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(Chest. 2006;130:968-975.)
© 2006 American College of Chest Physicians

Association Between Lung Cancer Incidence and Family History of Lung Cancer*

Data From a Large-Scale Population-Based Cohort Study, the JPHC Study

Jun-ichi Nitadori, MD; Manami Inoue, MD, PhD; Motoki Iwasaki, MD, PhD; Tetsuya Otani, MD, PhD; Shizuka Sasazuki, MD, PhD; Kanji Nagai, MD, PhD; Shoichiro Tsugane, MD, PhD; the JPHC Study Group{dagger}

* From the Epidemiology and Prevention Division (Drs. Nitadori, Inoue, Iwasaki, Otani, Sasazuki, and Tsugane), Center for Cancer Prevention and Screening, National Cancer Center, Tokyo; and Thoracic Oncology Division (Dr. Nagai), National Cancer Center Hospital East, Chiba, Japan. {dagger} Study group members are listed in the Appendix.

Correspondence to: Manami Inoue, MD, PhD, Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 Japan; e-mail: mnminoue{at}gan2.res.ncc.go.jp

Abstract

Study objectives: To clarify the possibility of a hereditary predisposition to lung cancer, we investigated the association between a family history of lung cancer and subsequent risk of lung cancer in a large-scale, population-based cohort study.

Design: We investigated 102,255 middle-aged and older Japanese subjects (48,834 men and 53,421 women) with 13-year follow-up. A total of 791 cases of lung cancer were newly diagnosed during the follow-up period.

Results: A family history of lung cancer in a first-degree relative was associated with a significantly increased risk of lung cancer (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.31 to 2.88). The association was stronger in women than in men (HR, 2.65; 95% CI, 1.40 to 5.01 and HR, 1.69; 95% CI, 1.03 to 2.78, respectively), and in never-smokers than in current smokers (HR, 2.48; 95% CI, 1.27 to 4.84 and HR, 1.73; 95% CI, 0.99 to 3.00, respectively). In addition, family history was more strongly associated with the risk of squamous cell carcinoma than with other histologic types (HR, 2.79; 95% CI, 1.37 to 5.68), while no clear increase in risk was observed in adenocarcinoma and small cell carcinoma. A family history of overall cancer was not associated with an increased risk of lung cancer.

Conclusions: These results suggest that those with a family history of lung cancer are more likely to acquire lung cancer themselves.

Key Words: cancer incidence • familial aggregation • family history • lung cancer • population-based cohort study

According to the world estimate of cancer incidence and mortality in the year 2002 by the International Agency for Research on Cancer,1 lung cancer accounts for an estimated 1.35 million new cases each year, representing 12.4% of all cancers excluding skin cancer. After nonmelanocytic skin cancer, it is the most frequent malignant neoplasm in humans and the highest cause of death from neoplasia.2 In Japan, the mortality of lung cancer overtook that of gastric cancer in 1998, and the condition now accounts for 13% of all cancers (66,453) and 18% of all cancer deaths (56,367), representing the most common cause of cancer death in Japanese men.1

Tobacco smoking has long been established as the predominant risk factor for lung cancer,34 accounting for 90% of lung cancer incidence.567 However, it has long been postulated that individuals differ in their susceptibility to environmental risk factors. Hereditary predisposition has been reported to play an important role in carcinogenesis, and previous studies8910111213141516171819202122232425 have reported an increased familial risk for cancer. Familial lung cancer clustering has been demonstrated among relatives of lung cancer patients,89101112 but the genetic characteristics influencing lung cancer susceptibility have not been precisely clarified.

Many epidemiologic studies have investigated the association between family history and lung cancer incidence, primarily using retrospective case-control891012131415161718192021222627 and cohort methodologies.232425 Based on an analysis of family history data of 791 lung cancer patients over 1,000,000 person-years, the present study is to our knowledge the largest cohort study on the familial risk of lung cancer in Japan. We examined the incidence of lung cancer in the first-degree relatives of study participants, with the aim of testing the hypothesis that those with a family history of lung cancer are more likely to acquire lung cancer themselves.

Materials and Methods

Study Population
The Japan Public Health Center-based prospective study was launched in 1990 for cohort I and in 1993 for cohort II. Cohort I comprised five prefectural public health center (PHC) areas, and cohort II comprised six PHC areas. The details of the study design have been described elsewhere.2829 The study protocol was approved by the Institutional Review Board of the National Cancer Center, Japan. In the present analysis, one PHC area was excluded because data on cancer incidence were not available.

