Inherited Predisposition to Malignant Mesothelioma: Germline BAP1 Mutations and Beyond

European Review for Medical and Pharmacological Sciences 2021; 25: 4236-4246 Inherited predisposition to malignant mesothelioma: germline BAP1 mutations and beyond

F. PAGLIUC A1, F. ZITO MARINO1, F. MORGILLO2, C. DELLA CORTE2, M. SANTINI3, G. VICIDOMINI3, G. GUGGINO4, G. DE DOMINICIS5, S. CAMPIONE5, M. ACCARDO1, I. COZZOLINO1, R. FRANCO1

1Department of Mental and Physical Health and Preventive Medicine, Pathology Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy 2Department of Precision Medicine, Medical Oncology Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy 3Department of Translational Medicine, Thoracic Surgery Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy 4Antonio Cardarelli Hospital, Thoracic Surgery Unit, Naples, Italy 5Antonio Cardarelli Hospital, Pathology Unit, Naples, Italy

Abstract. – Malignant mesothelioma (MM) Introduction is a rare aggressive neoplasm arising from mesothelial lining of body cavities, most common- Malignant mesothelioma (MM) is a rare but ly pleura and peritoneum. It is characterised by highly lethal tumour derived from mesothelial a poor prognosis and limited treatment options. cells. MM has traditionally been considered an A universally recognised risk factor for the development of MM is exposure to asbestos. How- occupational disease due to its strong association ever, evidence supporting a genetic suscepti- with exposure to asbestos, a group of naturally bility to the development of MM has been accu- occurring minerals extensively used in the con- mulating during the last decades. Intensive re- struction industry1. Despite many countries having search for the identification of MM susceptibil- banned asbestos in recent years, the incidence of ity genes has led to the discovery of BAP1 and MM has kept increasing worldwide2. This trend to the definition of the so-called BAP1 “ -related tumour predisposition syndrome”. Patients is partially explained by the long latency period carrying germline BAP1 mutations have an in- (30-50 years) between exposure to asbestos and the creased risk for the early development of tu- development of the neoplasm3. The existence of mours, including MMs, uveal melanomas, cuta- other types of minerals with still unknown patho- neous melanocytic lesions, clear cell renal cell genetic properties may also contribute4. Exposure carcinomas and basal cell carcinomas. Further- to mineral carcinogens, however, is not the only more, pathogenic variants in tumour suppres- risk factor for MM. It is clearly established that sor genes with a role in DNA repair have been recently described in families with clustered MM genetic factors play a fundamental role in deter- cases. These genetic alterations seem to confer mining individual susceptibility and modulating exaggerate sensitivity to asbestos carcinogen- response to environmental factors5. In fact, only ic effect and, arguably, increased response to a minority of highly asbestos-exposed individuals specific chemotherapeutic strategies. While the 4 develop MM , in absence of any dose-response translational significance of BAP1 alterations is relationship6. Furthermore, it was early noticed explored in the research field, the identification of families carrying germline BAP1 mutations is that cases of MM tend to cluster in some fami- mandatory to start appropriate surveillance pro- lies, suggesting the existence of hereditary factors grams and guarantee the best clinical manage- conferring exaggerated vulnerability to asbestos7. ment to these patients. To date, still little is known about the genomic landscape of MM and the inherited predisposition Key Words: to this malignancy. The present review will focus Mesothelioma, BAP1, BAP1-related tumour predisposition syndrome. on the current knowledge about genetic alterations in sporadic MM, the definition of familial MM, its

