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1 ORIGINAL CONTRIBUTION Risk of Lung Cancer Among White and Black Relatives of Individuals With Early-Onset Lung Cancer Michele L. Coté, PhD Sharon L. R. Kardia, PhD Angela S. Wenzlaff, MPH John C. Ruckdeschel, MD Ann G. Schwartz, PhD, MPH CIGARETTE SMOKING HAS LONG been established as the major risk factor for lung cancer in the general population. 1 However, familial aggregation of disease, even after adjusting for smoking habits, has also been identified. 2-4 Greatest risk is seen in families with early-onset disease compared with those whose onset of lung cancer occurred at older ages. 5-8 The recent identification of a susceptibility region on chromosome 6 provides more evidence that lung cancer development is not only a disease of environmental origins (ie, tobacco smoking) but that a genetic predisposition to lung cancer also exists. 9 However, discovery of the specific germline mutations and development of a predictive genetic test for lung cancer are still years off. In the interim, approximately new diagnoses were estimated to have occurred in the United States in 2004 alone. 10 Many of these individuals will seek clinical advice for what this diagnosis means for their relatives. This study quantifies risk of lung cancer across a lifetime by race, smoking status, and family history of earlyonset lung cancer, which could be used to identify high-risk individuals and to Context Evidence exists that lung cancer aggregates in families and recent findings of a chromosomal region linked to lung cancer susceptibility support a genetic component to risk. Family studies of early-onset lung cancer patients offer a unique opportunity to evaluate lifetime risk of lung cancer in relatives. Objective To measure lung cancer aggregation and estimate lifetime risk among relatives of early-onset cases and population-based controls. Design and Setting Familial aggregation and cumulative risk estimates from interview data of incident cases and concurrently ascertained controls between 1990 and 2003 in metropolitan Detroit, Mich. Participants The study included 7576 biological mothers, fathers, and siblings of 692 early-onset cases and 773 frequency-matched controls. One third of the population was black. Main Outcome Measures Cumulative lifetime risk of lung cancer, stratified by race and smoking behavior in relatives of early-onset cases and controls. Results Smokers with a family history of early-onset lung cancer in a first-degree relative had a higher risk of developing lung cancer with increasing age than smokers without a family history. An increase in risk occurs after age 60 years in these individuals, with 17.1% (SE 2.4%) of white case relatives and 25.1% (SE 5.8%) of black case relatives diagnosed with lung cancer by age 70 years. Relatives of black cases were at statistically significant increased risk of lung cancer compared with relatives of white cases (odds ratio, 2.07, 95% confidence interval, ) after adjusting for age, sex, pack-years, pneumonia, and chronic obstructive lung disease. Conclusions First-degree relatives of black individuals with early-onset lung cancer have greater risk of lung cancer than their white counterparts, and these risks are further amplified by cigarette smoking. These data provide estimates of lung cancer risk that can be used to offer counseling to family members of patients with early-onset lung cancer. JAMA. 2005;293: counsel families with a history of earlyonset lung cancer. METHODS Study Population Families were identified through population-based lung cancer cases diagnosed before age 50 years (case probands) and population-based controls younger than 50 years (control probands). Eligible cases were identified through the Metropolitan Detroit Cancer Surveillance System (MDCSS), a participant in the National Cancer Insti- Author Affiliations: Population Studies and Prevention Program, Karmanos Cancer Institute at Wayne State University, Detroit, Mich (Drs Coté, Ruckdeschel, and Schwartz and Ms Wenzlaff) and University of Michigan School of Public Health, Ann Arbor (Dr Kardia). Corresponding Author: Michele L. Coté, PhD, Epidemiology, 110 E Warren Ave, Detroit, MI JAMA, June 22/29, 2005 Vol 293, No. 24 (Reprinted) 2005 American Medical Association. All rights reserved.

