Association Between Lung Cancer Incidence and Family History of Lung Cancer* Data From a Large-Scale Population-Based Cohort Study, the JPHC Study

Transcription

1 CHEST Association Between Lung Cancer Incidence and Family History of Lung Cancer* Original Research 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; for the JPHC Study Group LUNG CANCER 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. (CHEST 2006; 130: ) Key words: cancer incidence; familial aggregation; family history; lung cancer; population-based cohort study Abbreviations: CI confidence interval; HR hazard ratio; OR odds ratio; PHC public health center 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 *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. Study group members are listed in the Appendix. 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. 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 The authors have no conflicts of interest to disclose. Manuscript received February 8, 2006; revision accepted May 17, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Manami Inoue, MD, PhD, Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tsukiji, Chuo-ku, Tokyo Japan; mnminoue@gan2.res.ncc.go.jp DOI: /chest Original Research

2 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, 3,4 accounting for 90% of lung cancer incidence. 5 7 However, it For editorial comment see page 936 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 studies 8 25 have reported an increased familial risk for cancer. Familial lung cancer clustering has been demonstrated among relatives of lung cancer patients, 8 12 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 casecontrol 8 10,12 22,26,27 and cohort methodologies 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. Study Population Materials and Methods 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. 28,29 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, 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, 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 CHEST / 130 / 4/ OCTOBER,

3 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). 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. 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. 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 studies may have been due to shared environmental as well as hereditary predisposition. Study 8,18,33 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 Lilienfeld 8 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. McDuffie 18 also found evidence of a Table 1 Baseline Characteristics of the Study Subjects (n 102,255)* Men Women Characteristics Total Nonsmoker Past Smoker Current Smoker Total Nonsmoker Past Smoker Current Smoker Subjects, No. 48,834 11,610 11,595 25,629 53,421 49, ,542 Age, yr Passive smoking almost every day, % Family history of lung cancer, % Parents or siblings Parents Siblings Lung cancer histology, % of cases Adenocarcinoma Squamous cell carcinoma Small cell carcinoma Others and unknown *Data are presented as mean SD unless otherwise indicated. 970 Original Research

4 Table 2 Prevalence of Lung Cancer According to Family History of Lung Cancer and Overall Cancer in First- Degree Relatives (Parents and Siblings)* Family History of Lung Cancer Family History of All Cancers Parents or Siblings Parents Siblings Parents or Siblings Parents Siblings Variables No Yes No Yes No Yes No Yes No Yes No Yes Person-years 1,094,533 22,199 1,099,152 17,580 1,111,918 4, , , , ,759 1,047,294 69,438 Total cohort No. of cases HR % CI (Ref) (Ref) (Ref) (Ref) (Ref) (Ref) Gender Men No. of cases HR % CI (Ref) (Ref) (Ref) (Ref) (Ref) (Ref) Women No. of cases HR % CI (Ref) (Ref) (Ref) (Ref) (Ref) (Ref) Smoking history Never-smokers No. of cases HR % CI (Ref) (Ref) (Ref) (Ref) (Ref) (Ref) Current smokers No. of cases HR % CI (Ref) (Ref) (Ref) (Ref) (Ref) (Ref) Histologic type Adenocarcinoma No. of cases HR % CI (Ref) (Ref) (Ref) (Ref) (Ref) (Ref) Squamous cell carcinoma No. of cases HR % CI (Ref) (Ref) (Ref) (Ref) (Ref) (Ref) Small cell carcinoma No. of cases HR % CI (Ref) (Ref) (Ref) (Ref) (Ref) (Ref) *Adjusted for age, gender, study area (10 PHC areas), smoking status (never, former, or current; pack-years 1 to 19, 20 to 29, 30 to 39, 40 ), and passive smoking at the workplace. Ref reference. 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, McDuffie 18 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 studies have found similar relative risks, with results ranging between 1.7 and 2.0. Several case-control studies 18 20,34 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 Among a number of studies 21,22,35 44 investigating gender differences in susceptibility to lung cancer, Hemminki and Li 44 assessed sex chromosome effects and interactions between background and familial rates, and found that relative risks were similar. Most have shown that CHEST / 130 / 4/ OCTOBER,

