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Familial malignant mesothelioma
CORRESPONDENCE
Familial malignant mesothelioma Sir—Michele Carbone and Joseph Testa (June 2, p 1804)1 envisage the probable contribution of genetic factors to asbestos-related mesotheliomas. They maintain that they showed genetic susceptibility to mesothelioma in the Cappadocian region of Turkey in a previous report,2 in which they stated “Analysis of a six-generation extended pedigree of 526 individuals showed that mesothelioma was genetically transmitted, probably in an autosomal way”. We can find no support in that report for such an assertion. First, if in the unselected entire population of the Karain and Tuzköy villages malignant mesothelioma causes 50% of deaths in men and women (for Karain this value is in line with our own data3), the finding that 50% of each generation was affected also within the selected subgroup of nuclear families with the disease simply corresponds to what would be expected even without genetic clustering. Second, the expected segregation ratio of affected to non-affected children for autosomal dominant transmission in a group of families with one or two parents affected— heterozygous or homozygous for the putative pathological gene—is not 1:1, but is higher. Instead, the observed segregation ratio does not diverge significantly from 1:1, which speaks, if anything, against Carbone and Testa’s hypothesis. Third, 50% of the cases of mesothelioma occurred between ages 26 and 55 years, within the reproductive period. There is, therefore, a selective pressure against the permanence of a hypothetical autosomal and lethal gene at the very high frequency implied by the mesothelioma rates. Fourth, we wonder how a diagnosis of mesothelioma could be established and confirmed by review of the medical records for the six-generation extended pedigree, since records from the 19th century would be needed. Before 1978, when Baris4 discovered the endemic, mesothelioma was diagnosed as tuberculosis, lung cancer, metastatic cancers, or other disorders. The report by Roushdy-Hammady and co-workers2 shows in pedigree B a third-generation case who died at age 61 years, and his grandfather died at 55. Even under the most favourable assumptions—death of the case in 2000, age at reproduction 17 years— the grandfather could not have died later than 1960, which is long before
THE LANCET • Vol 358 • November 24, 2001
local recognition of the disease. As late as 1979–83, when we contributed to establishing the causal role of environmental erionite,3,5 we could only rely on the direct diagnostic investigations done with Baris and his team rather than on seldom existent medical records. The conjecturing of a genetic component in the causation of some mesotheliomas is one thing; to show its actual role is another, requiring much more information than reported. This evidence is essential scientifically and for the wider public-health implications, given the weight that a genetic factor may carry when debating liability in asbestos-related mesotheliomas. *Rodolfo Saracci, Lorenzo Simonato *Division of Epidemiology, IFC-National Research Council, Via Trieste 41, 56100 Pisa, Italy; and Department of Environmental Medicine and Public Health, University of Padua, Padova (e-mail: [email protected]) 1
2
3
4
5
Carbone M, Testa JR. Genetic susceptibility and familial malignant mesothelioma. Lancet 2001; 357: 1804. Roushdy-Hammady I, Siegel J, Enri S, Testa JR, Carbone M. Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey. Lancet 2001; 357: 444–45. Baris Y, Simonato L, Artvinli M, et al. Epidemiological and environmental evidence of the health effects of exposure to erionite: a four-year study in the Cappadocian region of Turkey. Int J Cancer 1987; 39: 10–17. Baris YI, Sahin AA, Ozesmi M, et al. An outbreak of pleural mesothelioma and chronic fibrosing pleurisy in the village of Karain/Urgup in Anatolia. Thorax 1978; 33: 181–92. Saracci R, Simonato S, Baris Y, et al. The age-curve of endemic pleural mesothelioma in Karain, Central Turkey. Br J Cancer 1982; 45: 147–49.
