Mesothelioma families without inheritance of a BAP1 predisposing mutation

Familial malignant mesothelioma clusters are ideal candidates to explore BAP1 genomic status as a predisposing risk factor. We report data on BAP1 analysis in four families with multiple mesothelioma cases to investigate possible BAP1 alterations associated with an inherited cancer syndrome. We also recorded family history of cancer and assessed asbestos exposure. By genomic direct sequencing, we found no evidence of a BAP1 germline mutation in tumor DNA samples (one mesothelioma per family: n = 3 epithelioid; n = 1 biphasic). On the other hand, we identified a novel BAP1 somatic alteration (c.329_335delinsTC) in exon 5 (n = 1 biphasic), and we hypothesized the occurrence of somatic inactivating events not identifiable by sequencing in the other cases (n = 3 epithelioid), as demonstrated by the loss of nuclear BAP1 immunostaining. History of other cancers was in sites not typical of the BAP1 cancer syndrome. Asbestos exposure was occupational (n = 2 clusters), household (n = 1), and unknown (n = 1). These family units without inheritance of a BAP1 predisposing mutation expand the number of unmutated germline BAP1 families with multiple mesothelioma cases. This suggests that besides the exposure to asbestos other currently unknown genetic or epigenetic factors may be responsible for the high incidence of mesothelioma in BAP1-unmutated families.

Introduction

Malignant mesothelioma (MM) occurs as sporadic cancer (one affected individual in the family) generally in association with asbestos exposure. Its occurrence as clusters among blood-relatives (two or more individuals are affected) suggests increased genetic susceptibility.

BAP1 (BRCA1-associated protein 1) is a tumor suppressor gene located on chromosome 3p21.1, encoding for a deubiquitinating enzyme that requires nuclear localization (1). BAP1 regulates cell cycle control, target genes transcription, and DNA damage repair (2). The germline mutation in the BAP1 gene is associated with a hereditary tumor predisposition syndrome (BAP1-TPDS, OMIM#614327) that occurs in family members with several cancer types: MM, uveal/cutaneous melanoma, renal cell carcinoma, basal cell carcinoma and other cancers 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. 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 mutations described to date are nucleotide-level mutations.

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. Those of pathogenic significance have been described in association with BAP1-TPDS malignancies 4, 21, 24, 25, 26, 27, 28. On the other hand, somatic mutations of BAP1 are a frequent event in MM 26, 28, 29, with a variable rate of occurrence depending on the molecular assay used. Somatic mutations described to date are both nucleotide-level and chromosomal mutations (30).

MM familial clusters among blood-relatives are ideal candidates to identify BAP1 germline carriers associated with the putative BAP1 cancer syndrome. Familial mesothelioma is defined by the diagnosis of two or more blood-relatives affected by MM. 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.