2 tute s Surveillance, Epidemiology, and End Results program. Cases were defined as those with a primary neoplasm of the lung or bronchus (invasive behavior, International Classification of Diseases, Ninth Revision (ICD-9) codes C , any histology excluding , , 9140, , and ), residing in Wayne, Macomb, or Oakland counties of Michigan at the time of diagnosis. Populationbased controls in the same age ranges were ascertained concurrently via random-digit dialing. Case and control probands were frequency matched by (selfreported by choosing from a list) race, sex, 5-year age group, and county of residence. All analyses were restricted to white and black individuals. Data for 3663 family members of cases (mean of 5.3 per case proband) and 3913 family members of controls (mean of 5.1 per control proband) were included in these analyses. Data Collection This protocol was approved by the local institutional review board. Written informed consent was mailed to probands. If signed consent forms were not returned prior to initiation of the interview, verbal consent was obtained from all probands at the start of the interview. Risk-factor information for firstdegree relatives (biological parents, siblings, children) was obtained from probands or their proxies. Because lung cancer is almost nonexistent in children, only parents and siblings 18 years and older were included in these analyses. Smoking status, number of cigarettes smoked per day, and years of smoking were collected for each family member. Past medical history for each relative included asking if a physician had ever diagnosed any of the following conditions: asthma, allergies, chronic bronchitis, emphysema, pneumonia, chronic obstructive pulmonary disease (COPD), tuberculosis, or cancer. Statistical Analyses Case and control probands were not included in the analysis. Distributions of categorical variables were compared between case and control relatives using 2 tests and means of continuous variables were compared using t tests. Kaplan-Meier survival analysis was used to estimate the lifetime risks and age at diagnosis distribution in relatives of the probands. Estimates of cumulative risk of lung cancer for relatives were calculated with stratification by race and reported pack-years of tobacco smoking. Kaplan-Meier survival analysis was also used to estimate the cumulative risk by pack-year history at diagnosis for relatives of cases and controls, stratified by race. P values from log-rank tests of equality were used to assess statistically significant differences between the strata. To determine whether familial risk of lung cancer was present after adjustment for risk factors among relatives, unconditional logistic regression models using generalized estimating equations (GEEs), that take into account family correlation structures were used to estimate odds ratios and P values. 11 The final multivariable model used in all regression analyses for case and control relatives included variables found to be significant ( =.05) in the multivariable models: age, race, sex, packyears, history of chronic obstructive lung disease (for analysis, the variable included any report of COPD, chronic bronchitis, or emphysema), and history of pneumonia, as well as family history of early-onset lung cancer. Risk in black case relatives compared with white case relatives was evaluated using an unconditional logistic regression GEE model, adjusting for age, sex, pack-years, history of chronic obstructive lung disease, and history of pneumonia for each relative. SAS version 8.02 was used for all Kaplan-Meier and GEE analyses. 12 RESULTS Cumulative risk estimates and odds ratios (ORs) were based on family data provided by 692 early-onset cases and 773 controls. Among case probands, 311 (44.9%) had adenocarcinomas, 90 (13.0%) had small cell lung cancers, 86 (12.4%) had squamous cell carcinoma, 65 (9.4%) had large cell carcinoma, and the remaining 27 (3.5%) cases were non small cell not specified, or 113 (14.6%) other histologic types. In this study group, 13.6% of cases reported having at least 1 firstdegree relative with lung cancer. Only 7.9% of controls reported having a first-degree relative with lung cancer. Family history of lung cancer did not vary by the proband s histologic type (P =.85). Characteristics of family members are reported in TABLE 1. Data were available for 95.8% of case mothers and 94.2% of case fathers. Similarly, information was obtained for 96.6% of control mothers and 95.0% of control fathers. Information was available for 98.7% of case siblings and 98.0% of control siblings. Mother:father and sister: brother ratios did not differ by race. Case mothers and siblings were 1.1 and 2.1 years older at age of death or age at interview, respectively, compared with control mothers and siblings (P=.03 and P.001, respectively). This age difference was not seen in fathers. Approximately two thirds of case and control family members were white. Diagnoses of emphysema (P=.001), pneumonia (P=.002), and tuberculosis (P=.01) were reported more often for case vs control relatives. An allergy diagnosis (P=.03) was reported more often for control relatives. Case family members were more likely to be ever smokers and have higher mean pack-years of smoking compared with control family members (P.001). The strength of familial aggregation of lung cancer was determined by adjusting for age, race, sex, pack-years, history of chronic obstructive lung disease, and pneumonia for each relative in this population. Risk of lung cancer was 1.91-fold greater in first-degree relatives of early-onset cases vs relatives in the control population (95% confidence interval [CI], ; TABLE 2). No statistically significant increase in risk was seen in relatives related to a nonsmoking, early-onset case after adjusting for age and pack-years of smoking in the relatives (OR, 1.08; 2005 American Medical Association. All rights reserved. (Reprinted) JAMA, June 22/29, 2005 Vol 293, No