Authors’ reply Sir—The proportion of deaths due to mesothelioma was higher in the selected subgroup of nuclear families with the disease than in the entire unselected population of Karain and Tuzköy. 50% of each generation of the entire population of these villages was affected. Moreover, the small size of these inbred villages may have led to genetic drift, resulting in a high frequency of a genetic mutation in a putative cancer gene or a polymorphism in a tumour-modifier locus that may make some families very susceptible to erionite. Only three of 22 nuclear families had two affected parents. Also, Rodolfo Saracci and Lorenzo Simonato’s comments about the 1:1 segregation ratio do not take into account the possibility of incomplete
penetrance. Moreover, within the nuclear families with high tumour incidence, the ratio of affected to nonaffected individuals exceeds 1:1. Furthermore, many individuals are still young and still could develop mesothelioma. The median age at death from mesothelioma was 55 years (median survival <1 year). However, only one mesothelioma death occurred in a patient younger than 30 years, and only seven in patients younger than 40. Thus, most individuals are past their prime reproductive years by diagnosis, lessening the effect of genetic pressure. In addition, women in Cappadocia have most of their children in their early 20s. Information about mesothelioma was limited to the three most recent generations. Most mesotheliomas were diagnosed after 1970. All diagnoses were confirmed by SE, who worked on Baris’s team.1 Of course genetic studies must be done to isolate this putative mesothelioma susceptibility gene, and, later, functional studies should be done to delineate its role in the pathogenesis of the disease. However, the information we report is a crucial first step. Our concern is science, not litigation issues. Finally, and most importantly, we do not dispute the role of erionite as a causal factor in the development of mesotheliomas. Erionite is extremely carcinogenic in rats, more so than asbestos.2,3 However, animal data must be interpreted with caution. For example, in hamsters, although SV40 is much more potent than asbestos in causing mesothelioma,2 we would not suggest that SV40 is the main cause of human mesothelioma and that asbestos has a secondary role. The type of erionite did not differ in houses in Karain (high incidence of mesothelioma) and Tuzköy. Individuals in adjacent houses in the same village have very different incidence of mesothelioma, despite similar exposures, which suggests that other factors also contribute to mesothelioma. Few erionite fibres are thought to be required to initiate mesothelioma.2 Since fibres are present in all the houses in and even sample air Karain and Tuzköy,1 all of the villagers should have contracted mesothelioma, if erionite were the only cause. Instead, nuclear families with different tumour rates lived in different houses, which suggests a genetic predisposing factor. Our analyses suggest a genetic factor for susceptibility to erionite carcinogenicity. Whether this genetic
1813
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Familial malignant mesothelioma Sir—Michele Carbone and Joseph Testa (June 2, p 1804)1 envisage the probable contribution of genetic factors to asbestos-related mesotheliomas. They maintain that they showed genetic susceptibility to mesothelioma in the Cappadocian region of Turkey in a previous report,2 in which they stated “Analysis of a six-generation extended pedigree of 526 individuals showed that mesothelioma was genetically transmitted, probably in an autosomal way”. We can find no support in that report for such an assertion. First, if in the unselected entire population of the Karain and Tuzköy villages malignant mesothelioma causes 50% of deaths in men and women (for Karain this value is in line with our own data3), the finding that 50% of each generation was affected also within the selected subgroup of nuclear families with the disease simply corresponds to what would be expected even without genetic clustering. Second, the expected segregation ratio of affected to non-affected children for autosomal dominant transmission in a group of families with one or two parents affected— heterozygous or homozygous for the putative pathological gene—is not 1:1, but is higher. Instead, the observed segregation ratio does not diverge significantly from 1:1, which speaks, if anything, against Carbone and Testa’s hypothesis. Third, 50% of the cases of mesothelioma occurred between ages 26 and 55 years, within the reproductive period. There is, therefore, a selective pressure against the permanence of a hypothetical autosomal and lethal gene at the very high frequency implied by the mesothelioma rates. Fourth, we wonder how a diagnosis of mesothelioma could be established and confirmed by review of the medical records for the six-generation extended pedigree, since records from the 19th century would be needed. Before 1978, when Baris4 discovered the endemic, mesothelioma was diagnosed as tuberculosis, lung cancer, metastatic cancers, or other disorders. The report by Roushdy-Hammady and co-workers2 shows in pedigree B a third-generation case who died at age 61 years, and his grandfather died at 55. Even under the most favourable assumptions—death of the case in 2000, age at reproduction 17 years— the grandfather could not have died later than 1960, which is long before
