1 Respiratory Medicine (2007) 101, Identification of a mesothelioma phenotype Jill A. Ohar a,, Elizabeth J. Ampleford b, Suzanne E. Howard a, David A. Sterling c a Wake Forest University School of Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Medical Center Boulevard, Winston-Salem, NC , USA b Wake Forest University School of Medicine, Public Health Sciences and Center for Human Genomics, Medical Center Boulevard, Winston-Salem, NC , USA c School of Public Health, Saint Louis University Health Science Center, 3545 Lafayette Avenue, Saint Louis, MO 63104, USA Received 16 December 2005; accepted 30 June 2006 KEYWORDS Asbestos; Occupational disease; Mesothelioma Summary Despite the strong association of asbestos exposure to mesothelioma, only a fraction of persons exposed develop this neoplasm which is characterized by long latency and shortened survival. Familial clustering implicates both exposure and genetic predisposition as causative, but a biologically relevant mesothelioma phenotype essential to genetic analysis has not been defined. To identify a more extensive set of traits that would define a mesothelioma phenotype for the purpose of genetic analysis, we set to determine characteristics that distinguish mesothelioma patients from others exposed to asbestos and to identify factors that predict the presence of mesothelioma over other mesenchymal tumors of the peritoneum and carcinoma metastatic to the pleura. We compared demographics in four asbestos-exposed groups (controls n ¼ 347, bronchogenic cancer n ¼ 67, mesothelioma n ¼ 179 and benign asbestos-induced lung disease (BALD) n ¼ 3757). Within the mesothelioma group, we compared traits to identify characteristics associated with shortened survival. We found that compared to other asbestos-exposed groups, subjects with mesothelioma were younger at first asbestos exposure, had a greater risk of a second cancer diagnosis (odds ratio ¼ 3.29), had a longer disease latency, and had a greater risk of cancer among first-degree relatives (point estimate for risk 2.93; 95% CI ). Thoracic tumor location, work exposure and male gender were consistently associated with shortened survival ( years). We conclude that thoracic tumor location, work exposure, male gender, long latency, early age at first exposure, presence of a second cancer, and first-degree relative with cancer define a phenotype that sets mesothelioma patients with a short survival apart from other asbestos-exposed individuals. We propose that this phenotype be applied to candidate gene analysis. & 2006 Elsevier Ltd. All rights reserved. Corresponding author. Tel.: ; fax: address: (J.A. Ohar) /$ - see front matter & 2006 Elsevier Ltd. All rights reserved. doi: /j.rmed
2 504 Introduction Asbestos exposure can cause asbestosis, benign pleural disease, lung cancer and mesothelioma. Only a small portion of exposed individuals develop an asbestos-related disease and a still smaller fraction develops mesothelioma. In spite of the large number of exposures, malignant mesothelioma is a rare disorder with new cases reported annually in the US. 1 Tragically, patients with mesothelioma have a median survival of 12 months and rarely survive greater than 2 years after diagnosis despite vigorous therapy. 2 4 A history of asbestos exposure can be elicited in more than 80% of mesothelioma patients, and long latency is the only demographic that reportedly sets mesothelioma victims apart from other asbestos-exposed individuals. 5 7 Mesothelioma may have a familial distribution, suggesting a genetic role in its development Genes located at 1p, 6q 9p, 13q and 14q have been implicated in familial clusters of mesothelioma. 12,13 Development of mesothelioma is likely the result of a complex interaction among multiple genes, host factors and the environment as seen in chronic obstructive pulmonary disease and asthma. 