In addition, melanoma-specific network analysis followed by Kaplan-Meier analysis along with log-rank tests identified tyrosinase, hedgehog acyltransferase, BRCA1-associated protein 1 and melanocyte inducing transcription factor as potential therapeutic targets for melanoma.
Mutation gene analysis identified that BRCA1‑associated protein 1 (BAP1) had a higher mutation frequency and survival analysis, and its associated genes in the BAP1‑associated PPI network, including ASXL transcriptional regulator 1 (ASXL1), proteasome 26S subunit, non‑ATPase 3 (PSMD3), proteasome 26S subunit, non ATPase 11 (PSMD11) and ubiquitin C (UBC), were statistically significantly associated with the overall survival of patients with melanoma.
To the best of our knowledge, this is the first reported series of cutaneous melanomas with loss of BAP1 expression arising in patients without a family history of cancer.
We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n = 3 BAP1, n = 15 MITF p.E318K; diagnostic yield 4.0%).
Since then, physicians have considered this diagnosis for patients with a characteristic personal or family history of BAP1-associated tumours (mainly uveal and cutaneous melanoma, pleural/peritoneal mesothelioma, renal cell carcinoma and BAP1-deficient melanocytic lesions).
Prior studies have shown that nuclear reactivity for BRCA1-associated protein-1 (BAP1) yields prognostic information for paraffin-embedded uveal melanomas.
Germline mutations in BAP-1 are associated with a cancer syndrome that involves uveal and cutaneous melanoma, malignant mesothelioma, atypical Spitz tumors, and clear-cell renal cell carcinoma.
Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma.
Loss of BAP1 function is implicated in the oncogenesis of several types of cancers including uveal, mucosal and some cutaneous melanomas in humans, as well as in mesothelioma.
Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation.
Our findings suggest that the genetic profile of coexistent GNAQ or GNA11 mutations with BAP1 or SF3B1 mutations can aid the histopathological diagnosis of blue nevus-like melanoma and distinguish blue nevus-like melanoma from conventional epidermal-derived melanomas.
The recent technological advances have allowed the identification of new genes involved in melanoma susceptibility: breast cancer 1 (BRCA1), BRCA1-associated protein 1 (BAP1), and telomerase reverse transcriptase (TERT).Tests on these genes allow to identify a larger number of high-risk individuals with a potential of developing familial melanoma and primary multiple melanomas.
Germline BAP1 mutations cause a novel cancer syndrome characterised by early onset of multiple atypical Spitz tumours and increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma and various other malignancies.
While many uveal melanomas harbor mutations in the BRCA-Associated Protein 1 (BAP1) gene, the genetics of non-BAP1 associated tumors are not completely understood.
Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes.
Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas.
Various features that are unique to specific disorders, such as the appearance of melanocytic BAP1-mutated atypical intradermal tumors in cases of BAP1melanoma syndrome, should also be recognized early.