The study population was defined as all registered Japanese inhabitants in the 10 PHC areas aged 40 to 59 years in cohort I and 40 to 69 years in cohort II at the beginning of the respective baseline survey. The Japanese inhabitants were identified by residential registries maintained by the local municipalities. Initially, 133,323 subjects were identified as the study population. During the study period, 351 subjects were found to be ineligible and were excluded because of non-Japanese nationality (n = 51), residential relocation before the questionnaire survey (n = 290), incorrect birth date (n = 6), and duplication of registration in our cohorts (n = 4). Finally, a population-based cohort of 132,972 subjects was established.

Baseline Survey
A baseline self-administered questionnaire survey on various lifestyle factors was conducted in 1990 for cohort I and in 1993 to 1994 for cohort II. A total of 106,217 subjects responded to the questionnaire, giving a response rate of 82%.30 Questions included the family history of all cancers and of lung cancer among first-degree relatives. Numbers of affected first-degree relatives for each parent and sibling were summed for each family history item. We excluded 2,219 subjects who reported previous cancer in the baseline questionnaire. We also excluded subjects with incomplete information on family history of lung cancer and smoking status (n = 1,740). As a result, 102,255 subjects (48,834 men, 53,421 women) were used for the present analysis.

Follow-up
Subjects were followed up from baseline survey until December 31, 2003. Residence status, including survival, was confirmed annually through municipal residential registries. Residence and death registration is required in Japan by law, and the registries are believed to be complete. Inspection of the residential registry is available to anyone under the residential registration law. Information on the cause of death was supplemented with permission by checking against death certificate files, and the cause of death was defined according to the International Classification of Diseases, Tenth Revision.31 Among the study subjects, 7.8% moved away and 0.06% were unavailable for follow-up during the study period.

The occurrence of cancer was identified by active patient notification from the major hospitals in the study areas, and data linkage with population-based cancer registries, with permission. Death certificate information was used as a supplementary information source. The site of origin and histologic type were coded using the International Classification of Diseases for Oncology, Third Edition (C34.0-C34.9).32

In our cancer registry system, the proportion of cases for which information was obtained from death certificates only was 5.1% during the study period. This level of information quality was considered satisfactory. For multiple primary lung cancers at different times, the earliest diagnosis was used. Through this procedure, a total of 791 newly diagnosed lung cancer cases (584 men, 207 women) were identified as of December 31, 2003.

Statistical Analysis
We calculated person-years of follow-up from the start in each cohort until the date of diagnosis of lung cancer, the date of a subject’s death, the date of moving from a PHC area, or December 31, 2003, whichever occurred first.

Multivariate-adjusted hazard ratios (HRs) with the corresponding 95% confidence interval (CI) of lung cancer incidence for family history were estimated by the Cox proportional hazards model. In addition, we evaluated whether the effect of a family history of lung cancer was influenced by smoking status using a test of interaction by entering into the model multiplicative interaction terms between the two factors.

The estimates were adjusted for the following potential confounding factors incorporated into the model: age at baseline (continuous), gender, study area, smoking status (never, former, or current; pack-years [1 to 19, 20 to 29, 30 to 39, ≥ 40]) and passive smoking in the work place (never, one to three times a month, one to four times a week, almost every day). Smoking habits were categorized as never, former, and current smoker. Former smokers were defined as people who had quit smoking at least 1 year before the survey. These variables are either known or suspected risk factors for lung cancer or have been found to be associated with lung cancer in previous study.28 Statistical analysis was performed using statistical software (STATA version 9; StataCorp; College Station, TX).

Results

During the 1,116,731 person-years of follow-up (average follow-up period, 10.9 years) for the 102,255 subjects (48,834 men, 53,421 women), a total of 791 cases of newly diagnosed lung cancer (584 men, 207 women) were documented. At baseline, the mean age of the study subjects was 51.7 years (range, 40 to 69 years) [Table 1 ]. Male and female subjects were of almost same age (mean age, 51.6 years and 51.9 years, respectively).