4236 Corresponding Author: Renato Franco, MD; e-mail: [email protected] Inherited predisposition to malignant mesothelioma: germline BAP1 mutations and beyond clinical, pathological and molecular peculiarities, Three main histological subtypes are recog- and their supposed therapeutic and translational nized: epithelioid, sarcomatoid and biphasic. implications. Epithelioid MMs constitute approximately 60% of all cases; sarcomatoid MMs are less Epidemiology, Pathogenesis, Clinical common, accounting for approximately 20% of and Pathological Features of MM all. Biphasic MMs are characterised by a com- MM arises from the mesothelial layer of serous bination of both epithelioid and sarcomatoid his- membranes, including pleura, peritoneum, peri- tologies. Survival is associated with histological cardium and tunica vaginalis of the testis, cover- subtype10,11: a pure epithelioid histology correlates ing body cavities. Mesothelial cells derive from with the longest survival while patients with sar- the embryonic mesoderm. They express both comatoid histology have the worst survival. mesenchymal and epithelial markers and form a Currently, combination chemotherapy consist- protective monolayer with an important role in ing of pemetrexed plus cisplatin remains the the regulation of inflammation, wound healing only established treatment for advanced MM. and antigen presentation. The pleura is the most Other approaches, including immune checkpoint frequently site for MM, accounting for 80-90% inhibithors and targeted therapies have failed of all cases, followed by the peritoneum (10-15% to show brilliant results. Innovative treatment of all cases). The incidence of MM greatly varies strategies, such as vaccines and adoptive T-cell according to geographic areas, but it is generally therapy, are still under investigation. higher among male patients, affected approximately 4 times more than females. The Genetic Landscape of Sporadic MM A universally-recognised causative agent for The genomic landscape of MM stands out the development of MM is exposure to a group of for the abundance of chromosomal aberrations, mineral fibres collectively referred to as ‘asbes- with copy number losses and/or gains involving tos’. The roles of other factors, such as exposure most chromosomes and an overall low mutation to Simian Virus 40 (SV40)8 or radiations, is still burden. In the past years, pivotal studies based controversial. In the past, asbestos products have on whole genome sequencing of MM have also been widely exploited in construction and other identified recurrent somatic alterations in a set of industries for their appealing physical properties1. tumour suppressor genes, with a role in cell cycle In the last decades, since its recognition as the progression, DNA repair or regulation of inflam- main etiological agent for MM, asbestos has been matory response12,13. The most prevalent somatic banned in more developed countries. However, it mutations in MM involve, in order of frequency, is still used in several emerging countries, often the following genes: BRCA-1 associated protein 1 without adequate measures for worker safety. (BAP1), neurofibromin 2 (NF2), encoding merlin, Asbestos-related carcinogenesis requires a long and cyclin-dependent kinase inhibitor 2A (CDK- latency period (30-50 years)3. As a result, the in- N2A), encoding p16INK4A and p14ARF. cidence of MM has dramatically increased in the A detailed overview about the genetics of last twenty years2 in the industrialized countries sporadic mesothelioma is beyond the scope of the and it is expected to peak around 2020-2025. present work. Herein, we will focus on BAP1. In The most recent incidence data available for fact, the presence of germline mutations in BAP1 the USA, published by the Surveillance, Epide- has been associated to a specific tumour predis- miology and End Results (SEER) of the National position syndrome accounting for a proportion of Cancer Institute (NCI), report an incidence rate familial MM cases14-17. of 0,8/100.000 for the period 2014-2018, with a median age at diagnosis of 74 years9. From the Very Beginning: MM is usually diagnosed in advanced stage, the ‘Cappadocia Epidemic’ when radical surgery is not achievable and only The first observations in favour of a genetic few and poorly efficient systemic treatment op- risk factor for MM date back to more than 50 tions are available. Clinical presentation is usual- years ago. In the Seventies, a group of research- ly subtle, with non-specific symptoms and signs. ers led by professor Baris from the Department These include fatigue, chest pain, dyspnea and of Chest Disease of University of Ankara, Tur- cough for pleural mesothelioma; abdominal pain, key, started autonomous on-field investigation abdominal distension and anorexia for peritoneal in central Anatolia. Their aim was to study mesothelioma. the epidemiology of asbestos-related diseases