5 Table 3 Family History of Lung Cancer in First-Degree Relatives and Smoking Status* Parents or Siblings Parents Siblings Variables No Yes No Yes No Yes Person-years 1,094,533 22,199 1,099,152 17,580 1,111,918 4,814 By smoking status Never-smokers No. of cases HR % CI (Ref) (Ref) (Ref) Past smokers No. of cases HR % CI (Ref) (Ref) (Ref) Current smokers No. of cases HR % CI (Ref) (Ref) (Ref) pack-years No. of cases HR % CI (Ref) (Ref) (Ref) pack-years No. of cases HR % CI (Ref) (Ref) (Ref) pack-years No. of cases HR % CI (Ref) (Ref) (Ref) pack-years No. of cases HR % CI (Ref) (Ref) (Ref) By lung cancer family history Never-smokers No. of cases HR % CI (Ref) (Ref) (Ref) (Ref) (Ref) (Ref) Past smokers No. of cases HR % CI Current smokers No. of cases HR % CI pack-years No. of cases HR % CI pack-years No. of cases HR % CI pack-years No. of cases HR % CI pack-years No. of cases HR % CI Interaction between lung cancer and family history, p value Smoking status (never, past, current) Pack-years of smoking *Adjusted for age, gender, study area (10 PHC areas) and passive smoking in the workplace. See Table 1 for expansion of abbreviation. 972 Original Research

6 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 study 21 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 al 46 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 al 47 and by Sellers et al, 48 who found no difference in association by histology of lung cancer. In addition, Li and Hemminki 49 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 populationbased 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 evidence 50,51 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 al 52 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 Morrison 53 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 CHEST / 130 / 4/ OCTOBER,

7 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. 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. ACKNOWLEDGMENT: 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. Conclusions In conclusion, our long-term follow-up of a largescale, 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. References 1 Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide. IARC Cancer- Base No. 5. version 2.0, Lyon, France: IARCPress, Available at: Accessed February 8, Boffeta P, Trichopoulos D. Cancer of the lung, larynx, and pleura. In: Adami HO, Hunter D, Trichopoulos D, eds. Textbook of cancer epidemiology. New York, NY: Oxford University Press, 2002; Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 1981; 66: IARC monographs on the evaluation of carcinogenic risks to humans: tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum Suppl 2004; 83: Stanley KE. Lung cancer and tobacco: a global problem. Cancer Detect Prev 1986; 9: U.S. Department of Health and Human Service. The health consequences of smoking: cancer; a report of Surgeon General, Rockville, MD: Department of Health and Human Services, Public Health Service, Office on Smoking and Health, 1982; DHHS publication No. (PHS) Sobue T, Suzuki T, Fujimoto I, et al. Case control study for lung cancer and cigarette smoking in Osaka, Japan: comparison with the results from Western Europe. Jpn J Cancer Res 1994; 85: Tokuhata GK, Lilienfeld AM. Familial aggregation of lung cancer in humans. J Natl Cancer Inst 1963; 30: Ooi WL, Elston RC, Chen VW, et al. Increased familial risk for lung cancer. J Natl Cancer Inst 1986; 76: Sellers TA, Ooi WL, Elston RC, et al. Increased familial risk 974 Original Research