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  		Table 1. Baseline Characteristics of the Study Subjects (n = 102,255)*

 
Table 2 shows HRs and their 95% CI of lung cancer according to family history of lung cancer and of overall cancer. With regard to total cases, a family history of lung cancer was associated with a significantly increased risk of lung cancer compared with a family history of overall cancer (HR, parents or siblings, 1.95; parents, 1.79; siblings, 2.37). With regard to gender, women’s family history of lung cancer was associated with a significantly increased risk of lung cancer compared with men (HR, 2.65; 95% CI, 1.40 to 5.01; and HR, 1.69; 95% CI, 1.03 to 2.78, respectively). With regard to smoking status, never-smokers’ family history of lung cancer was more strongly associated with a significantly increased risk of lung cancer than current smokers (HR, 2.48; 95% CI, 1.27 to 4.84; HR, 1.73; 95% CI, 0.99 to 3.00, respectively). With regard to histologic type, a positive family history of squamous cell carcinoma was more strongly associated with a significantly increased risk of lung cancer than other histologic types (HR, 2.79; 95% CI, 1.37 to 5.68). Family history of overall cancer was not associated with a significantly increased risk of lung cancer compared with that of lung cancer.


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  		Table 2. Prevalence of Lung Cancer According to Family History of Lung Cancer and Overall Cancer in First-Degree Relatives (Parents and Siblings)*

 
We examined whether the effect of a family history of lung cancer on lung cancer risk was modified by smoking status (Table 3 ). A family history of lung cancer was associated with an increased risk of lung cancer regardless of smoking status (never, past, current). In current smokers, a significantly increased risk was observed in those with the highest pack-year category. In addition, a risk increase by current smoking and by increased pack-years of smoking was observed regardless of the family history of lung cancer. No significant interaction was detected between smoking status and family history of lung cancer.


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  		Table 3. Family History of Lung Cancer in First-Degree Relatives and Smoking Status*

 
Discussion

The purpose of the present study was to determine the association between a family history of lung cancer and subsequent risk of lung cancer in a Japanese population. To our knowledge, this is the first prospective study of this association in Japan.

The familial risk of lung cancer documented in previous studies232425 may have been due to shared environmental as well as hereditary predisposition. Study81833 findings suggest that the long-held belief that lung cancer is not hereditary may in fact be wrong, and that heredity may be at least in part causative. One of the earliest such findings goes back to the 1960s, when Tokuhata and Lilienfeld8 found that the first-degree relatives of lung cancer patients were at high risk of acquiring lung cancer. When the family history of tobacco exposure was accounted for, they found that the family members of smoking patients, especially female members, were at high risk of cancer. McDuffie18 also found evidence of a close association between the development of lung cancer and hereditary factors. They compared the prevalence of lung cancer in the first-degree relatives of lung cancer patients and healthy subjects and found that the patients were more likely to report the presence of one or more relatives with any cancer than healthy subjects. Given that the most commonly reported cancers were smoking related, including those of the larynx, esophagus, and lung, McDuffie18 also discussed the possible interaction between hereditary and environmental factors in the development of lung cancer.

In the present study, overall lung cancer incidence in a first-degree relative was associated with a 95% increase in lung cancer on 13-year follow-up. Some cohort studies232425 have found similar relative risks, with results ranging between 1.7 and 2.0. Several case-control studies18192034 have also shown an increase in lung cancer risk for relatives of lung cancer patients, with odds ratios (ORs) ranging from 1.8 to 2.8. Further, our results also showed that lung cancer risk was higher in women than in men, with respective HR values of 2.65 and 1.69. Among a number of studies212235363738394041424344 investigating gender differences in susceptibility to lung cancer, Hemminki and Li44 assessed sex chromosome effects and interactions between background and familial rates, and found that relative risks were similar. Most have shown that lung cancer risk in women; for example, Matakidou et al,22 in a case-control study of familial lung cancer risk in a population of British women, indicated a significant increase in risk associated with a family history of the disease in a first-degree relative (OR, 1.49; 95% CI, 1.13 to 1.96). These findings support the hypothesis that genetic susceptibility to lung cancer might act as both an independent risk factor and an effect modifier of environmental risk factors.

