BAP1 Tumour Predisposition Syndrome: An Inherited Gene Change Behind Mesothelioma and Eye Melanoma

Most mesotheliomas follow asbestos exposure, and most eye melanomas appear in people with no family history at all. A small number of families, however, carry an inherited change in one gene, BRCA1-associated protein 1 (BAP1), that raises the chance of several cancers at once: mesothelioma, melanoma of the eye (uveal melanoma), melanoma of the skin, kidney cancer and a distinctive kind of skin-coloured mole. This page explains what the gene does, how the syndrome was found in 2011, what cohort studies report about each cancer, why mesothelioma in these families behaves differently, how the gene appears to interact with asbestos and erionite, and what published guidelines say about genetic testing and check-up schedules. The main Mesothelioma page covers the disease itself.

Table of Contents

  1. What the BAP1 Gene Does
  2. How the Syndrome Was Found in 2011
  3. How the Gene Change Is Inherited
  4. The Cancers Linked to the Syndrome
  5. Mesothelioma in People Who Carry the Gene Change
  6. Asbestos, Erionite and the Gene–Environment Question
  7. Published Criteria for Genetic Testing
  8. Published Check-Up Schedules
  9. What Is Not Yet Known
  10. Key Research Papers
  11. Connections
  12. Featured Videos

What the BAP1 Gene Does

BAP1 is a tumour-suppressor gene: its normal job is to help keep cell growth in check, and cancer becomes more likely when both working copies are lost. The protein it makes is an enzyme that removes small "ubiquitin" tags from other proteins, a step that changes how those proteins behave. The 2011 study that linked the gene to skin tumours described it as a gene "which encodes a ubiquitin carboxy-terminal hydrolase", and later laboratory work measures this tag-removing (deubiquitinating) activity to judge whether an unusual gene variant still works.

A 2020 review in Cancer Discovery summarised what laboratory studies have found about the protein. In the cell nucleus it takes part in DNA repair and in switching genes on and off; in the surrounding cytoplasm it influences cell death and the way mitochondria handle energy. The review described its tumour-suppressor activity as "cell type- and context-dependent" and called BAP1 "a key regulator of gene-environment interaction".

Germline changes and tumour-only changes

Two kinds of BAP1 change appear in the research, and they mean very different things for a family:

In people born with one faulty copy, the tumours that develop have usually lost the second copy as well. The 2011 mesothelioma study found somatic changes in BAP1 within family members' tumours, "indicating biallelic inactivation" (both copies out of action), and the 2011 skin study reported that most of the moles studied had "lost the remaining wild-type allele". Because tumour-only changes are so common, finding a BAP1 change in a tumour sample does not by itself show that the change is inherited; the 2023 European guideline describes automatic germline testing after a tumour result as inappropriate for that reason.

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How the Syndrome Was Found in 2011

The syndrome was described in three papers in 2011, each starting from a different cancer.

Mesothelioma families. Joseph Testa, Michele Carbone and colleagues started from a puzzle: only a small fraction of asbestos-exposed people develop mesothelioma, and the disease clusters in some families. Writing in Nature Genetics, they reported inherited BAP1 changes in two families with a high rate of mesothelioma; some carriers in those families developed uveal melanoma instead. Among 26 people with mesothelioma and no family pattern, 2 carried an inherited BAP1 change, and both had previously been diagnosed with uveal melanoma. The authors named "a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma", and put forward the hypothesis that "mesothelioma predominates upon asbestos exposure".

Families with unusual moles. In the same issue of the journal, Thomas Wiesner and colleagues described two families with a dominantly inherited pattern of multiple raised, skin-coloured mole-like growths. Under the microscope these ranged from benign epithelioid moles to "atypical melanocytic proliferations that showed overlapping features with melanoma", and some family members developed uveal or skin melanoma. Inactivating BAP1 changes ran with the trait through the families.

An eye-melanoma family. Mohamed Abdel-Rahman and colleagues screened 53 people with uveal melanoma who looked at high risk of an inherited cancer. One carried a BAP1 change that cut the protein short; it ran through several relatives with uveal melanoma, lung adenocarcinoma, meningioma and other cancers. The authors also noted that BAP1 explained "only a small subset of hereditary UM [uveal melanoma]", pointing to other genes still to be found.

Kidney cancer was added in 2013. A French team found an inherited BAP1 change in a family with four relatives with renal cell carcinoma; in a wider screen, 6 of 11 BAP1-carrying families included 9 people with renal cell carcinoma. No BAP1 changes turned up in 32 other families with kidney cancer alone. Basal cell carcinoma was proposed in 2015, when carriers in four families developed it and their basal cell tumours had lost the BAP1 protein, while 53 ordinary basal cell carcinomas had not.