11,14,15 Identification of such genes requires rigorous phenotypic classification, but such a comprehensive system is not currently available. We believe that a clinically meaningful phenotype must incorporate salient features of this disease, including the heterogeneity of biological responses to asbestos, the long latency in development of mesothelioma, and the abbreviated survival associated with this neoplasm. To delineate a set of traits that would define a mesothelioma phenotype essential to genetic analysis, we set two specific aims: to identify characteristics that (1) distinguish mesothelioma patients from others exposed to asbestos and that (2) predict the presence of mesothelioma over other mesenchymal tumors of the peritoneum and cancer metastatic to the pleura. To determine characteristics that distinguish mesothelioma patients from others exposed to asbestos, we report demographic data from 179 subjects diagnosed with mesothelioma compared with data from similarly exposed subjects with asbestos-induced bronchogenic cancer, benign asbestosinduced lung disease (BALD) and exposed subjects that were free of demonstrable asbestos-induced disease (controls). Because shortened survival is the only previously reported condition that suggests mesothelioma over other mesenchymal tumors of the peritoneum and metastatic cancer to the pleura, 7,16 we compared traits within the mesothelioma group to find those associated with shortened survival. Methods Asbestos-exposure histories, demographic characteristics, personal and family medical history of 4350 consecutive referrals for independent medical evaluation (IME) were compared. Mesothelioma patients (n ¼ 179) were compared to subjects who were free of radiologically detectable asbestos-induced disease (controls n ¼ 347), or had benign radiographic manifestations of their asbestos exposure (BALD n ¼ 3757) or lung cancer (LC n ¼ 67). BALD refers to all nonmalignant asbestos-related disease defined by the American Thoracic Society as: asbestosis, pleural thickening or asbestos-related pleural fibrosis (plaques or diffuse fibrosis). 17 The details of this population have already been reported. 18 A chest X-ray and an extensive questionnaire were obtained as part of the referral process. B-readings and ILO scores J.A. Ohar et al. Chest X-rays were performed and interpreted by one of several certified B-readers. 18 X-rays were also reread by a single non-b-reader physician investigator. Chest X-ray abnormalities were quantified by the B-reader according to the International Labor Organization (ILO) scoring system. 19 Subjects who were classified as controls due to lack of radiographic findings were recruited through the same mechanisms, worked in the same trades and for the same duration as other subjects. Controls, however, were screened on two separate occasions, at least 10 years apart to exclude subclinical or slowly evolving asbestos-induced lung disease that was not apparent at the time of the first evaluation. To qualify as a control, the chest X-ray had to be completely free of asbestos-induced abnormalities on both occasions. Asbestos exposure and health history questionnaire Detailed information about prior employment, smoking history, personal and family health history was obtained using a self-administered questionnaire. Subjects quantified their tobacco use according to method of smoking (cigarette, cigar, or pipe), packs per day, age of initiation and cessation of tobacco use. Subjects listed every job since completion of schooling (name of company, job title and tasks performed). Personal health history questions included a listing of all medications and hospitalizations including dates of confinement and diagnoses. A personal history of cardiovascular, other respiratory diseases and the occurrence of cancer were obtained. Subjects were asked the age and cause of death of their parents and siblings. A family history of cancer was queried. Other questions included the year of first exposure to asbestos and employment in trades or at locations known to be associated with asbestos exposure. Asbestos exposure qualified as occupational when it entailed working directly with or beside tradesmen working directly with asbestos-containing materials. Exposure was deemed bystander if asbestos dust was brought home on work clothing, through ambient air currents from a neighborhood factory or household remodeling All questionnaire responses were discussed and verified with the patient by the physician investigator (JO) at the time of the evaluation. Survival after diagnosis of mesothelioma was calculated as the time in years between the date of diagnosis and the date of death. For mesothelioma subjects surviving at the time of analysis (September 2005) survival was calculated as the time in years between the date of diagnosis and the date of analysis.
