Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations

Abstract

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact.

Keywords: Asbestos; BAP1; Cancer genetics; Germline mutations; Mesothelioma; Tumor predisposition syndromes.

Figure 1.. Incidence of different cancer types in carriers of germline BAP1 mutations.

Compiled from 97 papers from Pubmed from 2011 – January of 2022, including a total of 689 individuals (309 female, 268 male, and 112 unknown), in which 553 developed cancer: 27% had 2–7 tumor types. Percentage of tumors indicated in the figure represent the percentage of carriers of germline BAP1 mutations who develop that specific tumor type. Age range: 12-years-old with meningioma, 84 years-old with mesothelioma. Median age of mesothelioma diagnosis was 55-years-old. MM, malignant mesothelioma; UVM, uveal melanoma; CM, cutaneous melanoma; ccRCC, clear cell renal cell carcinoma: BCC, basal cell carcinoma; SCC, squamous cell carcinoma; ca, cancer; MBAITs, melanocytic BAP1-mutated atypical intradermal tumor.

Figure 2.. Pedigree of the P-family.

Date of birth and date of death are indicated when known. MM, malignant mesothelioma, ccRCC, clear cell renal cell carcinoma, UVM, uveal melanoma. The diagnoses are based on review of medical records and information from treating physicians; the diagnoses of mesothelioma were further verified by the review of the histology and of the imunostains. Information about some of the patients in this pedigree can be found in ref.

Figure 3.. Early mesothelioma nodules in carriers of germline BAP1 mutations from the P-family.

These nodules were identified during laparoscopy (patient 1 and patient 2), and VATS (patient 3, see histology in Supplementary Figure 1). These nodules are common in carriers of germline BAP1 mutations, and they often have an indolent biological behavior for several years.

Figure 4.. Schematic representation of the BAP1 protein with pathogenic and likely pathogenic variants reported as of February 2022.

The previously reported, and some unreported (M.C. et al, unpublished), BAP1 variants were classified according to the American College of Medical Genetics and Genomics (ACMG) model. The deubiquitylating enzyme, BAP1, contains a catalytically active ubiquitin carboxy-terminal hydrolase domain (UCH 1–240), an unstructured non-organized region (NORS 241–598), a C-terminal domain (CTD 599–699), and a nuclear localization signal (NLS 656–661 and 717–722). The locations of pathogenic and likely pathogenic variants are shown on the BAP1 protein in their associated domains. Missense mutations are marked with a green dot, truncating variants are shown with a red dot. Graphical representation does not include large germline deletions found in four families, including two families affected by multiple malignancies carrying a whole heterozygous BAP1 gene deletion (ref. and M.C. et al., unpublished observations), variants lacking protein structure prediction, variants of unknown significance (VUS, as classified using the ACMG model), benign variants, and others that did not meet the cut off criteria for ACMG scoring due to high population frequency or lack of critical information. For additional information of the variants, see Supplementary Table 1. Fs: frame shift; * stop codon; splice: aberrant splicing. Created with Biorender.com.

Figure 5.. BAP1 Immunostaining.

A-B. Benign mesothelial hyperplasia. A. Cystic mesothelial inclusion in a patient that had previous surgery for ectopic pregnancy and developed peritoneal adhesions (H/E stain). B. The single layer of mesothelial cells showing nuclear BAP1 staining, evidence that this is a benign lesion. C-F. Peritoneal epithelioid mesothelioma. C. Single layer of benign mesothelial cells forming a nodular area known as “in situ” mesothelioma (H/E stain); D. BAP1 nuclear expression is retained in normal and lost in malignant cells (nodule) supporting a diagnosis of mesothelioma in situ (pre-invasive malignant lesion). This patient had another focus of frankly invasive mesothelioma whose cells had lost BAP1 nuclear expression). E-F. Malignant peritoneal epithelioid mesothelioma (E, H/E staining) with BAP1 loss and adjacent fibrosis with benign spindle reactive mesothelial cells and fibroblasts in which nuclear BAP1 staining is retained (F). G-H. Pleural biopsy. Same patient as E, F, developed a year later mesothelioma in the pleura. G (H/E stain) shows a microcystic papillary pleural mesothelioma that appears to be a very early lesion (new primary appears more likely than spread from previous peritoneal mesothelioma). H. BAP1 immunostaining shows normal mesothelium with retained BAP1 next to malignant mesothelium with BAP1 loss. I-L Malignant biphasic pleural mesothelioma, epithelioid component (I-J), sarcomatoid component (K-L). There is BAP1 nuclear loss in both epithelioid and sarcomatoid components, evidence that both round and spindle cells are malignant. Note that BAP1 is retained in the nuclei of background reactive benign mesothelial spindle cells; the latter can be distinguished by the malignant cells because of their smaller size and bland nuclear features.