Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases

Abstract

The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a recently identified hereditary cancer syndrome. Germline mutations in this tumor suppressor gene predispose families to the development of various malignancies. The molecular functions of the gene as well as the clinical phenotype of the syndrome are still being clarified. We sought to conduct a comprehensive review of published research into BAP1-TPDS to more thoroughly delineate the clinical implications of germline BAP1 mutations. We also report two additional families with germline BAP1 mutations. Current evidence demonstrates that germline BAP1 mutations predispose families to uveal melanoma, renal cell carcinoma, malignant mesothelioma, cutaneous melanoma, and possibly to a range of other cancers as well. Some of these cancers tend to be more aggressive, have a propensity to metastasize, and onset earlier in life in patients with BAP1 mutations as compared to non-predisposed patients with equivalent cancers. Although further research is necessary, this information can aid in the management, diagnosis, and therapy of these patients and their families, and highlights the importance of genetic counseling.

Gene of the month:BAP1

“…The remaining functional allele is inactivated later in life. There is a high risk of developing tumours, including atypical Spitz tumours (ASTs), UM and cutaneous melanoma (CM), epithelioid malignant mesothelioma (MM) and clear cell RCC 14. For these five main tumour types, the earliest age of onset ranges between 16 and 36 years 14.…”

Mesothelioma families without inheritance of a BAP1 predisposing mutation

“…Investigators have examined BAP1 in families: i) with high incidence of MM [3,7,9,11,14]; ii) referred to genetic or cancer centers for uveal melanoma [9,12,15] or other melanocytic tumors [13,17]; iii) affected by basal cell carcinoma [16]; iv) having a family history suggestive of the BAP1 cancer syndrome [18]. Other families were examined as part of asbestos surveillance program [10].…”

“…BAP1 regulates cell cycle control, target genes transcription, and DNA damage repair [2]. The germline mutation in the BAP1 gene is associated with a hereditary tumor predisposition syndrome (BAP1-TPDS, OMIM#614327) that occurs in family members with several cancer types: MM, uveal/cutaneous melanoma, renal cell carcinoma, basal cell carcinoma and other cancers [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. As of March 2016, forty-six families with multiple cases of MM have been analyzed for BAP1 germline alterations.…”

Identification of novel hereditary cancer genes by whole exome sequencing

“…Whole exome sequencing and subsequent validation studies on familial melanoma revealed a role of MITF and POT1 mutations; however, their actual impact on the disease incidence remains to be determined [52][53][54][55][56]. BAP1 germline mutations were initially identified upon the study of uveal melanoma [57] and later turned out to be involved in the development of several other tumor types [58][59][60][61][62][63][64][65][66][67][68][69][70][71][72]. Instances of lung cancer clustering due to high-penetrance mutations are very infrequent; however, the analysis of individual large families revealed potentially relevant genes [50,51].…”