8 for non-lung cancer among relatives of lung cancer patients. Am J Epidemiol 1987; 126: Lynch HT, Kimberling WJ, Markvicka SE, et al. Genetics and smoking-associated cancers: a study of 485 families. Cancer 1986; 57: Samet JM, Humble CG, Pathak DR. Personal and family history of respiratory disease and lung cancer risk. Am Rev Respir Dis 1986; 134: Shaw GL, Falk RT, Pickle LW, et al. Lung cancer risk associated with cancer in relatives. J Clin Epidemiol 1991; 44: Wu AH, Yu MC, Thomas DC, et al. Personal and family history of lung disease as risk factors for adenocarcinoma of the lung. Cancer Res 1988; 48: Horwitz RI, Smaldone LF, Viscoli CM. An ecogenetic hypothesis for lung cancer in women. Arch Intern Med 1988; 148: Osann KE. Lung cancer in women: the importance of smoking, family history of cancer, and medical history of respiratory disease. Cancer Res 1991; 51: Wu AH, Fontham ET, Reynolds P, et al. Family history of cancer and risk of lung cancer among lifetime nonsmoking women in the United States. Am J Epidemiol 1996; 143: McDuffie HH. Clustering of cancer in families of patients with primary lung cancer. J Clin Epidemiol 1991; 44: Kreuzer M, Kreienbrock L, Gerken M, et al. Risk factors for lung cancer in young adults. Am J Epidemiol 1998; 147: Bromen K, Pohlabeln H, Jahn I, et al. Aggregation of lung cancer in families: results from a population-based case-control study in Germany. Am J Epidemiol 2000; 152: Schwartz AG, Yang P, Swanson GM. Familial risk of lung cancer among nonsmokers and their relatives. Am J Epidemiol 1996; 144: Matakidou A, Eisen T, Bridle H, et al. Case-control study of familial lung cancer risks in UK women. Int J Cancer 2005; 116: Poole CA, Byers T, Calle EE, et al. Influence of a family history of cancer within and across multiple sites on patterns of cancer mortality risk for women. Am J Epidemiol 1999; 149: Hemminki K, Vaittinen P. Familial cancers in a nationwide family cancer database: age distribution and prevalence. Eur J Cancer 1999; 35: Li X, Hemminki K. Familial and second lung cancers: a nationwide epidemiologic study from Sweden. Lung Cancer 2003; 39: Gao YT, Blot WJ, Zheng W, et al. Lung cancer among Chinese women. Int J Cancer 1987; 40: Tsugane S, Watanabe S, Sugimura H, et al. Smoking, occupation and family history in lung cancer patients under fifty years of age. Jpn J Clin Oncol 1987; 17: Tsugane S, Sasaki S, Tsubono Y. Under- and overweight impact on mortality among middle-aged Japanese men and women: a 10-y follow-up of JPHC study cohort I. Int J Obes 2002; 26: Sobue T, Yamamoto S, Hara M, et al. JPHC Study Group. Japanese Public Health Center. Cigarette smoking and subsequent risk of lung cancer by histologic type in middle-aged Japanese men and women: the JPHC study. Int J Cancer 2002; 99: Tsugane S, Sobue T. Baseline survey of JPHC study: design and participation rate; Japan Public Health Center-based prospective study on cancer and cardiovascular diseases. J Epidemiol 2001; 11:S24 S29 31 International classification of diseases and health related problems, tenth revision. Geneva, Switzerland: World Health Organization, International classification of diseases for oncology. 3rd ed. Geneva, Switzerland: World Health Organization, Ambrosone CB, Rao U, Michalek AM, et al. Lung cancer histologic types and family history of cancer: analysis of histologic subtypes of 872 patients with primary lung cancer. Cancer 1993; 72: Ooi WL, Elston RC, Chen VW, et al. Increased familial risk for lung cancer. J Natl Cancer Inst 1986; 76: Lubin JH, Blot WJ. Assessment of lung cancer risk factors by histologic category. J Natl Cancer Inst 1984; 73: McDuffie HH, Klaassen DJ, Dosman JA. Female-male differences in patients with primary lung cancer. Cancer 1987; 59: Zang EA, Wynder EL. Cumulative tar exposure: a new index for estimating lung cancer risk among cigarette smokers. Cancer 1992; 70: Risch HA, Howe GR, Jain M, et al. Are female smokers at higher risk for lung cancer than male smokers? A case-control analysis by histologic type. Am J Epidemiol 1993; 138: Dwyer T, Blizzard L, Shugg D, et al. Higher lung cancer rates in young women than young men: Tasmania, 1983 to Cancer Causes Control 1994; 5: Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996; 88: Thun MJ, Day-Lally CA, Calle EE, et al. Excess mortality among cigarette smokers: changes in a 20-year interval. Am J Public Health 1995; 85: Bach PB, Kattan MW, Thornquist MD, et al. Variations in lung cancer risk among smokers. J Natl Cancer Inst 2003; 95: Bain C, Feskanich D, Speizer FE, et al. Lung cancer rates in men and women with comparable histories of smoking. J Natl Cancer Inst 2004; 96: Hemminki K, Li X. Gender effects in familial cancer. Int J Cancer 2002; 102: Salber EJ, MacMahon B. Cigarette smoking among high school students related to social class and parental smoking habits. Am J Public Health 1961; 51: Cote ML, Kardia SL, Wenzlaff AS, et al. Risk of lung cancer among white and black relatives of individuals with earlyonset lung cancer. JAMA 2005; 293: Kreuzer M, Kreienbrock L, Muller KM, et al. Histologic types of lung carcinoma and age at onset. Cancer 1999; 85: Sellers TA, Elston RC, Atwood LD, et al. Lung cancer histologic type and family history of cancer. Cancer 1992; 69: Li X, Hemminki K. Inherited predisposition to early onset lung cancer according to histological type. Int J Cancer 2004; 112: Nakachi K, Imai K, Hayashi S, et al. Genetic susceptibility to squamous cell carcinoma of the lung in relation to cigarette smoking dose. Cancer Res 1991; 51: Kawajiri K, Nakachi K, Imai K, et al. Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P450IA1 gene. FEBS Lett 1990; 263: Bartsch H, Nair U, Risch A, et al. Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers. Cancer Epidemiol Biomarkers Prev 2000; 9: Gauderman WJ, Morrison JL. Evidence for age-specific genetic relative risks in lung cancer. Am J Epidemiol 2000; 151: CHEST / 130 / 4/ OCTOBER,