3 95% CI, ). Risk was nearly 2-fold higher in relatives of ever smoking, early-onset probands vs relatives of ever-smoking control probands after adjustment (OR, 1.98; 95% CI, ). A 5-fold increased risk was identified in white siblings of cases (95% CI, ) with similar risk estimates between sexes (data not shown). Although this finding is statistically significant, it is based on a small number of reported lung cancer diagnoses. Risk of lung cancer among first-degree relatives of black cases was 3.23-fold higher than that of relatives of black controls after adjustment (95% CI, ) and was similar for parents and siblings. Relatives of black cases were at statistically significant increased risk of lung cancer vs relatives of white cases (OR, 2.07; 95% CI, ; data not shown). Cumulative risk estimates for firstdegree relatives, stratified by race and pack-years of cigarette smoking are shown in TABLE 3 and FIGURE 1.Asexpected, greatest risk was seen in case relatives with extensive smoking histories. In smoking relatives who smoked more than 30 pack-years, 5.6% (SE 1.2%) of white case relatives and 10.6%(SE 3.2%) of black case relatives were diagnosed with lung cancer by age 60 years. By age 70 years, risk in these groups had increased to 17.1% (SE 2.4%) in white case relatives and 25.1% (SE 5.8%) in black case relatives as shown in Table 3 and Figure 1, which illustrates that in both white and black control relatives who smoke, going from 30 or fewer packyears of exposure to more than 30 packyears of exposure increases risk primarily after age 65 years. Being related to a case compared with being related to a control increases lung cancer risk across most age groups. FIGURE 2 illustrates the cumulative risk of lung cancer increasing as pack-years of smoking accumulate. Black individuals who are related to a case were at highest risk, exceeding risk in black individuals related to a control(p.001)andexceedingriskinwhite Table 1. Characteristics of First-Degree Relatives of Early-Onset Lung Cancer Cases and Controls Family Characteristics (n = 3663) (n = 3913) P Value Relationship, No. (%) Mother 663 (18.1) 747 (19.1) Father 652 (17.8) 734 (18.8) Sibling 2348 (64.1) 2432 (62.1) Age, mean (SD), y Mother 65.5 (9.5) 64.4 (9.7).03 Father 64.3 (11.4) 64.7 (11.0).54 Sibling 43.0 (8.6) 40.9 (8.7).001 Race, No. (%) White 2397 (65.4) 2503 (64.0) Black 1266 (34.6) 1410 (36.0).18 Ever diagnosed, No. (%) Allergies 168 (4.6) 224 (5.7).03 Asthma 141 (3.9) 157 (4.0).72 Bronchitis 97 (2.7) 82 (2.1).11 COPD 27 (0.7) 31 (0.8).78 Emphysema 142 (3.9) 101 (2.6).001 Pneumonia 198 (5.4) 154 (3.9).002 Tuberculosis 47 (1.3) 28 (0.7).01 Smoking status, No. (%)* Never 1297 (36.1) 1815 (47.0) Ever 2296 (63.9) 2047 (53.0).001 Pack-years among smokers, mean (SD) 35.4 (31.3) 31.9 (29.9).001 Abbreviation: COPD, chronic obstructive pulmonary disease. *Missing data for 70 relatives related to a case and 51 relatives related to a control. Pack-years were unable to be calculated for 484 smoking case relatives and 364 smoking control relatives. individuals related to a case (P.001). White relatives of cases and controls have similar risks at lower levels of pack-year exposure. Risk diverges at approximately 80 pack-years, and elevated risk is seen among those related to a case compared with control relatives although there was not a statistically significant difference across all pack-years of exposure (P=.22). COMMENT In the clinical setting, family members of patients with lung cancer often recognize cigarette smoking as a contributing factor to lung cancer development but are unaware of the potential heritable component of this disease. Recent media coverage of the discovery of a chromosomal region linked to familial lung cancer by the Genetic Epidemiology of Lung Cancer Consortium coupled with increasing interest in genetic testing for cancers will result in more requests by relatives for estimates of their own risk. The results of this study represent the largest population-based sample of case families with early-onset lung cancer to date and provide clinically relevant lung cancer risk estimates for white and black families. Risk of lung cancer varies significantly by race. From 1990 through 2001, the average annual age-adjusted incidence rate of lung cancer in white men was 88.1 per while the average annual age-adjusted rate in black men was per Average incidence rates for black and white women during this time do not show as large a disparity, at 54.5 and 52.2 per per year, respectively. 13 Our findings demonstrate that lung cancer risk associated with family history of lung cancer is stronger in blacks than in whites. This finding could be the result of a higher degree of underlying susceptibility or aggregation of unmeasured risk factors for lung cancer in black families. Familial aggregation of smoking is well established. 14,15 In our analysis, when models were created without adjusting for smoking in each relative (data not shown), the estimated ORs were ap JAMA, June 22/29, 2005 Vol 293, No. 24 (Reprinted) 2005 American Medical Association. All rights reserved.

