Familial malignant mesothelioma: A population-based study in Central Italy (1980–2012)
Introduction
Asbestos is the well-established major aetiological risk factor for mesothelioma, a rare cancer. As the majority of common neoplasms, mesothelioma is a sporadic cancer (one individual is affected in the family). However, clusters among blood relatives (two or more affected individuals), often referred to as ‘familial’, have been reported since the 1970s [1]. It is clear that a familial aggregation of mesothelioma may simply be due to shared asbestos exposures, as reported in the vast majority of studies [1], [2], [3], [4]; however, there is the possibility that the occurrence of family clusters might be due genetic susceptibility [5]. There are several pieces of evidence that corroborate this hypothesis. Only a relatively small fraction of asbestos exposed individuals develop the disease [6], [7] and given asbestos exposure, a family history of cancer may indicate an increased susceptibility [8]. Some metabolic gene polymorphisms may modify the risk of developing mesothelioma [9], [10]. Recent genome-wide association studies have identified genetic variants associated with increased risk of malignant pleural mesothelioma [11], [12]. There are reports of this malignancy in subjects affected by rare inherited diseases, i.e., multiple exostoses [13], Li–Fraumeni syndrome [14], Marfan and Ehlers–Danlos syndromes [15], neurofibromatosis type 2 [16], familial Mediterranean fever [17] and acne inversa [18]. To-date, the evidence for a genetic predisposition is also suggested the occurrence of mesothelioma in familial cancer syndromes, as observed in carriers of TP53 [19], [20] and BRCA1 associated-protein1 (BAP1) gene mutations [21]. Finally, almost a twofold risk of mesothelioma was found in blood relatives of mesothelioma patients in the Wittenoom cohorts of workers exposed to crocidolite [22].
Because of the rarity of familial mesothelioma, there are limited epidemiological investigations and its occurrence is likely to be underestimated. The available studies have not been able to estimate the burden of familial mesothelioma, namely the proportion of cases with an affected relative (familial proportion) [23]. Among the family studies, only a few were at the population level [1], [22].
We aimed to provide epidemiological data on familial mesothelioma, taking advantage of a population-based mesothelioma registry operating in central Italy [24], covering 5.5 million inhabitants (about one tenth of the country population). This registry is part of the network of the Italian National Mesothelioma Register (ReNaM); it represents roughly one tenth of the mesothelioma burden in Italy [25]. We estimated the proportion of familial mesotheliomas in the population covered by the registry. In addition, we report the details of the familial clusters, including the generation pattern involved, and the family history of cancer.
Section snippets
Data source of cases
The mesothelioma registry of the Lazio region (including the city of Rome) (Regional Operative Center, COR-Lazio), covers for the period 2001–2012 all residents with a new diagnosis of mesothelioma and collects information on the individual exposure to asbestos. It is based on the compulsory notification of cases and on active search also. The procedures and the criteria for assessing the level of diagnostic certainty are described in the ReNaM guidelines (//www.ispesl.it/dml/leo/download/RenamGuidelines.pdf
Results
In the 32-year-period of the study (1980–2012), we identified 34 familial mesotheliomas (13 probands) in the database of 997 cases, accounting for a familial proportion of 3.4% of all mesotheliomas. The male-to-female ratio was 1.6 among the familial cases and 2.3 among all other cases. Thirty-one were mesothelioma of the pleura and three of the peritoneum (only men). Table 1 shows that 20 cases (12 probands) were incident in the 12 years of the COR-Lazio activity 2001–2012, and 14 (1 proband)
Discussion
Our analysis of families with two or more mesotheliomas extends the limited literature on familial mesothelioma, and further defines its characteristics on a population basis. It shows a not negligible proportion (exceeding 3%) of familial mesotheliomas among a large case-series.
The majority of common cancers are sporadic, 5–10% are inherited, and 10–15% are referred to as ‘familial’ [30]. On the basis of the largest Family-Cancer Database available in the world, the proportion of familial
Conflict of interest
None of the authors have any conflicts of interest.
Acknowledgments
The authors want to thank Dr. Carolina Mensi (COR of Lombardia), Dr. Cristiana Pascucci (COR Marche), and Dr. Gert Schallenberg (COR Trento) for their helpful contribute in acquiring family data for three family clusters.
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Cited by (28)
The Role of Germline Mutations in Thoracic Malignancies: Between Myth and Reality
2023, Journal of Thoracic OncologyMalignant mesothelioma and constitutional BAP1 gene mutations
2019, Revue des Maladies RespiratoiresFamilial risk of pleural mesothelioma increased drastically in certain occupations: A nationwide prospective cohort study
2018, European Journal of CancerCitation Excerpt :However, the prevalence of germ line BAP1 mutations in sporadic pleural mesothelioma patients is low, which suggests a minor role of germ line BAP1 mutation in the pathogenesis of sporadic pleural mesothelioma [10,11]. Some studies showed that risk of mesothelioma is increased when relatives are diagnosed with mesothelioma [12–14]. A comprehensive study showed an increased risk of mesothelioma in specific occupations [15].
Epidemiology of Environmental Exposure and Malignant Mesothelioma
2017, Journal of Thoracic OncologyCitation Excerpt :For the purpose of this review, all nonoccupational asbestos exposure was classified as EE and further grouped into the following four categories: (1) exposure to NOA in areas where studies of the geological structure have shown the presence of asbestos but asbestos-related industries are absent; (2) neighborhood exposure based on residence in close proximity to industrial/mining sources of asbestos; (3) household exposure for family members of occupationally exposed subjects, which includes what some authors call familial exposure19,25 and what Camiade et al.43 and Mensi et al.28 called paraoccupational exposure, referring to those who live with an asbestos worker and those who clean asbestos-contaminated clothes; and (4) other nonoccupational exposures, which includes home-related28 or domestic exposure24,41,54 (for example, exposure occurring during hobby/leisure activities,24,26 do-it-yourself (DIY) projects during home maintenance and renovations,28,38 or residence in urban or polluted areas.46,49 The term familial has often been used to refer to studies of genetic susceptibility to MM.21,65 For example, Ascoli et al.21 used familial MM to define a proband or index case in which MM was diagnosed in at least one first-degree relative (parent or sibling), regardless of the type of exposure, in an attempt to disentangle the genetic component of MM from the familial component deriving from a shared environment.
Mesothelioma families without inheritance of a BAP1 predisposing mutation
2016, Cancer GeneticsCitation Excerpt :Over the past 30 years, we have detected 13 MM familial clusters in a population-based study (19). One of these, an asbestos-exposed family with multiple cases of pleural MM and without inheritance of a predisposing BAP1 mutation has been recently reported (30). We have decided to investigate further if additional MM clusters are associated or not with inheritance of a BAP1 germline mutation.