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How the Gene Change Is Inherited

The syndrome is inherited in an autosomal dominant way: one altered copy, from either parent, is enough to carry the raised risk. According to the GeneReviews entry on the syndrome (last updated December 2024), each child of a carrier has a 50% chance of inheriting the change and a 50% chance of not inheriting it. Most people diagnosed have a parent who carries it, though the parent may have had different BAP1-related tumours, or none yet; some cases arise from a new (de novo) change not present in either parent.

Not every variant in the gene is harmful. A 2019 Finnish study sequenced the whole gene, including its switch regions and non-coding stretches, in 433 people with uveal melanoma. It found 21 different rare variants but judged only five likely to cause disease, and it reclassified four variants in one part of the gene as harmless after laboratory testing and a look at family histories. One harmful change lay deep inside a non-coding stretch of the gene, where standard tests can miss it. The authors concluded that family history and laboratory function tests are "indispensable" for deciding whether an unusual variant matters.

The type of change seems to matter too. A 2018 worldwide collation of 181 carrier families (140 different variants) found that families with "null" variants, which stop the protein being made, developed cancers at younger median ages than families with "missense" variants, which swap a single protein building block. The difference held for all tumours combined, for mesothelioma, for skin melanoma and for non-melanoma skin cancer.

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The Cancers Linked to the Syndrome

The 2023 European guideline, produced by a Delphi survey of 34 specialists across Europe, agreed that five tumour types form the "core" of the syndrome, defined as tumours occurring in 10% or more of carriers: mesothelioma (pleural and peritoneal), uveal melanoma, skin melanoma, renal cell carcinoma and BAP1-inactivated melanocytic tumours of the skin. It placed meningioma in the wider spectrum but outside the core, listed liver cancer (hepatocellular carcinoma) and bile-duct cancer (cholangiocarcinoma) as suggested but needing further evidence, and agreed that breast and lung cancer are not at present counted as part of the syndrome. The GeneReviews entry includes basal cell carcinoma, meningioma and cholangiocarcinoma in its list, and names nail growths called onychopapillomas, hepatocellular carcinoma and ovarian sex cord-stromal tumours as possible additions.

How often each cancer appears in published carriers

A 2017 review of 215 carriers (10 seen in one dermatology clinic and 205 from the medical literature) gave these figures:

CancerCarriers who had itCarriers who did not
Uveal melanoma60 of 215 (28%)about 72%
Mesothelioma48 of 215 (22%)about 78%
Skin (cutaneous) melanoma38 of 215 (18%)about 82%
Renal cell carcinoma20 of 215 (9%)about 91%

The 2023 European guideline's text (read in full, not only the summary) quotes the 2018 worldwide family study: among 141 "probands" (the first person in a family to be tested) the rates were 36.2% for uveal melanoma, 24.5% for mesothelioma, 23.4% for skin melanoma and 5.7% for renal cell carcinoma, while among 183 relatives found by testing afterwards they were 15.9%, 16.9%, 12.0% and 4.9%. The lower figures in relatives matter: the first person tested is usually tested because they already have cancer, so series built around such people overstate the risk. The guideline's abstract gives the overall lifetime risk of at least one BAP1-associated tumour as "up to 85%" and adds that "due to ascertainment bias, current estimates of risk are likely to be overestimated". A 2020 review by researchers who first described the mesothelioma families states, on the other hand, that "nearly all individuals inheriting a BAP1 mutant allele developed one or more malignancies during their lifetime" among more than 200 families. The two statements come from the same body of family data read in different ways.

BAP1-inactivated melanocytic tumours of the skin

These are skin-coloured, raised growths, once called "atypical Spitz tumours", made of pigment cells that have lost BAP1. They tend to appear earlier in life than the cancers of the syndrome, which is why dermatologists describe them as an early clue. In the 2017 review, 40 of 53 carriers (75%) who had a full-body skin examination had at least one; in the other 25% none was found. Most of these growths are not cancers. They also occur in people without an inherited change: a 2018 study of such tumours estimated that about 12% of people who have one carry a germline BAP1 change, and about 88% do not. A large flat (junctional) component of BAP1-lacking cells, a past melanoma or more than one such tumour were the features linked to an inherited change. The 2023 European guideline states that expert opinion puts the risk of one of these growths turning into melanoma as low, similar to that of ordinary atypical moles.