3 Identification of a Mesothelioma phenotype 505 Statistical analysis To support the two specific aims the data were analyzed two ways; among groups and between groups. To determine traits that set mesothelioma victims apart from others exposed to asbestos, subjects were grouped by clinical condition into one of four categories: mesothelioma, lung cancer, BALD and controls. Variables assessed included gender, age at first exposure, latency, history of cigarette smoking, pack/years of cigarette exposure, personal history of cancer, family history of cancer, education, job classification and milieu of exposure based on whether exposure was occupational or bystander. Variables were compared among the four clinical groups (mesothelioma, lung cancer, BALD and controls) and differences for continuous variables were determined by analysis of variance (ANOVA). Significance of differences was determined by Tukey Kramer post hoc testing. Categorical variables were compared using w 2. Because survival may predict the presence of mesothelioma over other mesenchymal tumors of the peritoneum and cancer metastatic to the pleura, the second aim was to identify traits that were associated with a shortened survival among mesothelioma patients. The variables listed above and the following characteristics were compared between the mesothelioma groups: type of exposure (occupational or bystander) location of tumor (pleural vs. peritoneal), gender, cell type (epithelial, sarcomatoid, and biphasic), age at first exposure, latency, survival and family history of cancer. A set of algorithms was then constructed to define a subset of mesothelioma subjects with shortened survival to be used in combination with the demographic traits found to identify asbestos-exposed individuals at greatest risk for mesothelioma. Results Variables that distinguish mesothelioma subjects from other asbestos-exposed groups Subjects with mesothelioma were first exposed to asbestos at an earlier age than all other groups (Table 1). When bystander-exposed mesothelioma subjects were excluded from the analysis, a significant difference in age at first exposure to asbestos persisted between occupationally exposed mesothelioma subjects and BALD ( vs years, respectively, Po0.0001). Because the age at diagnosis was similar for all groups, mesothelioma subjects had a significantly greater latency compared with all other groups. Subjects with cancer (mesothelioma and lung cancer) had a significantly (odds ratio estimate ¼ 3.29 ( ) 95% CI Po0.0001) greater risk of an additional second cancer diagnosis compared with subjects without cancer (BALD and controls). The most common second primary cancer in mesothelioma patients was prostate cancer. The point estimate for risk of a first degree relative of a mesothelioma patient having cancer was 2.93 (95% CI ) compared with first-degree relatives of subjects with lung cancer, BALD, or controls. When first-degree relatives were characterized further as siblings, children and parents of a mesothelioma patient the point estimate for risk of having cancer was 2.9 ( ; 95% CI), 6.75 ( ; 95% CI) and 2.3 ( ; 95% CI), respectively, compared with first-degree relatives of subjects with BALD. Gastro-intestinal neoplasia was the most common cancer type among first-degree relatives of mesothelioma patients. Mesothelioma patients were slightly more educated ( years) compared with subjects with lung cancer, BALD and controls ( , and years of schooling, respectively: Po0.001). The mean ILO score expressed on a continuous linear scale revealed no significant differences between mesothelioma, lung cancer and BALD. Mesothelioma patients smoked less than subjects with lung cancer and BALD but not controls (Table 1). Twenty-seven percent of mesothelioma patients never smoked compared with less than 1% of subjects with BALD and 1% of controls. All subjects with lung cancer smoked. Mesothelioma phenotype that predicts survival Mean survival after diagnosis for mesothelioma subjects was years. Predictors for a shortened survival within the mesothelioma group were thoracic location or work exposure or male gender (Table 2). Based on these variables, three sets of algorithms were created to identify a mesothelioma phenotype with characteristics that predicted survival (Table 3). Whatever the order in which they were implemented, the same 166 subjects were identified with each algorithm with a mean survival post-diagnosis of years. The 13 subjects consistently excluded by this algorithm (mean survival post-diagnosis of years) had bystander exposures and peritoneal tumor Table 1 Subjects with mesothelioma were exposed early, had a longer latency and smoked less than comparators. Mesothelioma Lung cancer Benign asbestos Control Age at first exposure (years) 16.3 (8.1) 23.7 (7.8) 23.6 (6.5) 23.1 (6.6) Latency (years) 47.9 (11) 40 (10) 41 (10.3) 39 (10.5) Age at diagnosis (years) 64.2 (13.5) 64 (8.9) 64.6 (9.8) 62.2 (10.2) Pack years 31.1 z (37.8) 55.6 y (35.1) 41.8 (33.9) 34.8 (46.1) Data reported as mean (SD). Po0.001 vs. all others. Po vs. controls. y Po0.01 vs. all others. z Po0.005 vs. BALD.