THE LANCET • Vol 358 • November 24, 2001
local recognition of the disease. As late as 1979–83, when we contributed to establishing the causal role of environmental erionite,3,5 we could only rely on the direct diagnostic investigations done with Baris and his team rather than on seldom existent medical records. The conjecturing of a genetic component in the causation of some mesotheliomas is one thing; to show its actual role is another, requiring much more information than reported. This evidence is essential scientifically and for the wider public-health implications, given the weight that a genetic factor may carry when debating liability in asbestos-related mesotheliomas. *Rodolfo Saracci, Lorenzo Simonato *Division of Epidemiology, IFC-National Research Council, Via Trieste 41, 56100 Pisa, Italy; and Department of Environmental Medicine and Public Health, University of Padua, Padova (e-mail: [email protected]) 1
2
3
4
5
Carbone M, Testa JR. Genetic susceptibility and familial malignant mesothelioma. Lancet 2001; 357: 1804. Roushdy-Hammady I, Siegel J, Enri S, Testa JR, Carbone M. Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey. Lancet 2001; 357: 444–45. Baris Y, Simonato L, Artvinli M, et al. Epidemiological and environmental evidence of the health effects of exposure to erionite: a four-year study in the Cappadocian region of Turkey. Int J Cancer 1987; 39: 10–17. Baris YI, Sahin AA, Ozesmi M, et al. An outbreak of pleural mesothelioma and chronic fibrosing pleurisy in the village of Karain/Urgup in Anatolia. Thorax 1978; 33: 181–92. Saracci R, Simonato S, Baris Y, et al. The age-curve of endemic pleural mesothelioma in Karain, Central Turkey. Br J Cancer 1982; 45: 147–49.
Authors’ reply Sir—The proportion of deaths due to mesothelioma was higher in the selected subgroup of nuclear families with the disease than in the entire unselected population of Karain and Tuzköy. 50% of each generation of the entire population of these villages was affected. Moreover, the small size of these inbred villages may have led to genetic drift, resulting in a high frequency of a genetic mutation in a putative cancer gene or a polymorphism in a tumour-modifier locus that may make some families very susceptible to erionite. Only three of 22 nuclear families had two affected parents. Also, Rodolfo Saracci and Lorenzo Simonato’s comments about the 1:1 segregation ratio do not take into account the possibility of incomplete
penetrance. Moreover, within the nuclear families with high tumour incidence, the ratio of affected to nonaffected individuals exceeds 1:1. Furthermore, many individuals are still young and still could develop mesothelioma. The median age at death from mesothelioma was 55 years (median survival <1 year). However, only one mesothelioma death occurred in a patient younger than 30 years, and only seven in patients younger than 40. Thus, most individuals are past their prime reproductive years by diagnosis, lessening the effect of genetic pressure. In addition, women in Cappadocia have most of their children in their early 20s. Information about mesothelioma was limited to the three most recent generations. Most mesotheliomas were diagnosed after 1970. All diagnoses were confirmed by SE, who worked on Baris’s team.1 Of course genetic studies must be done to isolate this putative mesothelioma susceptibility gene, and, later, functional studies should be done to delineate its role in the pathogenesis of the disease. However, the information we report is a crucial first step. Our concern is science, not litigation issues. Finally, and most importantly, we do not dispute the role of erionite as a causal factor in the development of mesotheliomas. Erionite is extremely carcinogenic in rats, more so than asbestos.2,3 However, animal data must be interpreted with caution. For example, in hamsters, although SV40 is much more potent than asbestos in causing mesothelioma,2 we would not suggest that SV40 is the main cause of human mesothelioma and that asbestos has a secondary role. The type of erionite did not differ in houses in Karain (high incidence of mesothelioma) and Tuzköy. Individuals in adjacent houses in the same village have very different incidence of mesothelioma, despite similar exposures, which suggests that other factors also contribute to mesothelioma. Few erionite fibres are thought to be required to initiate mesothelioma.2 Since fibres are present in all the houses in and even sample air Karain and Tuzköy,1 all of the villagers should have contracted mesothelioma, if erionite were the only cause. Instead, nuclear families with different tumour rates lived in different houses, which suggests a genetic predisposing factor. Our analyses suggest a genetic factor for susceptibility to erionite carcinogenicity. Whether this genetic
1813
For personal use. Only reproduce with permission from The Lancet Publishing Group.