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

Foretová, Lenka; Navrátilová, Marie; Svoboda, Marek; Házová, Jana; Vašíčková, Petra; Sťahlová, Eva Hrabincová; Fabián, Pavel; Schneiderová, Monika

doi:10.14735/amko2019s118

Cited by 8 publications

(6 citation statements)

References 18 publications

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“…The enrollment of 22 melanoma patients with atypical Spitz nevi with relatives developing BAP1 -related tumors can explain an increased prevalence of BAP1 mutation carriers in this Italian study. Germline BAP1 mutations were rarely identified in Czech patients so far, dominantly in probands with uveal melanoma or Spitz nevi [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

et al. 2020

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Cutaneous melanoma is the deadliest skin malignity with a rising prevalence worldwide. Patients carrying germline mutations in melanoma-susceptibility genes face an increased risk of melanoma and other cancers. To assess the spectrum of germline variants, we analyzed 264 Czech melanoma patients indicated for testing due to early melanoma (at <25 years) or the presence of multiple primary melanoma/melanoma and other cancer in their personal and/or family history. All patients were analyzed by panel next-generation sequencing targeting 217 genes in four groups: high-to-moderate melanoma risk genes, low melanoma risk genes, cancer syndrome genes, and other genes with an uncertain melanoma risk. Population frequencies were assessed in 1479 population-matched controls. Selected POT1 and CHEK2 variants were characterized by functional assays. Mutations in clinically relevant genes were significantly more frequent in melanoma patients than in controls (31/264; 11.7% vs. 58/1479; 3.9%; p = 2.0 × 10−6). A total of 9 patients (3.4%) carried mutations in high-to-moderate melanoma risk genes (CDKN2A, POT1, ACD) and 22 (8.3%) patients in other cancer syndrome genes (NBN, BRCA1/2, CHEK2, ATM, WRN, RB1). Mutations in high-to-moderate melanoma risk genes (OR = 52.2; 95%CI 6.6–413.1; p = 3.2 × 10−7) and in other cancer syndrome genes (OR = 2.3; 95%CI 1.4–3.8; p = 0.003) were significantly associated with melanoma risk. We found an increased potential to carry these mutations (OR = 2.9; 95%CI 1.2–6.8) in patients with double primary melanoma, melanoma and other primary cancer, but not in patients with early age at onset. The analysis revealed affected genes in Czech melanoma patients and identified individuals who may benefit from genetic testing and future surveillance management of mutation carriers.

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Section: Discussionmentioning

confidence: 99%

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

et al. 2020

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“…Clinical follow-up was obtained from the patients, their physicians, or from referring pathologists. Four cases have been previously reported 4,21 .…”

Section: Materials and Methods Case Selectionmentioning

confidence: 97%

Novel insights into the BAP1-inactivated melanocytic tumor

et al. 2022

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BAP1-inactivated melanocytic tumor (BIMT) is a group of melanocytic neoplasms with epithelioid cell morphology molecularly characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, and a mutually exclusive mitogenic driver mutation, more commonly BRAF. BIMTs can occur as a sporadic lesion or, less commonly, in the setting of an autosomal dominant cancer susceptibility syndrome caused by a BAP1 germline inactivating mutation. Owing to the frequent identification of remnants of a conventional nevus, BIMTs are currently classified within the group of combined melanocytic nevi. "Pure" lesions can also be observed. We studied 50 BIMTs from 36 patients. Most lesions were composed of epithelioid melanocytes of varying size and shapes, resulting extreme cytomorphological heterogeneity. Several distinctive morphological variants of multinucleated/giant cells were identified. Some hitherto underrecognized microscopic features, especially regarding nuclear characteristics included nuclear blebbing, nuclear budding, micronuclei, shadow nuclei, peculiar cytoplasmic projections (ant-bear cells) often containing micronuclei and cell-in-cell structures (entosis). In addition, there were mixed nests of conventional and BAP1-inactivated melanocytes and squeezed remnants of the original nevus. Of the 26 lesions studied, 24 yielded a BRAF mutation, while in the remaining two cases there was a RAF1 fusion. BAP1 biallelic and singe allele mutations were found in 4/22 and 16/24 neoplasms, respectively. In five patients, there was a BAP1 germline mutation. Six novel, previously unreported BAP1 mutations have been identified. BAP1 heterozygous loss was detected in 11/22 lesions. Fluorescence in situ hybridization for copy number changes revealed a related amplification of both RREB1 and MYC genes in one tumor, whereas the remaining 20 lesions studied were negative; no TERT-p mutation was found in 14 studied neoplasms. Tetraploidy was identified in 5/21 BIMTs. Of the 21 patients with available follow-up, only one child had a locoregional lymph node metastasis. Our results support a progression of BIMTs from a conventional BRAF mutated in which the original nevus is gradually replaced by epithelioid BAP1-inactivated melanocytes. Some features suggest more complex underlying pathophysiological events that need to be elucidated.

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“…The artifactual construction of borders in time and space (104) and multiplicity concerns likely underlie the increased incidence of UvM in reported clusters (94). Clusters of UvM also may be attributable to familial cases BAP1 tumor predisposition syndrome (168)(169)(170). However, in comparison with somatic mutations, germline BAP1 mutations in the 3p21 chromosomal region occur infrequently in UvMs (171)(172)(173).…”

Section: Limitationsmentioning

confidence: 99%

The evidence for Mycobacterium avium subspecies paratuberculosis (MAP) as a cause of nonsolar uveal melanoma: a narrative review

Pierce¹,

Jindal²,

Choi³

et al. 2023

Transl Cancer Res

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Background and Objective: Animal microorganisms have been proposed as a cause of human cancers associated with farming, agricultural occupation or residence, and related downstream exposures. Several studies have described uveal melanoma (UvM) as a farming-associated cancer. A possible suspect is the animal microorganism Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of paratuberculosis in dairy cows. This microbe is transmitted to humans through various means, including contact with animal faeces, contaminated dust and soil, organic fertilizers, and as workers in slaughterhouses/ animal processing facilities. The objective of the current manuscript was to examine the putative association between Mycobacterium avium sub-species paratuberculosis and non-solar UvM.Methods: Online data sources (PubMed, Scopus, Cochrane Library, and Google) published in English between 1980 to present were searched for key words pertaining to MAP exposure, farming-related occupations and activities, and locations with or in the vicinity of dairy cattle.

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

Cited by 8 publications

References 18 publications

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

Novel insights into the BAP1-inactivated melanocytic tumor

The evidence for Mycobacterium avium subspecies paratuberculosis (MAP) as a cause of nonsolar uveal melanoma: a narrative review

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