4237 F. Pagliuca, F. Zito Marino, F. Morgillo, C. Della Corte, M. Santini, et al in a Turkish region rich in asbestos mines and detected by immunohistochemistry on forma- asbestos workers18. During their explorations, lin-fixed and paraffin-embedded tissues (Figure they identified a group of three closely proxi- 1-2). It usually derives from chromosomal de- mal Cappadocian villages where mesothelioma letions involving its locus on chromosome 3, a incidence was about 1000 times higher than in recurrent event in numerous human malignancies the rest of the region. Moreover, it showed an such as renal cell carcinoma, non-small cell lung equal, 1:1 distribution between men and women cancer and breast carcinoma. However, inactivat- and between pleural and peritoneal cases19. At ing mutations of various types, including inser- that time, in those villages, over 50% of deaths tions, deletions, frameshift and base substitutions could be attributed to mesothelioma20. Levels may also account for BAP1 loss of function. No of asbestos and erionite, another carcinogenic mutational hotspot has been currently identified fibrous mineral, were present at high concentra- for the BAP1 gene. Regardless of its specific type, tions in the buildings of the area. However, they all pathogenetically relevant mutations of BAP1 did not exceed those observed in surrounding cause the impairment of the deubiqinating activi- villages and could not explain such dramat- ty or loss of the nuclear localization sequences of ic epidemiological anomalies21. Thanks to the the protein. combined efforts of professor Baris crew and Dr. M. Carbone and collaborators from United Germline BAP1 Mutations and States, it was ascertained that susceptibility to Familial Mm: The “BAP1-Related MM among the population experiencing the Tumour Predispotion Syndrome” mesothelioma ‘epidemic’ seemed to be inherit- Germline mutations of BAP1 are inherited in ed as an autosomal-dominant character22. After an autosomal dominant pattern with high, albeit years and years of tireless research, a mesotheli- incomplete, penetrance31. They underlie the so- oma susceptibility gene was finally identified in called, recently described, “BAP1-related tumour 2011. That gene was BAP123. Amusingly, BAP1 predisposition syndrome” (OMIM #614327). Ac- mutations could account for only a minority of cording to the Knudson ‘two-hit’ hypothesis, af- familial mesothelioma cases spotted in various fected individuals inherit a non-functioning copy countries all over the world; in particular, BAP1 of the gene while the second allele is inactivated germline alterations failed to be demonstrated later during their lifetime. Patients have an in- in the Cappadocian mesotheliomas, raising the creased risk for the early development of tumours possibility of other, still undiscovered, germline such as, in decreasing order of frequency, uveal mutations underlying the inherited predisposition melanomas, MMs, atypical Spitz tumours/cuta- to MM24. Apart from its rare germline vari- neous melanomas, clear cell renal cell carcino- ants, BAP1 mutations are currently recognised as mas and basal cell carcinomas32,33. the most frequent genetic alterations in sporadic Other neoplasms which have been proposed as MMs, followed by alterations in neurofibromin 2 part of the spectrum of BAP1-related syndrome (NF2) and cyclin-dependent kinase inhibitor 2A are breast and ovarian carcinomas, cholangiocar- 25 (CDKN2A) genes . They have been associated cinomas, lung adenocarcinomas, meningiomas, with younger age at onset, epithelioid histological neuroendocrine carcinomas and some soft tissue subtype and improved prognosis26-30. tumours (fibrous histiocytomas and undifferen- tiated pleomorphic sarcomas). However, further BAP1 Gene and Protein Function investigation is needed to sharply define the full The BAP1 gene (BRCA1-associated protein phenotype of the syndrome34,35. 1) is located on the short arm of chromosome 3 The most recent and comprehensive review (3p21.1). Identified and firstly described in 1998, on the topic counted 181 different families it encodes a 729 amino acid-deubiquitinating worldwide carrying BAP1 variants, encompass- hydrolase with nuclear localization29 with mul- ing 140 unique pathogenetic variants36. None- tiple functional domains and binding partners. theless, these numbers are expected to steadily It cooperates in the regulation of many cellular increase in the next future. In fact, according processes such as DNA repair, cellular differen- to the results of studies performed on large tiation, proliferation and cell-cycle progression, exome-sequencing databases, BAP1 syndrome acting as a tumour suppressor30. is likely underrecognized and underreported, BAP1 loss of function has been observed in being actually much more frequent than initially many sporadic tumours and can be promptly thought37.

4238 Inherited predisposition to malignant mesothelioma: germline BAP1 mutations and beyond

Figure 1. A case of MM with BAP1 loss. 66-year-old woman with right pleural mass. VATS biopsies show a proliferation of atypical epithelioid cells with a predominant papillary architecture (A). Immunohistochemical stains for calretinin (B) and WT-1 (C) were positive, supporting a diagnosis of epithelioid mesothelioma. The tumour was consistently BAP1-negative (D), with positive internal control of endothelial and stromal cells. (Original magnification: 200×).

Familial BAP1-Related MM: Clinical and taneous melanomas/atypical Spitz tumours and Pathological Peculiarities clear cell renal cell carcinomas. MM is recognised as one of the four main (or MMs related to germline BAP1 mutations ‘core’) tumours associated with germline BAP1 account for approximately 1-5% of unselected 38 mutations, together with uveal melanomas, cu- MM cases . They seem to show distinctive

Figure 2. A case of MM with retained BAP1 expression. This tumour showed epithelioid morphology (A) and positive BAP1 nuclear staining (B). Interestingly, the patient was from a family with clustered MM cases (Original magnification: 200×).