With regard to smoking status, the effect of a family history on lung cancer risk was notably higher in never-smokers than in current smokers (HR, 2.48 and HR, 1.73, respectively). In addition, although no significant interaction between smoking status and family history of lung cancer was detected in the present study, in current smokers, lung cancer risk was significantly increased only in those in the highest pack-year category. Smoking is the most important environmental risk factor of lung cancer, and the association between a person’s smoking habit and that of his parents or siblings has been well described.45 Tokuhata and Lilienfeld,8 in a comprehensive analysis of familial risk of lung cancer, referenced the smoking habits of family members and indicated an excess risk in case relatives compared to control relatives regardless of the relative’s smoking history. Further, the familial risk estimate in their study was greater for nonsmokers than for smokers, suggesting that the higher risk was not simply due to shared smoking habits in the families of lung cancer patients. A population-based case control study21 of familial lung cancer risk in nonsmokers found that lung cancer patients were more likely to have a first-degree relative with lung cancer than control subjects (OR, 1.4; 95% CI, 0.8 to 2.5), and that the risk was greater for female than male subjects (OR, 1.7 and OR, 0.5, respectively). Meanwhile, recent work by Cote et al46 showed that in a family with a young-onset lung cancer patient, the other family members who smoked had a significantly increased risk. It appears that the presence or otherwise of an effect modification between lung cancer and smoking is still unresolved, and that this issue therefore requires further study.

With regard to histologic type, lung cancer risk associated with a family history of lung cancer was particularly high for squamous cell carcinoma (HR, 2.79), whereas no clear increase in risk was observed in adenocarcinoma and small cell carcinoma. From previous clinical observations, similar histologic findings to ours were reported by Ambrosone and colleagues,33 who found that patients with squamous cell carcinoma were more likely to report a family history of cancer than those with other types, especially women aged < 57 years. However, inconsistent results were also reported by Kreuzer et al47 and by Sellers et al,48 who found no difference in association by histology of lung cancer. In addition, Li and Hemminki49 reported a high risk by parental lung cancer in adenocarcinoma and large cell carcinoma compared with that in squamous cell carcinoma and small cell carcinoma using a population-based cancer registry data. The strong association of squamous cell carcinoma with tobacco smoking is well known, and most cases in the present study were current or past smokers (92%; data not shown). Carcinogens present in tobacco and tobacco smoke are converted into DNA-reactive metabolites by cytochrome P450-related enzymes, several of which display genetic polymorphism. In particular, the evidence5051 indicates that CYP1A1, which often displays genetic polymorphism, converts many tobacco carcinogens into DNA-binding metabolites in target cells, thereby modulating intermediate effect markers such as DNA adducts and ultimately increasing the risk of lung cancer. Bartsch et al52 summarized the results of case-control studies published since 1990 on the effects of genetic variants of CYP1A1, 1A2, 1B1, 2A6, 2D6, 2E1, 2C9, 2C19, 17, and 19 alone or in combination with detoxifying enzymes as modifiers of risk for tobacco-related cancers, and have also analyzed the results of their own studies on gene-gene interactions and the dependence of smoking-related DNA adducts on genotype. Results showed that a number of CYP variants are associated with an increased risk of cancer of the lung. However, few of the epidemiologic studies that reported an association between lung cancer and a family history of cancer also evaluated risk by the histologic type of lung cancer. Further epidemiologic evidence to address this issue is warranted.

Evidence exists that lung cancer aggregates in families and findings of a chromosomal region linked to lung cancer susceptibility support a genetic component to risk. In addition to the familial aggregation method, Gauderman and Morrison53 employed discriminant analysis to investigate the mode of inheritance and found the best-fitting model included an autosomal dominant locus. Using the Cox proportional hazards model, they estimated that age- and genotype-specific rates of carrying the high-risk allele were 90% among patients with onset at age ≤ 60 years. However, this possession rate was estimated to decrease with age to approximately 10% among patients with later onset at age ≥ 75 years. As understanding of the human genome develops, molecular epidemiologic studies of familial aggregation of lung cancer will identify genes that influence the development of this condition, and correspondingly help to identify the etiology of nonsmoking lung cancer, which has a markedly high incidence in Japan.

In the present study, we considered lifestyle factors and dietary habits possibly associated with lung cancer in previous reports as potential confounding factors, with the expectation that statistical adjustment might be to some degree possible if information on associated variables were available. A number of limitations of our study should be described. Participants themselves provided information on family history, but diagnoses were not verified through medical sources or health records. The possibility of random misclassification of this information in both subjects with or without subsequent lung cancer exists, and may have led to an underestimation of true risk. A further limitation is the lack of information on family size and age of relatives, raising the possibility of bias in calculations of familial risks in all first-degree relatives or siblings. The prospective design precludes the possibility of recall bias, since information on lifestyle exposure was collected before diagnosis. Although the ratio of patients unavailable for to follow-up was negligible, we cannot preclude the possibility of loss of study subjects with diagnoses made outside of the study areas.

