high future priority.