4239 F. Pagliuca, F. Zito Marino, F. Morgillo, C. Della Corte, M. Santini, et al clinical-pathological features and some striking (8,69 and 8,55 months respectively). Similar differences in terms of prognosis and outcome findings were reported by Ohar et al40 in 2017. when compared to sporadic MMs. The very Their work was designed to assess the frequency first study to assess MM survival and clinical of BAP1 germline mutations in a cohort of 150 features among patients with germline BAP1 MM patients with familiar history of cancer in mutations was published in 201539. Compared comparison with a cohort of asbestos-exposed to a general cohort composed of all MM cases patients with no neoplasms other than MM and recorded at the Surveillance, Epidemiology and a cohort of asbestos-exposed individuals with no End Results (SEER) program between 1973 and history of cancer. Nine out of 150 patients (6%) 2010, germline BAP1 mutated MMs had seven in the study cohort harboured germline BAP1 times longer survival, with a 5-year survival mutations while none was detected in the control rate of 47% vs. 6.7% in the control cohort. BAP1 cohorts. BAP1 mutation carriers developed MM mutation carriers had a statistically significant at an earlier mean age (58.5 vs. 68.2 in the con- earlier mean age at diagnosis (56.3 vs. 72 years), trol cohorts), exhibited an excess of peritoneal a lower M:F sex ratio with slight predominance MMs (55.6% vs. 17.7% in the control cohorts) of female patients (0.73:1 vs. 4:1) and a higher and an increased prevalence of epithelioid sub- proportion of peritoneal MMs (50% vs. 14.2%). type (88.9% vs. 74.6%). Furthermore, they had a Each case in this group showed epithelioid mor- 3.5-fold prolonged median survival (60 months phology. Additionally, more than half of BAP1 vs. 17 months) 40. In summary, from an epide- mutation carriers (56.5%) had at least one other miological point of view, familial BAP1-related cancer diagnosed apart from MM. 13% had MM cases present earlier and more frequently multiple MMs, with both pleural and peritoneal affect female patients. They can be multiple and location. Another interesting finding from this often occur in association with other synchro- study was that survival was not related to age nous or metachronous neoplasms. Finally, they in the BAP1 cohort. In fact, 5-year survival rate are more commonly located in the peritoneum was 45% in patients younger than 55 years (vs. than sporadic MMs. Despite lacking absolute- 17.4% in the SEER cohort) and 51% in patients ly specific histopathological features, the vast older than 55 years (vs. 5.1% in the SEER co- majority of familial BAP1-related MMs shows hort). According to such observations, the im- an epithelioid morphology. The most noticeable proved survival in the BAP1 cohort should not peculiarities, however, concern their prognosis. be related to the younger mean age of patients In fact, familial BAP1-related MMs demonstrate in this group, although the limited number of a dramatically longer median survival than spo- patients did not allow studies of significance. radic MMs, independently of patient age at pre- Moreover, patients with peritoneal MM in the sentation and, supposedly, of received therapies. BAP1 cohort exhibited significantly longer me- Studies on larger cohorts of patients are needed dian survival than patients with pleural MM (10 to confirm these data. The main epidemiological years and 2 years, respectively). In contrast, no and pathological differences between sporadic differences in survival between peritoneal and MMs and familial BAP1-related MMs are sum- pleural MMs were noted in the SEER cohort marized in Table I.

Table I. Real time PCR primers. Sporadic mm Germline BAP1-mutated mm

Sex distribution M:F = 4:1 M:F = 1:1 Mean Age at Diagnosis (years) 72 56.3 Association with asbestos exposure Very strong Nd Location Pleura>>>peritoneum Pleura = peritoneum Multiple locations Nd 13% Association with other tumors Nd Uveal melanoma bap1 inactivated melanocytic tumors of skin Histological subtype Epithelioid Epithelioid (100%) Biphasic Sarcomatous 5-year survival rate 6.7% 47%