Conclusions

In conclusion, our long-term follow-up of a large-scale, population-based cohort identified a significant increase in the risk of lung cancer associated with a family history of lung cancer in a first-degree relative in a Japanese population. Our results suggest that those with a family history of lung cancer are more likely to acquire lung cancer themselves, although further studies are needed to clarify if there is an effect modification between family history of lung cancer and smoking.

Appendix

Members of the Japan Public Health Center-based prospective study group are as follows: S. Tsugane, M. Inoue, T. Sobue, T. Hanaoka, National Cancer Center, Tokyo; J. Ogata, S. Baba, T. Mannami, A. Okayama, National Cardiovascular Center, Suita; K. Miyakawa, F. Saito, A. Koizumi, Y. Sano, I. Hashimoto, Iwate Prefectural Ninohe Public Health Center, Ninohe; Y. Miyajima, N. Suzuki, S. Nagasawa, Y. Furusugi, N. Nagai, Akita Prefectural Yokote Public Health Center, Yokote; H. Sanada, Y. Hatayama, F. Kobayashi, H. Uchino,Y. Shirai, T. Kondo, R. Sasaki, Y. Watanabe, Y. Miyakawa, Nagano Prefectural Saku Public Health Center, Saku; Y. Kishimoto, E. Takara, T. Fukuyama, M. Kinjo, M. Irei, H. Sakiyama, Okinawa Prefectural Chubu Public Health Center, Okinawa; K. Imoto, H. Yazawa, T. Seo, A. Seiko, F. Ito, F. Shoji, Katsushika Public Health Center, Tokyo; A. Murata, K. Minato, K. Motegi, T. Fujieda, Ibaraki Prefectural Mito Public Health Center, Mito; K. Matsui, T. Abe, M. Katagiri, Niigata Prefectural Kashiwazaki Public Health Center, Kashiwazaki, M. Suzuki, Niigata Prefectural Nagaoka Public Health Center, Nagaoka; M. Doi, A. Terao, Y. Ishikawa, Kochi Prefectural Chuo-Higashi Public Health Center, Tosayamada; H. Sueta, H. Doi, M. Urata, N. Okamoto, F. Ide, Nagasaki Prefectural Kamigoto Public Health Center, Arikawa; H. Sakiyama, N. Onga, H. Takaesu, Okinawa Prefectural Miyako Public Health Center, Hirara; F. Horii, I. Asano, H. Yamaguchi, K. Aoki, S. Maruyama, M. Ichii, Osaka Prefectural Suita Public Health Center, Suita; S. Matsushima, S. Natsukawa, Saku General Hospital, Usuda; M. Akabane, Tokyo University of Agriculture, Tokyo; M. Konishi, K. Okada, Ehime University, Matsuyama; H. Iso, Osaka University, Osaka; K. Tsubono, Tohoku University, Sendai; K. Yamagishi, Y. Honda, Tsukuba University, Tsukuba; H. Sugimura, Hamamatsu University, Hamamatsu; M. Kabuto, National Institute for Environmental Studies, Tsukuba; S. Tominaga, Aichi Cancer Center, Nagoya; M. Iida, W. Ajiki, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka; S. Sato, Osaka Medical Center for Health Science and Promotion, Osaka; N. Yasuda, Kochi Medical School, Nankoku; S. Kono, Kyushu University, Fukuoka; K. Suzuki, Research Institute for Brain and Blood Vessels Akita, Akita; Y. Takashima, Kyorin University, Mitaka; E. Maruyama, Kobe University, Kobe; the late M. Yamaguchi, S. Watanabe, Y. Matsumura, S. Sasaki, National Institute of Health and Nutrition, Tokyo; and T. Kadowaki, Tokyo University, Tokyo.

Acknowledgements

The authors thank all staff members in each study area for their efforts with baseline and follow-up surveys. We also thank the Iwate, Aomori, Ibaraki, Niigata, Osaka, Kochi, Nagasaki, and Okinawa Cancer Registries for providing the incidence data.

Footnotes

Abbreviations: CI = confidence interval; HR = hazard ratio; OR = odds ratio; PHC = public health center

This work was supported by a Grant-in-Aid for Cancer Research and for the Third Term Comprehensive 10-Year-Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan.

The authors have no conflicts of interest to disclose.

Received for publication February 8, 2006. Accepted for publication May 17, 2006.

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A. G. Schwartz
Lung cancer: family history matters.
Chest, October 1, 2006; 130(4): 936 - 937.
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