Uveal melanoma

In the Finnish population study of people with uveal melanoma diagnosed between 2010 and 2017, 9 of 433 (2%) carried a harmful inherited BAP1 change; 98% did not. Among the 16 families with more than one case of the eye cancer, 4 (25%) did. GeneReviews states that uveal melanoma in carriers "tends to be a more aggressive class 2 tumor with higher risk for metastasis". The Uveal Melanoma page explains how BAP1 loss inside the tumour, together with loss of one copy of chromosome 3, predicts the risk of spread for anyone with the disease.

Kidney cancer

Renal cell carcinoma in carriers is usually of the clear-cell type, according to GeneReviews. The 2023 European guideline (full text) cites a study that found an inherited BAP1 change in 1% (3 of 254) of people with advanced renal cell carcinoma, and another in which 3 of 190 people diagnosed under 45 (1.6%) carried one. It also notes reports of tumours in both kidneys or several tumours in one kidney, and an average age at diagnosis around 10 years younger than in kidney cancer without the syndrome. The Renal Cell Carcinoma page covers the tumour-only BAP1 changes that large genome projects find in 6–10% of these cancers.

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Mesothelioma in People Who Carry the Gene Change

Inherited BAP1 changes explain only a small share of mesothelioma overall. In a 2018 University of Chicago study that sequenced 85 cancer-risk genes in 198 people with mesothelioma, 6 carried a BAP1 change (about 3%, so about 97% did not), and 23 of the 198 (12%) carried a harmful change in some cancer-risk gene. The odds of carrying one were lower for pleural disease (odds ratio 0.23), for people exposed to asbestos (odds ratio 0.28) and with each year of older age (odds ratio 0.95), and higher for people with a second cancer (odds ratio 3.33). In another study, of 150 people with mesothelioma and a family history of cancer, 9 (6%) carried a BAP1 change, while none was found in 50 asbestos-exposed people with family cancers other than mesothelioma or in 153 asbestos-exposed people without family cancer. An Italian series found BAP1 changes in 3 of 39 patients (7.7%) with familial pleural mesothelioma.

Younger, more often in the abdomen

The family study of 150 patients reported that carriers "developed mesothelioma at an earlier age that was more often peritoneal than pleural (five of nine)". In a 2015 pooled group of 23 carriers with mesothelioma, 10 had peritoneal disease (in the lining of the abdomen), 10 pleural disease (in the lining of the chest) and 3 both. In the general mesothelioma population, by comparison, the chest lining is the site in roughly 90% of cases, as the main Mesothelioma page describes.

Longer survival in the reported series

The 2015 study compared those 23 carriers with 10,556 people with mesothelioma in the United States Surveillance, Epidemiology, and End Results (SEER) cancer registry from 1973 to 2010. Median survival was 5 years in carriers and under 1 year in the registry group; 5-year survival was 47% (95% confidence interval 24–67%) against 6.7%. The authors described this as a 7-fold improvement in long-term survival, independent of sex and age. Carriers with peritoneal disease had a median survival of 10 years, a difference that fell just short of statistical significance (P = 0.0571). This is a small group compared with a whole registry, and the comparison is not a trial.

A 2022 paper in the Journal of Thoracic Oncology, written by most of the clinicians who have published cases in carriers, reports that mesotheliomas in these patients are "significantly less aggressive". It states that some carriers have mesothelioma without symptoms that "can be followed by close clinical observation without apparent adverse outcomes" and "may survive many years without therapy", while others grow aggressively "but very often respond to therapy". The paper presents this as the authors' clinical experience and recommendations, not as the result of a controlled trial. GeneReviews adds that mesothelioma in carriers, especially pleural disease, "responds better to platinum chemotherapy" than mesothelioma without the inherited change.

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Asbestos, Erionite and the Gene–Environment Question

A recurring question is whether carriers develop mesothelioma on their own or whether they need a mineral fibre exposure, perhaps a smaller one than other people. The evidence comes in several kinds, and each is labelled here.

Experiments in mice

Observations in people

Taken together, mouse experiments point to an inherited change raising sensitivity to fibres, and human series show carriers with less exposure, or none recorded at work. No study in people has measured how much exposure, if any, a carrier needs.

