Inference on germline BAP1 mutations and asbestos exposure from the analysis of familial and sporadic mesothelioma in a high‐risk area

Abstract

Inherited loss-of-function mutations in the BAP1 oncosuppressor gene are responsible for an inherited syndrome with predisposition to malignant mesothelioma (MM), uveal and keratinocytic melanoma, and other malignancies. Germline mutations that were inherited in an autosomal dominant fashion were identified in nine families with multiplex MM cases and 25 families with multiple melanoma, renal cell carcinoma, and other tumors. Germline mutations were also identified in sporadic MM cases, suggesting that germline mutations in BAP1 occur frequently. In this article, we report the analysis of BAP1 in five multiplex MM families and in 103 sporadic cases of MM. One family carried a new truncating germline mutation. Using immunohistochemistry, we show that BAP1 is not expressed in tumor tissue, which is in accordance with Knudson's two hits hypothesis. Interestingly, whereas the three individuals who were possibly exposed to asbestos developed MM, the individual who was not exposed developed a different tumor type, that is, mucoepidermoid carcinoma. This finding suggests that the type of carcinogen exposure may be important for the cancer type that is developed by mutation carriers. On the contrary, the other families or the 103 sporadic patients did not show germline mutations in BAP1. Our data show that BAP1 mutations are very rare in patients with sporadic MM, and we report a new BAP1 mutation, extend the cancer types associated with these mutations, and suggest the existence of other yet unknown genes in the pathogenesis of familial MM.

Mesothelioma families without inheritance of a BAP1 predisposing mutation

“…IHC findings in three epithelioid MM cases (C-II-1, D-II-3, O-II-3) suggest that the loss of nuclear staining occurred via somatic mutation Page 10 of 19 (see Figure 1). BAP1 nuclear staining retained in one sarcomatoid MM (G-II-8) is in agreement with other studies reporting data of positive BAP1 staining on sarcomatoid MM [25] and on the absence of BAP1 mutation [9,10,18,19]. Considering all families with multiple cases of MM analyzed to date for BAP1 germline mutations (see Table 2), those described in the present study without a predisposing germline BAP1 mutation are similar to those reported by other investigators [9,10,19].…”

“…Other families were examined as part of asbestos surveillance program [10]. Our families were actively searched based on the Italian Mesothelioma Registry, and detected because the proband (index case) and at least one blood-relative were diagnosed with MM according to the Registry available information.…”

“…Our families were actively searched based on the Italian Mesothelioma Registry, and detected because the proband (index case) and at least one blood-relative were diagnosed with MM according to the Registry available information. Therefore, the recruitment of cases is on a population basis, as those reported by other Italian investigators [10,18,19].…”

“…As of March 2016, forty-six families with multiple cases of MM have been analyzed for BAP1 germline alterations. Some families were proven to carry BAP1 germline alterations in association with family history of either typical BAP1-TPDS cancers [9,10,17] or not typical BAP1-TPDS cancers [9,10,18,19]. In addition, families with multiple cases of MM without inheritance of a predisposing germline BAP1 mutation have been reported [20].…”

“…Germline BAP1 alterations are a rare event in sporadic MM [10,18,[21][22][23]. The majority are benign polymorphisms (SNPs) or variants of unknown significance (VUS) [4,5,23].…”