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Ocular Tumors
Published in Ching-Yu Cheng, Tien Yin Wong, Ophthalmic Epidemiology, 2022
Vishal Raval, Alexander Melendez, Hansell Soto, Alléxya Affonso, Rubens Belfort Neto, Arun D. Singh
Germ line BAP1 gene mutations have been identified in roughly 5% of uveal melanoma cases, with the gene located in chromosome 3p21.1.61,62 This gene has been related to BAP1 tumor predisposition syndrome (BAP1 TPS), an autosomal-dominant condition associated with the development of multiple cancers such as uveal melanoma, cutaneous melanoma, mesothelioma, lung adenocarcinoma, and renal cell carcinoma.63 The syndrome has also been implicated with the occurrence of phenotypic variants of uveal melanoma, such as familial uveal melanoma and bilateral primary uveal melanoma (Table 17.2).64,65 In a recent study, the point prevalence of uveal melanoma in patients with germ line BAP1 pathogenic variants was estimated at 2.8% (95% CI, 0.88–4.81%) in the US population.66
Renal Cell Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
The Memorial Sloane–Kettering Cancer Center and Cancer Genome Atlas Cohort provided outcome data on 609 patients with genetic mutations in these chromosome 3p chromatin regulating genes. Around one-third of patients exhibited PBRM1 mutations which were not seen to impact cancer-specific survival. Approximately 10% had mutations in SETD2, and just under 10% BAP1 mutations. Both were seen to negatively affect cancer-specific survival, BAP1 in both patient cohorts (MSKCC-HR 7.71 95%CI 2.08–28.6, TGCA-HR 2.21 95%CI 1.35–3.63), and SETD2 in the TCGA cohort (HR 1.68 95%CI 1.04–2.73).40
BAP1 Tumor Predisposition Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Initially identified in 1998, BAP1 (BRCA1-associated protein) is a deubiquitinating hydrolase that binds to the RING finger domain of the BRCA1 protein and suppresses the growth of human breast cancer cells in soft agar. As a nuclear protein encoded by the BAP1 gene located on chromosome 3p21.1, BAP1 partially interacts through its deubiquitinase activity with other proteins (e.g., HCFC1, YY1, OGT, ASXL1/2, and FOXK1/2), and participates in several cellular processes, including chromatin remodeling, cell cycle progression, cell differentiation, and DNA damage responses [2,3]. Germline mutations in the BAP1 gene result in haploinsufficiency of the BAP1 protein that either lacks the nuclear localization sequence or displays reduced deubiquitinase activity [4,5], thus confirming the role of BAP1 as a bona fide tumor suppressor [6,7].
BAPoma presenting as an incidental scalp papule: case report, literature review, and screening recommendations for BAP1 tumor predisposition syndrome
Published in Journal of Dermatological Treatment, 2022
Marcus Zaayman, Peter Nguyen, Annika Silfvast-Kaiser, Jillian Frieder, Cameron West, Katherine Tumminello, So Yeon Paek
One of the primary manifestations in patients with BAP1-TPDS is the progressive development of cutaneous melanocytic lesions known as BIMTs (10). These lesions develop as early as the 2nd decade of life and are estimated to occur in 75% of patients with BAP1-TPDS (10). Although screening guidelines are not formally established, it has been recommended that the presence of BIMTs with strong personal or family history of BAP1-TPDS associated malignancies should prompt genetic testing and screening for cancers. Individuals with BAP1-TPDS can have more than one type of primary aggressive cancer with median age of onset being younger than the general population (13,14). A large scale systematic review by Luchini et al. (11) found that patients with BAP1 mutations ultimately have increased mortality and higher likelihood of cancer relapse. Prompt investigation of a patient’s BAP1 mutation status can improve survival and outcomes with early cancer detection. It is important to recognize BIMTs as a potential marker for BAP1-TPDS.
Immunotherapy in uveal melanoma: novel strategies and opportunities for personalized treatment
Published in Expert Opinion on Investigational Drugs, 2021
Christos Masaoutis, Stefania Kokkali, Stamatios Theocharis
UM is marked by a distinct molecular pathology, which, interestingly, is largely shared with other tumors arising from melanocytes not residing within epithelia (i.e. blue nevus-related and leptomeningeal melanocytic neoplasms). These melanocytes originate from ventromedially instead of dorsolaterally migrating neural crest cells [1]. UM, unlike cutaneous melanoma, bears in general a minimal mutational burden and no UV radiation signature [1] and harbors rarely BRAF or KIT mutations. The earliest oncogenic molecular event, utterly characteristic of UM, is a mutation affecting the Gαq signaling pathway (GNA11, GNAQ, CYSLTR2 or PLCB4) usually followed by progressive addition of the following – but not necessarily all or in this chronological order: gains of chromosome 8q, which harbors the MYC oncogene; mutations affecting chromatin remodeling factors (mainly tumor suppressor BAP1); SF3B1 or EIF1AX mutations usually accompanied by additional oncogenic alterations (e.g. loss of CDKN2A or mutations affecting the PI3K pathway) [3]. Loss of chromosome 3-encoded BRCA1-associated protein 1 (BAP1) generally results from a hemizygous inactivating BAP1 mutation supervening on monosomy 3 (M3). Germline mutations account for the rare BAP1 cancer predisposition syndrome [1].
Unpacking the genetic etiology of uveal melanoma
Published in Expert Review of Ophthalmology, 2020
Sophie Thornton, Helen Kalirai, Karen Aughton, Sarah E. Coupland
BAP1, or ‘BRCA associated protein 1,’ is a gene encoding for a deubiquitinating enzyme and is found on the short arm of chromosome 3. BAP1 mutations are associated with cancers, such as clear cell renal carcinoma, mesothelioma, and non-small-cell lung cancer as well as UM [70,71]. Somatic mutations in BAP1 have been reported in 18–48% of all UM and in around 84% of M3-UM [39,72]. The bi-allelic inactivation of BAP1 frequently leads to a loss of nuclear BAP1 protein expression on immunohistochemistry, and this is strongly associated with metastasis and poor patient prognosis [33,39,51,73,78]. BAP1 is involved in numerous cellular processes, such as DNA damage response, regulation of transcription, cell cycling, and cell growth [79,82]. Germline mutations in BAP1 have also been reported to be associated with a tumor-predisposition syndrome increasing susceptibility to UM, cutaneous melanoma, mesothelioma, renal cell carcinoma, and other cancers [70,83,85]. In UM, the frequency of germline BAP1 mutations is around 19% increasing to over 20% in rare familial UM cases [85].