4240 Inherited predisposition to malignant mesothelioma: germline BAP1 mutations and beyond

BAP1 Germline Mutations sive and pro-tumorigenic microenvironment. In and Well-Differentiated their original study, Napolitano et al47 found that Papillary Mesothelioma peritoneal inflammatory response after exposure Well-differentiated papillary mesothelioma to low doses of asbestos in BAP1+/− mice was (WDPM) is a rare variant of epithelioid mesothe- radically altered, with preferential, alternative lioma. It is characterised by a papillary growth, M2-polarization of macrophages and lower levels with a myxoid fibrovascular core lined by bland of pro-inflammatory chemokines and cytokines. mesothelial cells, and only initial and limited Moreover, incidence of MM was significantly tendency, if any, to stromal invasion41. It mostly higher in BAP1+/− mice exposed to standard (i.e. develops in the peritoneum of young women, very low) doses of asbestos than in wild-type often as multifocal disease and in absence of any mice. In particular, BAP1+/− mice exposed to low correlation to asbestos exposure. It portends a doses of asbestos developed MMs at a similar good prognosis with excellent long-term surviv- rate as BAP1+/+ mice exposed to 10 times high- al. Few cases of WDPM have been reported in er doses. Taken together, the discussed results literature to date. As a consequence, the biology indicate that germline BAP1 mutations confer and related risk factors are still poorly under- exaggerated sensibility to the carcinogenic effect stood42; similarly, their optimal management has of mineral fibres, promoting the development to be still defined. Ribeiro et al43 reported the first of MM in their carriers even for minimal-dose (and unique) description of WDPMs clustering background exposition. in a family with a germline BAP1 mutation. In a retrospective analysis on a series of 8 WDPMs, Detection of Germline BAP1 Lee et al44 found complete immunohistochemical Mutation: Proposed Strategies and BAP1 loss in three of their cases. Interestingly, Practical Implications all these 3 patients had also developed a synchro- Currently, the importance of recognizing nous or metachronous MM, which also showed BAP1-mutated families and starting a surveillance absent BAP1 expression. However, published data program for the early identification ofBAP1 -relat- about the relationship between WDPM and BAP1 ed malignancies is widely accepted. In fact, some are controversial and need further investigation. of these tumours, uveal melanomas and renal cell carcinomas in particular, seem to have a more Germline BAP1 Mutations and Exposure aggressive course, portending a less favourable to Asbestos: a Supposed Paradigm of prognosis than sporadic cases. Active surveil- Gene-Environment Interaction lance in BAP1-mutated patients could allow early Whether exposure to asbestos or other car- diagnosis of BAP1-related malignancies, with pre- cinogenic mineral fibres is strictly required or cocious treatment and improved survival. Never- not for MM development in germline BAP1 theless, well-established screening guidelines for variant carriers still represents an open issue. patients harbouring a germline BAP1 mutation Based on published data, members affected by are still lacking as well as thorough assessment MM within some BAP1-mutated families had no of lifetime risks of developing BAP1-associated known occupational or environmental history cancers in mutation carriers. In 2014 Pilarski et of exposure to asbestos45. However, in vivo ex- al48 proposed a screening program with annual periments on BAP1+/− knockout mouse models medical check-ups. As a general rule, ophtalmo- have shown that knockout animals presented a logical and dermatological examinations should markedly higher incidence and accelerated on- be started at the age of 11 and of 22 years re- set of MM in comparison to their wild-type spectively. However, it is advisable to start sur- littermates when exposed to asbestos; on the veillance programs even earlier in those families other hand, no spontaneous MMs were detected where the proband is diagnosed with a BAP1-re- in BAP1+/− mice during a 20 month-follow up. lated neoplasm at a younger age, as suggested by Such findings suggest that low or even minimal the same research group in another paper49. In levels of exposure to carcinogenic fibres could be addition, yearly physical examinations for MM sufficient to trigger tumorigenesis in germline and a renal screening protocol consisting of ab- mutation carriers46. dominal ultrasound once a year and magnetic BAP1 heterozygosity likely influences inflam- resonance imaging every two years has been pro- matory response to external injuries, thus con- posed. The authors also recommend to undertake tributing to the creation of an immunosuppres- genetic testing for BAP1 mutations in all patients

