Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma

Abstract

Malignant mesothelioma (MM) is a uniformly fatal tumour caused predominantly by exposure to asbestos. It is not known why some exposed individuals get mesothelioma and others do not. There is some epidemiological evidence of host susceptibility. BAP1 gene somatic mutations and allelic loss are common in mesothelioma and recently a BAP1 cancer syndrome was described in which affected individuals and families had an increased risk of cancer of multiple types, including MM. To determine if BAP1 mutations could underlie any of the sporadic mesothelioma cases in our cohort of patients, we performed targeted deep sequencing of the BAP1 exome on the IonTorrent Proton sequencer in 115 unrelated MM cases. No exonic germline BAP1 mutations of known functional significance were observed, further supporting the notion that sporadic germline BAP1 mutations are not relevant to the genetic susceptibility of 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].…”

“…Investigators have examined BAP1 in families: i) with high incidence of MM [3,7,9,11,14]; ii) referred to genetic or cancer centers for uveal melanoma [9,12,15] or other melanocytic tumors [13,17]; iii) affected by basal cell carcinoma [16]; iv) having a family history suggestive of the BAP1 cancer syndrome [18]. 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. 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].…”