4 proximately 20% higher than in the smoking-adjusted models. A strength of this study was the ability to adjust for each relative s smoking exposure, so familial aggregation of smoking habits is less likely to be driving the findings reported herein. In our study, smoking habits among relatives were examined by race. Overall, the mean pack-years of smoking reported for black relatives was 26.3 (95% CI, ). In white relatives, the mean pack-years of smoking reported was significantly greater at 36.9 (95% CI, ). These data suggest that black individuals may be more susceptible to lung carcinogens, have different tobacco consumption patterns than their white counterparts that confer increased risk, or have other risk factors that aggregate in families that have not yet been identified. It is plausible that these factors are genetic in nature and seen more frequently in the black population. The analytical approach used capitalized on the availability of risk factor data for relatives. For comparison, we also analyzed our data using a traditional casecontrol analysis of the early-onset probands in our population. We found a 1.7- fold increased risk of lung cancer for individuals who had a first-degree relative with lung cancer compared with those without a family history of lung cancer after adjusting for race, age, sex, and pack-years of smoking (OR, 1.71; 95% CI, ; data not shown). When stratified by race, black cases in our population were nearly 3-fold more likely to have a family history of lung cancer compared with black controls, after adjusting for age, sex, and pack-years of smoking (OR, 2.86; 95% CI, ; data not shown). In our study, familial risk in the black population was higher than that in the white population (OR, 1.29; 95% CI, ; data not shown). These findings provide further evidence that lung cancer aggregates in families and that aggregation is stronger in blacks. Table 2. Risk of Lung Cancer Among First-Degree Relatives of Early-Onset Lung Cancer Cases vs First-Degree Relatives of Controls Affected Unaffected Age at Diagnosis, Mean (SD), y Affected Unaffected Age at Diagnosis, Mean (SD), y Odds Ratio (95% Confidence Interval) Total sample (9.9) (10.1) 1.91 ( )* Ever-smoker proband (9.2) (11.2) 1.98 ( ) Nonsmoker proband (16.6) (8.6) 1.08 ( ) White (9.6) (8.0) 1.48 ( ) Parent (8.3) (7.4) 1.38 ( ) Mother (9.3) (6.8) 1.32 ( ) Father (8.0) (7.8) 1.37 ( ) Sibling (7.8) (12.0) 5.22 ( ) Black (10.3) (13.7) 3.23 ( ) Parent (9.9) (9.7) 3.17 ( ) Mother (8.2) (4.9) 5.23 ( ) Father (9.5) (11.5) 1.57 ( ) Sibling (7.1) (22.6) 4.34 ( ) *Odds ratio adjusted for age, race, sex, pack-years, pneumonia, and chronic obstructive lung disease. Odds ratio adjusted for age and pack-years of smoking. Odds ratio adjusted for age, sex, pack-years, pneumonia, and chronic obstructive lung disease. Table 3. Cumulative Risk Percentage of Lung Cancer in First-Degree Relatives of Early-Onset Cases and Population-Based Controls Cumulative Risk (SE), % by Age, y by Age, y White relatives All 0.9 (0.2) 2.8 (0.5) 9.2 (1.2) 0.1 (0.1) 1.8 (0.4) 5.1 (0.9) In smoking relatives, pack-years Total 1.5 (0.4) 4.3 (0.9) 13.7 (1.8) 0.1 (0.1) 2.9 (0.8) 9.1 (1.6) (0.3) 1.9 (1.1) 5.5 (2.3) 0.0 (0.0) 3.1 (1.4) 3.9 (1.6) (0.7) 5.6 (1.2) 17.1 (2.4) 0.3 (0.3) 2.8 (0.9) 11.8 (2.3) Black relatives All 1.7 (0.5) 5.7 (1.1) 12.1 (2.0) 0.5 (0.3) 1.8 (0.6) 4.1 (1.2) In smoking relatives, pack-years Total 2.3 (0.96) 9.1 (2.1) 19.9 (3.8) 1.0 (0.6) 3.2 (1.6) 5.7 (2.1) (1.3) 7.0 (2.5) 12.9 (4.1) 1.6 (0.9) 3.5 (1.6) 3.5 (1.6) (0.8) 10.6 (3.2) 25.1 (5.8) 0.0 (0.0) 2.5 (1.8) 7.7 (3.9) 2005 American Medical Association. All rights reserved. (Reprinted) JAMA, June 22/29, 2005 Vol 293, No