4241 F. Pagliuca, F. Zito Marino, F. Morgillo, C. Della Corte, M. Santini, et al with two or more ‘core’ BAP1-related tumours tice but encouraging results about the feasibility (namely: uveal melanoma, cutaneous melanoma, of liquid biopsy-based strategies for the early MM and renal cell carcinoma) in themselves diagnosis of MM come from the research field. and/or first- or second-degree relatives. Families with multiple cutaneous melanomas only should Beyond BAP1: Are There Other Genes not be taken into account, due to the higher fre- Responsible for Inherited Predisposition quency of melanoma in the general population. to MM? However, the rarity of pathogenic BAP1 variants As previously underlined, BAP1 is not the only in unselected patients with BAP1-associated ma- gene accounting for inherited predisposition to lignancies rises the need to further discriminate mesothelioma. In 2014, Betti et al57 assessed the patients with an increased risk for BAP1 germline prevalence of germline BAP1 mutations in five mutations to be sent for genetic counselling. As families with multiple MMs and in 103 sporadic a consequence, Chau et al50 propose to age-ad- cases. While BAP1 pathogenic variants were seen just the previously mentioned criteria as follows: in none of the sporadic cases, only one family uveal melanoma with onset before 40 years of showed a truncating mutation, suggesting that age; cutaneous melanoma with onset before 18 germline BAP1 alterations are not so easily en- years; MM with onset before 50 years; renal countered among familial MM cases. Other stud- cell carcinoma with onset before 46 years. In ies from the same research group aimed to assess populations with high incidence of melanoma the prevalence of germline pathogenic variants in a minimum of three cutaneous melanomas per 39 patients with familial pleural MM, which was 58 patient should be diagnosed to initiate genetic found to be only 7.7% . They also investigated counselling in cases in which multiple cutaneous with a next-generation sequencing approach the melanomas are the only BAP1-associated malig- prevalence of germline pathogenic variants in nancy51. In patients receiving genetic counselling 94 cancer predisposing genes in 93 patients with and suspected to be BAP1 mutation carriers, the pleural MM with quantified levels of asbestos presence of the mutation must be confirmed with exposure59. direct sequencing techniques. However, when Truncating pathogenic variants were identified formalin-fixed paraffin-embedded tumour tissue in ten different tumour suppressor genes (PALB2, is already available, BAP1 immunohistochemis- BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, try could be considered an easy, cheap and rapid FANCF, PMS1 AND XPC), all involved, like screening test. Patients showing complete loss BAP1, in DNA repair mechanisms. Such variants of nuclear BAP1 expression could then undergo were demonstrated to be exceedingly infrequent genetic sequencing52. in a general population database. Importantly, Regarding active surveillance in BAP1 muta- patients harbouring pathogenic variants in one of tion carriers, no evidence that screening for MM the mentioned genes showed statistically signifi- of high-risk patients improves survival has been cant lower levels of asbestos exposure than other provided yet. In addition, it must be highlighted patients. Globally, these findings indicate that an that an early diagnosis of pleural and peritoneal inherited deficiency in cellular machineries ded- MM is difficult to achieve and still strictly re- icated to DNA repair enormously amplifies the lies on advanced imaging techniques (computed carcinogenic effects of mineral fibers60. tomography, magnetic resonance) and tissue bi- opsies53. BAP1 Mutations in MM: Nevertheless, in the latest years, several bio- Translational Significance markers have been proposed for the monitoring Undoubtedly, one of the most relevant aspects and early detection of MM in high-risk patients. of unveiling the genetic background of a certain Circulating tumour proteins such as mesothelin, tumour is the opportunity to translate the novel osteopontin and fibulin-3 are the best character- biomolecular discoveries in the development of ized so far. New promising markers include cir- alternative therapeutic strategies. This would be culating tumour DNA, circulating tumour cells particularly important for a tumour like MM, and circulating microRNAs54-56. They all hold the whose response to standard treatments is so poor. advantage of being analysed through sampling of Regarding BAP1-mutated MMs, interesting re- easily obtained biological fluids, with no risks for sults are emerging from recent literature. A re- the patients and reduced health costs. Currently, cent work has demonstrated in vitro that BAP1 none of them has been validated for clinical prac- status regulates the sensitivity of MM cells to