4 506 J.A. Ohar et al. Table 2 Thoracic location, male gender, and occupational exposure predict shorten survival. Location Exposure Gender Cell type Survival Peritoneal Thoracic Work Bystander M F Epith Non 42 years 16 (76) 52 (32) 40 (31) 28 (55) 43 (31) 25 (51) 58 (44) 9 (23) p2 years 5 (24) 106 (68) 88 (65) 23 (45) 92 (69) 19 (41) 71 (56) 30 (77) Total p ¼ p ¼ p ¼ p ¼ Data reported as n (%). Table 3 Peritoneal mesotheliomas were significantly younger at the time of first exposure, more likely the result of bystander exposure and experienced shorter latencies than pleural mesotheliomas. Exposure type Tumor location Sex Occupational Bystander Pleural Peritoneal Male Female n (%) 128 (72) 51 (28) 158 (88) 21 (12) 135 (75) 44 (25) first exposure (years) (mean7sd) 19.3 (5.1) 8.6 (9.5) z 17 (7.6) 11.4 (10.3) 17.9 (6.2) 11.5 (11) Latency (y) (mean7sd) 49.2 (9.6) 44.5 (13.5) y 49.2 (10.1) 38.9 (13.1) 49.1 (10) 44.5 (13.1) Age at diagnosis (years) (mean7sd) 68.5 (10.3) 53.7 (14.9) z 50.3 (16) 66.1 (12) 66.9 (11.6) 56 (15.4) Sex Male n (%) 118 (87) 17 (13) z 127 (94.1) 8 (5.9) Female n (%) 10 (23) 34 (77) z 21 (70.5) 13 (29.5) Tumor location Pleural n (%) 122 (95.3) 6 (4.7) Peritoneal n (%) 36 (70.6) 15 (29.4) Data reported as n (%). y Po0.05 exposure type. z Po exposure type. Po0.001 tumor location Po sex. Po0.05 sex. location. Those excluded may represent individuals with mesenchymal tumors other than mesothelioma. Table 4 analysis. Mesothelioma phenotype proposed for genetic Other demographics of the mesothelioma population African Americans were under represented in the cohort but were distributed equally among the four groups (mesothelioma ¼ 3.4%, lung cancer ¼ 6.0%, BALD ¼ 6.4% and controls ¼ 8.9%). Men accounted for 96.2% of the cohort however; there was a greater proportion of women (Po0.0001) in the mesothelioma group (24.6%) than in subjects referred for other asbestos-induced disorders. Female mesothelioma subjects were first exposed to asbestos at an earlier age and had a shorter latency than males (Table 4). Asbestos exposure factors: Work-related Early age Patient demographics: Male gender Second Cancer Cancer in first-degree relative Tumor factors: Thoracic location Long latency
5 Identification of a Mesothelioma phenotype 507 There were significantly more women than men in the bystander group. Age at first exposure was significantly less for individuals exposed as bystanders, but latency tended also to be shorter in bystander (Po0.05) compared to occupational exposure. Peritoneal mesotheliomas were more likely the result of bystander exposure than occupational exposure, whereby pleural mesothelioma was more frequently associated with occupational type exposures (Table 4). Subjects with peritoneal mesotheliomas were significantly younger at the time of first exposure to asbestos and experienced shorter latencies than subjects with pleural mesothelioma (Table 4). There was no significant association between gender, location or exposure milieu and mesothelioma cell type (epithelioid, sarcomatous or biphasic). Mesothelioma was diagnosed by cytologic examination and not typed in 11 subjects (6%). Pathologic examination of the remaining 168 subjects revealed the cell type to be epithelioid in 129 (77%), sarcomatoid in 16 (9%) and biphasic in 23 (14%). Although the commonest cell type in both men and women was epithelioid, there was a trend (P ¼ 0:06) toward men more frequently having the sarcomatous cell type than women and the inverse with biphasic type. Latency was longer for subjects with the sarcomatous cell type compared with the epithelioid cell type of mesothelioma ( vs years). There was no effect of location (pleural vs. peritoneal) or exposure milieu (occupational vs. bystander) on cell type. Discussion The object of this study was to characterize a mesothelioma phenotype that distinguished mesothelioma patients from other asbestos-exposed study participants and predicted the presence of mesothelioma over other mesenchymal tumors of the peritoneum or cancer metastatic to the pleura to be used in future candidate gene analysis. While familial distributions of mesothelioma have been described, genetic association studies for mesothelioma have yielded conflicting results. Hirvonen et al. 26,27 found an association between asbestos-related pulmonary disorders and GST mu, but only when coupled with an N-acetyl transferase (NAT) 2 slow-acetylator genotype. More recently, Neri et al. 28 found an increased odds ratio for mesothelioma in subjects who had genotypic low microsomal epoxide hydrolase activity. They also demonstrated augmentation of risk in subjects with NAT fast acetylator or glutathione-stransferase mu null genotypes in combination with genotypic low microsomal epoxide hydrolase activity. 