5 Figure 1. Cumulative Risk of Lung Cancer in Smoking Relatives by Pack-Years and Relation to an Early-Onset Case or Control White Relatives Black Relatives Cumulative Risk, % >30 Pack-Years of Smoking 30 Pack-Years of Smoking >30 Pack-Years of Smoking 30 Pack-Years of Smoking Cumulative Risk, % Age, y Age, y Figure 2. Cumulative Risk of Lung Cancer by Pack-Years and Relation to an Early-Onset Case or Control % In our early-onset population, no increase in risk was seen in family members of nonsmoking probands after adjusting for age and pack-years of smoking for each relative. Familial risk of lung cancer among nonsmokers and their relatives has been described in several studies. In a population-based study of nonsmokers in Detroit, Mich, Schwartz et al 16 reported that relatives related to a nonsmoking proband diagnosed between ages 40 and 59 years were at 6.1-fold increased risk after adjusting for smoking, occupational, and medical history in each family member (OR, 6.1; 95% CI, ). 16 However, these findings have not been replicated in other populations. A second population-based study examined lung cancer risk in relatives of both never and Black White Black White Pack-Years of Smoking former smokers who had lung cancer and did not identify significantly increased risk in fathers (OR, 1.85; 95% CI, ) or mothers (OR, 1.12; 95% CI, ) of these never and former smoking cases after adjustment for age and smoking status in each family member. 17 A hospital-based study from Texas also reported no evidence for increased risk of lung cancer among relatives of never-smokers, after adjusting for age and smoking status of the proband and relative (OR, 0.86; 95% CI, ). 18 It is difficult to compare results across studies with various inclusion criteria and study methods and limited sample sizes. This is an area that requires further study. Chronic obstructive pulmonary disease has been shown to be associated with an increased risk of lung cancer independent of smoking history 19,20 and familial aggregation has been observed In our population, aggregation of chronic obstructive lung disease with early-onset lung cancer was identified in white relatives (OR, 1.48; 95% CI, ) but not in black relatives (OR, 0.76; 95% CI, ) after adjusting for age, sex, packyears and history of pneumonia. Chronic obstructive lung disease was not prevalent enough in these relatives to calculate risk of lung cancer by disease status; however, it is possible that risk of lung cancer is even greater for those with a personal history of COPD and that underlying susceptibility varies by race. The associations between COPD, smoking, family history, and race need to be evaluated further. Limitations Our study has several limitations. We were unable to contact 37.2% of case probands identified during this period. However, there were no significant differences between participants and those who did not participate, stratified by race, age at diagnosis, sex, or histology. Data for both case and control family members were obtained from the proband or a proxy, due to the prohibitive cost of interviewing each family member. Proxy reporting has been shown to be accurate for cancers, 24,25 lung disease, 26 and cigarette consump JAMA, June 22/29, 2005 Vol 293, No. 24 (Reprinted) 2005 American Medical Association. All rights reserved.