4242 Inherited predisposition to malignant mesothelioma: germline BAP1 mutations and beyond

gemcitabine, the elective second-line chemother- 3) Tomasson K, Gudmundsson G, Briem H, Rafns- apeutic agent for advanced MM. In particular, a son V. Malignant mesothelioma incidence by functional BAP1 protein seems to be required for nation-wide cancer registry: a population-based gemcitabine-induced tumour cell apoptosis. Con- study. J Occup Med Toxicol 2016; 11: 37. sequently, BAP1-mutated MMs show resistance 4) Hodgson JT, Darnton A. The quantitative risks of 61 mesothelioma and lung cancer in relation to as- to gemcitabine effect . On the other hand, given bestos exposure. Ann Occup Hyg 2000; 44: 565- the role of BAP1 in DNA repair and chromatin 601. remodelling, it has been postulated that BAP1 5) Melaiu O, Gemignani F, Landi S. The genet- mutations could confer sensitivity to DNA re- ic susceptibility in the development of malignant pair targeted therapy, such as Poly(ADP-ribose) pleural mesothelioma. J Thorac Dis 2018; 10: polymerase (PARP) inhibitors and dual phospho- S246-S252. inositide 3-kinase (PI3K)-mammalian target of 6) Robinson BW, Lake RA. Advances in malignant rapamycin (mTOR) inhibitors, or to drugs known mesothelioma. N Engl J Med 2005; 353: 1591- as ‘epigenetic’ modulators, such as Vorinostat62,63. 1603. In vitro studies are ongoing to test this intriguing 7) Ugolini D, Neri M, Ceppi M, Cesario A, Dianzani I, Filiberti R, Gemignani F, Landi S, Magnani C, hypothesis, but the results obtained so far are not Mutti L, Puntoni R, Bonassi S. Genetic suscepti- univocal and still insufficient for in vivo transla- bility to malignant mesothelioma and exposure to tion, which is much awaited64. asbestos: the influence of the familial factor. Mu- tat Res 2008; 658: 162-171. 8) Carbone M, Gazdar A, Butel JS. SV40 and hu- Conclusions man mesothelioma. Transl Lung Cancer Res 2020; 9: S47-S59. The study of inherited genetic factors predis- 9) Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, posing to the development of MM constitutes an Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). emerging and promising field of research. Ger- SEER Cancer Statistics Review, 1975-2018, Na- mline BAP1-mutated MMs, as part of a recently tional Cancer Institute. Bethesda, MD, https:// characterized tumour syndrome, have specific seer.cancer.gov/csr/1975_2018/, based on No- epidemiological and pathological features and vember 2020 SEER data submission, posted to the SEER web site, April 2021. are likely to respond to unconventional therapies, 10) Meyerhoff RR, Yang CF, Speicher PJ, Gulack BC, as in vitro studies suggest. Meanwhile, identi- Hartwig MG, D’Amico TA, Harpole DH, Berry MF. fying and including in appropriate surveillance Impact of mesothelioma histologic subtype on out- programs patients carrying germline BAP1 muta- comes in the surveillance, epidemiology, and end tions is of primary importance, as early diagnosis results database. J Surg Res 201; 196: 23-32. still is, and always be, the best and more effective 11) Brcic L, Kern I. Clinical significance of histolog- treatment. This paper provides a concise over- ic subtyping of malignant pleural mesothelioma. view on current knowledge about BAP1-related Transl Lung Cancer Res 2020; 9: 924-933. tumour predisposition syndrome and emerging 12) Hylebos M, Van Camp G, van Meerbeeck JP, insights on genetic susceptibility to MM. Op de Beeck K. The genetic landscape of malignant pleural mesothelioma: results from massive- ly parallel sequencing. J Thorac Oncol 2016; 11: 1615-1626. 13) Kato S, Tomson BN, Buys TP, Elkin SK, Carter Conflict of Interest JL, Kurzrock R. Genomic landscape of malignant The Authors declare that they have no conflict of interests. mesotheliomas. Mol Cancer Ther 2016; 15: 2498- 2507. 14) Neri M, Ugolini D, Dianzani I, Gemignani F, Landi S, Cesario A, Magnani C, Mutti L, Puntoni R, Bon- References assi S. Genetic susceptibility to malignant pleural mesothelioma and other asbestos-associated 1) Baumann F, Ambrosi JP, Carbone M. Asbestos diseases. Mutat Res 2008; 659: 126-136. is not just asbestos: an unrecognised health haz- 15) Testa JR, Cheung M, Pei J, Below JE, Tan Y, Se- ard. Lancet Oncol 2013; 14: 576-578. mentino E, Cox NJ, Dogan AU, Pass HI, Trusa 2) Ferrante D, Mirabelli D, Tunesi S, Terracini B, S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Magnani C. Pleural mesothelioma and occupa- Comertpay S, Tanji M, Gaudino G, Yang H, Car- tional and non-occupational asbestos exposure: bone M. Germline BAP1 mutations predispose a case-control study with quantitative risk as- to malignant mesothelioma. Nat Genet 2011; 43: sessment. Occup Environ Med 2016; 73: 147-153. 1022-1025.

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