BAP1: case report and insight into a novel tumor suppressor

Abstract

BackgroundBRCA1-Associated-Protein 1 (BAP1) is a dynamic tumor suppressor which, when mutated, has been associated with an increased risk of uveal melanoma, cutaneous melanoma, mesothelioma, and several other cancers. Germline BAP1 mutations have been extensively studied, where they have been found to cause hereditary cancer susceptibility. However, their sporadic counterparts, tumors that display a loss of BAP1 expression due to somatically arising mutations in the BAP1 gene, remain a poorly described entity.Case presentationHere we present the case of a 49-year-old female who presented with an asymptomatic dome-shaped pink papule on the dorsal foot which was found on biopsy to be deficient in the BAP1 tumor suppressor. While the patient’s family history did not suggest the presence of a familial cancer syndrome, germline genetic testing was performed and was negative. The patient underwent surgical excision of this sporadically appearing “BAPoma” by Mohs surgery.ConclusionsGiven the relatively banal clinical appearance of these dome-shaped neoplasms, sporadic BAPomas may often be overlooked by clinicians and dermatologists. In addition to providing a representative case, here we also provide a synopsis of the current understanding of these neoplasms, both in terms of the histopathological features, as well as the molecular mechanisms underlying BAP1 function and its ability to prevent tumorigenesis.

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

“…17,18 The BAP1 gene product functions as a nuclear-localized deubiquitinase that holds roles in transcription, differentiation, and DNA damage response through the ataxia telangiectasia (ATM) pathway. 16,19,20 There is also a recent report that BAP1 controls IP3R3-mediated Ca 2+ flux from the endoplasmic reticulum to the cytosol and mitochondria thereby inducing apoptosis. 21 Thus, the site of BAP1 action may not be limited to nuclear functions.…”

“…Ubiquitin carboxyl‐terminal hydrolase BAP1 is from all standpoints known to operate as a classical tumor suppressor protein (independent of BRCA1), coded for by the BAP1 gene located on the short arm of chromosome 3 at position 21.1 (3p21.1) . The BAP1 gene product functions as a nuclear‐localized deubiquitinase that holds roles in transcription, differentiation, and DNA damage response through the ataxia telangiectasia (ATM) pathway . There is also a recent report that BAP1 controls IP3R3‐mediated Ca 2+ flux from the endoplasmic reticulum to the cytosol and mitochondria thereby inducing apoptosis .…”

BAP1 Tumour Predisposition Syndrome: A New Mutation in One Family

“…BAP1 is a deubiquitinating enzyme, involved in various cellular processes such as cell cycle progression, cell diffe- rentiation and DNA damage responses (5). In melanocytes, which have a longer turnover than keratinocytes, BAP1deficiency leads to an accumulation of DNA damage that increases the chance of neoplastic proliferation in patients with both sporadic and inherited deficiencies of BAP1 (6). BAP1 can achieve its tumour-suppressing role autonomously and in order to express the syndrome phenotypically, a double mutation (somatic and/or germline) is required.…”

BAP1 Syndrome – Predisposition to Malignant Mesothelioma, Skin and Uveal Melanoma, Renal and Other Cancers

“…Syndrom BAP1 je spojený i s vysokou frekvencí maligních kožních i uveálních melanomů, s výskytem vzácných atypických (spitzoidních) kožních tumorů (AST), s rizikem nádorů ledvin, meningeomů, nádorů plic, bazaliomů a jiných nádorů vč. nádorů prsu, ovarií a prostaty [1][2][3][4][5][6][7][8][9][10][11]. První údaje o proteinu BAP1 jako vazebném partneru BRCA1 byly publikovány v roce 1998 [12].…”