6 tion, 27 the types of data analyzed in this study. Lung cancer lifetime risk estimates provided by the Surveillance, Epidemiology, and End Results program are similar to the cumulative risks of lung cancer reported in our control relatives; therefore, it is unlikely that our study controls are underreporting family history of lung cancer. 13 Two of the most important variables, age and pack-years of cigarette smoking, were examined to determine the amount of missing data. Ages were missing for 1.9% of control relatives, including 1 relative with lung cancer, and 3.2% of case relatives, including 6 relatives with lung cancer. Exclusion of individuals with missing ages may bias the Kaplan-Meier estimates and the resulting age at onset distribution. 28 To determine whether the missing ages in our sample biased the results of this study, 3 data sets were created with imputed ages appropriate for each relationship and race strata. The resulting analyses using the imputed data sets did not appreciably alter the findings; thus, the original data set (without age imputation) was used. Pack-year information was unavailable for 484 case relatives (13.2%) and 364 control relatives (9.3%). Black men, regardless of relationship to a case or control, were more likely to have missing pack-year information. Individuals with missing information were excluded from analyses, thereby dropping 22 lung cancers among family members of cases (13 of which were black men) and 5 lung cancers in control families (2 of which were black men). Therefore, risk estimates are likely to be conservative. When data were reanalyzed using a smoking indicator with fewer missing data (number of cigarettes per day or years of smoking) instead of pack-years, the findings remained essentially the same. Because risk estimates are based on contributions of each relative, stratified by race and adjusting for their age, sex, and packyears of smoking, and not on an aggregate family history measure, differential missing data by race or sex should not bias these estimates. Overreporting of lung cancers, particularly for case relatives may also account for the magnitude of our findings. Therefore, attempts were made to verify the lung cancers reported among family members. We identified a subset of 115 case and control relatives with lung cancer for whom we had name, year of birth, and year of death information in an attempt to verify lung cancer status through the MDCSS and Michigan death certificates. Seventy-two (62.6%) were confirmed through these mechanisms. Lack of unique identifying information (ie, social security numbers) and recent institutional review board modifications restricting the reporting of certain information without the family member s consent made this process difficult. When analysis was performed including only confirmed lung cancer cases, the findings were essentially the same. The findings presented herein are applicable to first-degree relatives of earlyonset lung cancer cases. Early-onset cases ( 50 years at diagnosis) represent 6.7% of lung cancers diagnosed in the United States. 13 The focus of this study was on early-onset disease because there is a greater likelihood of a genetic component to risk in this group. Risk estimates presented herein, therefore, may not be applicable for counseling families with a history of lateronset lung cancer. Implications Familial aggregation of lung cancer was demonstrated in families identified through early-onset lung cancer cases, after other known risk factors were adjusted for in the analysis. These findings are similar to previous reports 3,4,29 but are the first to report risks for African American families. Additionally, Table 3 and Figure 1 and Figure 2 can be used by clinicians to counsel relatives of cases about their risk of developing lung cancer based on family history of early-onset disease and personal tobacco use. Family history assessment should be included when evaluating smokers or those presenting with symptoms consistent with lung disease. Further characterization of high-risk individuals is important to provide clinicians with counseling tools and to enhance the effectiveness of screening programs. Family history of early-onset lung cancer in a first-degree relative should be considered a risk factor in other relatives older than 18 years. As knowledge about risk factors (other than tobacco use) for lung cancer increases, physicians may be more likely to consider lung cancer as a differential diagnosis in their young patients. Earlier diagnosis and intervention may reduce mortality and morbidity in this population. Ongoing trials should evaluate the usefulness of screening modalities among those with a family history of early-onset lung cancer. Author Contributions: Dr Coté had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Coté, Schwartz. Acquisition of data: Coté, Schwartz. Analysis and interpretation of data: Coté, Kardia, Wenzlaff, Ruckdeschel, Schwartz. Drafting of the manuscript: Coté, Kardia, Schwartz. Critical revision of the manuscript for important intellectual content: Coté, Kardia, Wenzlaff, Ruckdeschel, Schwartz. Statistical analysis: Coté, Kardia, Schwartz. Obtained funding: Schwartz. Administrative, technical, or material support: Wenzlaff, Schwartz. Study supervision: Schwartz. Financial Disclosures: None reported. Funding/Support: This work was supported by National Cancer Institute grant RO1-CA60691 and contract NO1 CN65064 (Dr Schwartz). Role of the Sponsor: The National Cancer Institute played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. REFERENCES 1. Doll R, Hill A. A study of the aetiology of carcinoma of the lung. BMJ. 1952;2: Bromen K, Pohlabeln H, Jahn I, Ahrens W, Jockel KH. Aggregation of lung cancer in families: results from a population-based case-control study in Germany. Am J Epidemiol. 2000;152: Ooi WL, Elston RC, Chen VW, Bailey-Wilson JE, Rothschild H. Increased familial risk for lung cancer. J Natl Cancer Inst. 1986;76: Tokuhata G, Lilienfeld A. Familial aggregation of lung cancer in humans. 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