28 Stucker et al. 29 using pooled data from the Genetic Susceptibility and Environmental Carcinogens International Database, found no association between asbestos exposure and GST mu and t genotypes and asbestos-induced carcinogenesis. The mixed results of these susceptibility studies may be the result of failure to rigorously phenotype participants. This challenging task must take into account the variable clinical responses to asbestos exposure and biologic behavior of mesothelioma. To date, only long latency and shortened survival have been consistently reported as hallmarks of the mesothelioma phenotype. 2 6 We confirmed the long latency association. Moreover, we found that subjects with mesothelioma were younger at first asbestos exposure, had a greater risk of a second cancer diagnosis and had a greater risk to cancer for first-degree relatives. Furthermore, we found that thoracic tumor location, work (vs. bystanders) exposure and male gender-predicted shortened survival. The link between early age at first exposure to asbestos and mesothelioma in our data set persisted even after patients with bystander exposures were excluded from the analysis. We could find one other report in the literature associating age at first exposure to asbestos to risk for mesothelioma and this was in animals. 30 Berry and coworkers demonstrated in rats that early age of inoculation was a significant risk factor for mesothelioma. In contrast to our observations, Peto and coworkers found that age at first exposure was not an independent risk factor; however, Peto et al. 31 focused on occupationally exposed individuals with the youngest age at exposure being 15 years. The obvious explanation for early exposure as a mesothelioma risk is that immature lungs have increased sensitivity to carcinogens. Alternatively, it is possible that the smaller airways of children and women retain more fibers than do the larger airways of adults, especially men. Becklake et al. 32 and coworkers suggested that body size is a factor in mesothelioma development. 33 While others have reported that mesothelioma patients experience a longer latency, smoked less and had firstdegree relatives that developed cancer more frequently than asbestos-exposed comparators, major new findings in our data set are that subjects with mesothelioma are exposed to asbestos at an earlier age and had a second cancer diagnosed more frequently than other asbestosexposed groups. When first-degree relatives were further separated into siblings, parents and children of mesothelioma subjects, a startling increase in risk for cancer became apparent for children. Taken together, the observations that first-degree relatives of mesothelioma subjects developed cancer more frequently and that mesothelioma subjects develop another cancer other more frequently than comparators suggest an increased genetic susceptibility of mesothelioma subjects to cancer. Vianna and Polan 40 postulated such a genetic predisposition to malignant mesothelioma based on increased frequency of parental cancer in patients with mesothelioma compared to control frequencies. The frequency of a parent with malignancy was 17/52 (33%) in a cohort of women with mesothelioma from a bystander exposure. 40 Heineman et al. 41 also provided evidence for family history of cancer being a risk factor for mesothelioma. The increased likelihood of second cancers in mesothelioma patients and of cancer among first-degree relatives is important not only to investigation of genetic predispositions to neoplasia, but also to the comprehensive clinical care of mesothelioma patients and their families. We conclude that thoracic tumor location, work exposure, male gender, long latency, early age at first exposure, presence of a second cancer, and first-degree relative with cancer define a phenotype that sets mesothelioma patients with a shortened survival apart from other asbestos-exposed individuals. On the basis of the current observations derived from this prospectively studied, rigorously defined population, we propose the mesothelioma phenotype outlined in Table 3 for candidate gene analysis. Of these factors, male
6 508 J.A. Ohar et al. gender and pleural involvement were among independent predictors of shorted survival in previous multivariable analyses of mesothelioma cohorts. In addition, nonepithelial histology, associated with longer latency in our patients, has also been associated with worsened prognosis. Importantly, our shortened survival algorithm which includes thoracic tumor location, work exposure and male gender will exclude subjects who sustained a bystander exposure from genetic analysis. Bystander exposure is a common, clinically important and infrequently recognized risk for mesothelioma. The presence of a large percentage of women and a high frequency of bystander exposure distinguishes this mesothelioma cohort from others previously published. We acknowledge that the proposed phenotype represents a starting point, to be refined further as new analysis and epidemiologic investigations become available. 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