Erionite in Turkey and North Dakota

Erionite is an asbestos-like mineral found in volcanic rock. A 2011 study reported mesothelioma mortality of 20–50% of all deaths in some Cappadocian villages in Turkey, and 6.25% in the village of Boyali. In Dunn County, North Dakota, more than 300 miles of roads had been surfaced with erionite-containing gravel; airborne levels measured along roadsides, indoors and inside vehicles, including school buses, equalled or exceeded those in Boyali, and the erionite from both places behaved the same in laboratory tests. A 2010 study of the Turkish village of Karain, where mesothelioma caused 52 of 322 deaths (50.5%) between 1990 and 2006, found no cases in houses built without erionite-bearing stone, and 11 of 16 women who had married into the village from erionite-free villages and died had died of mesothelioma (69%). Those authors concluded that indoor erionite exposure explains the extreme risk and that genetic factors are likely minor, while noting that their study could not measure the genetic effect. These Turkish observations concern mineral exposure; the studies on this page do not show that inherited BAP1 changes explain the village cases.

GeneReviews lists asbestos (including naturally occurring tremolite and erionite), smoking, arc welding and unnecessary, prolonged sun exposure among agents and circumstances to avoid for carriers, as well as routine chest X-rays and computed tomography (CT) scans, which add radiation. The 2023 European guideline's core group gave similar lifestyle information on asbestos, smoking and ultraviolet light.

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Published Criteria for Genetic Testing

Different groups have written different thresholds for offering a BAP1 test. The criteria below are reported as each source states them.

2023 European guideline (read in full text)

The panel agreed that germline BAP1 testing be offered to:

It agreed that testing "may be considered" for a single mesothelioma before age 60 with no asbestos exposure, a single uveal melanoma before age 40, a single early kidney cancer or childhood skin melanoma (under 18) as part of a wider gene panel, and after a BAP1 change is found in a tumour, depending on the tumour type, the share of tumour cells carrying the change and family history. It agreed that testing is not routinely offered for a single isolated cancer of these types, where the panel estimated the rate of inherited changes at under 3%, against more than 10% for people with two core tumours or one plus a family history. Testing relatives for a known family change was placed from age 16–18, and only for variants classed as likely harmful or harmful.

Mesothelioma studies

The authors of the 2018 Chicago sequencing study concluded that their data "support clinical germline genetic testing for patients with MM [malignant mesothelioma]". The authors of the 150-patient family study concluded that mesothelioma patients "presenting with a family history of cancer" are candidates for BAP1 testing. The 2018 skin-tumour study proposed a large junctional component in a BAP1-inactivated melanocytic tumour, a personal history of melanoma or a previous such tumour as additional reasons for testing. The main Mesothelioma page reports the same 2018 study's conclusion.

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Published Check-Up Schedules

Two widely cited sources set out check-up (surveillance) schedules for carriers. They agree on eyes and skin and differ on the chest and kidneys. Neither rests on trials showing that surveillance lengthens life; the European guideline states that its surveillance recommendations are based on expert opinion and rates most of them as weak.

OrganGeneReviews (updated 2024)European guideline 2023
EyeYearly dilated eye examination from age 11–18 years or pubertyYearly dilated eye examination by an eye-cancer specialist or an ophthalmologist experienced in uveal melanoma, from age 16–18
SkinYearly full-body skin examination from age 18Yearly dermatology review with full-body examination and photography, from age 18–20
KidneyFrom age 30: kidney and abdominal ultrasound every two years, alternating with abdominal magnetic resonance imaging (MRI) every two years, so that one scan falls in each yearYearly kidney imaging from age 30, magnetic resonance imaging preferred, ultrasound if it is unavailable
MesotheliomaFrom age 30: yearly clinical check for signs of pleurisy, peritonitis, abdominal fluid or chest fluid, with chest ultrasound and chest magnetic resonance imaging alternating in the same two-year patternNo data show that chest X-ray or magnetic resonance imaging finds mesothelioma early; surveillance only within a research study

The European guideline explains that no surveillance programme for mesothelioma exists even for people with heavy asbestos exposure, and that the type and frequency of scanning are unknown. It mentions two United States National Cancer Institute studies that follow carriers prospectively to measure how often mesothelioma and other cancers arise. For the eye, it reasons that small tumours caught early have a better outlook than tumours that have spread, while noting that prospective studies are still needed to prove that surveillance helps. On the skin growths, it records agreement that, when there are few, removal is kept for growing, changing or uncertain lesions.

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What Is Not Yet Known

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Key Research Papers

  1. Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43(10):1022-5. PubMed PMID: 21874000
  2. Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43(10):1018-21. PubMed PMID: 21874003
  3. Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill JB, Christopher BN, Boru G, et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet. 2011;48(12):856-9. PubMed PMID: 21941004
  4. Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V, Dubois-d'Enghien C, et al. Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet. 2013;92(6):974-80. PubMed PMID: 23684012
  5. Wadt KA, Aoude LG, Johansson P, Solinas A, Pritchard A, Crainic O, et al. A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma. Clin Genet. 2015;88(3):267-72. PubMed PMID: 25225168
  6. Baumann F, Flores E, Napolitano A, Kanodia S, Taioli E, Pass H, et al. Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival. Carcinogenesis. 2015;36(1):76-81. PubMed PMID: 25380601
  7. Ohar JA, Cheung M, Talarchek J, Howard SE, Howard TD, Hesdorffer M, et al. Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer. Cancer Res. 2016;76(2):206-15. PubMed PMID: 26719535
  8. Haugh AM, Njauw CN, Bubley JA, Verzì AE, Zhang B, Kudalkar E, et al. Genotypic and Phenotypic Features of BAP1 Cancer Syndrome: A Report of 8 New Families and Review of Cases in the Literature. JAMA Dermatol. 2017;153(10):999-1006. PubMed PMID: 28793149
  9. Walpole S, Pritchard AL, Cebulla CM, Pilarski R, Stautberg M, Davidorf FH, et al. Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide. J Natl Cancer Inst. 2018;110(12):1328-1341. PubMed PMID: 30517737
  10. Panou V, Gadiraju M, Wolin A, Weipert CM, Skarda E, Husain AN, et al. Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma. J Clin Oncol. 2018;36(28):2863-2871. PubMed PMID: 30113886
  11. Betti M, Aspesi A, Ferrante D, Sculco M, Righi L, Mirabelli D, et al. Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes. Genes Chromosomes Cancer. 2018;57(11):573-583. PubMed PMID: 30338612
  12. Garfield EM, Walton KE, Quan VL, VandenBoom T, Zhang B, Kong BY, et al. Histomorphologic spectrum of germline-related and sporadic BAP1-inactivated melanocytic tumors. J Am Acad Dermatol. 2018;79(3):525-534. PubMed PMID: 29753057
  13. Repo P, Järvinen RS, Jäntti JE, Markkinen S, Täll M, Raivio V, et al. Population-based analysis of BAP1 germline variations in patients with uveal melanoma. Hum Mol Genet. 2019;28(14):2415-2426. PubMed PMID: 31058963
  14. Xu J, Kadariya Y, Cheung M, Pei J, Talarchek J, Sementino E, et al. Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma. Cancer Res. 2014;74(16):4388-97. PubMed PMID: 24928783
  15. Napolitano A, Pellegrini L, Dey A, Larson D, Tanji M, Flores EG, et al. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene. 2016;35(15):1996-2002. PubMed PMID: 26119930
  16. Carbone M, Baris YI, Bertino P, Brass B, Comertpay S, Dogan AU, et al. Erionite exposure in North Dakota and Turkish villages with mesothelioma. Proc Natl Acad Sci U S A. 2011;108(33):13618-23. PubMed PMID: 21788493
  17. Metintas M, Hillerdal G, Metintas S, Dumortier P. Endemic malignant mesothelioma: exposure to erionite is more important than genetic factors. Arch Environ Occup Health. 2010;65(2):86-93. PubMed PMID: 20439227
  18. Carbone M, Harbour JW, Brugarolas J, Bononi A, Pagano I, Dey A, et al. Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer. Cancer Discov. 2020;10(8):1103-1120. PubMed PMID: 32690542
  19. Carbone M, Pass HI, Ak G, Alexander HR Jr, Baas P, Baumann F, et al. Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations. J Thorac Oncol. 2022;17(7):873-889. PubMed PMID: 35462085
  20. Lalloo F, Kulkarni A, Chau C, Nielsen M, Sheaff M, Steele J, et al. Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome. Eur J Hum Genet. 2023;31(11):1261-1269. PubMed PMID: 37607989
  21. Pilarski R, Byrne L, Carlo MI, Hanson H, Cebulla C, Abdel-Rahman M. BAP1 Tumor Predisposition Syndrome. In: GeneReviews. Seattle (WA): University of Washington, Seattle; 2016 (updated 2024). PubMed PMID: 27748099

PubMed Topic Searches

  1. PubMed: BAP1 tumour predisposition syndrome
  2. PubMed: germline BAP1 and mesothelioma survival
  3. PubMed: germline BAP1 and uveal melanoma
  4. PubMed: BAP1-inactivated melanocytic tumours
  5. PubMed: BAP1, asbestos and gene–environment interaction
  6. PubMed: surveillance of BAP1 carriers

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Connections

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