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.
The coexistence of dysplastic nevus syndrome and a BAP1 germline mutation extends the spectrum of the BAP1 tumor predisposition syndrome and may confer a greater risk for cutaneous melanomas.
The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma.
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.
Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation.
Patients with germline BAP1 mutations exhibited increased frequency of family history of cancer (100% vs 65.9%, P = .06), particularly cutaneous melanoma (62.5% vs 9.9%, P < .001) and ocular melanoma (25.0% vs 1.9%, P = .01).
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.
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.
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.
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.
Patients with heterozygous germline mutations in BRCA1-associated protein 1 (BAP1), a tumor suppressor gene, develop a tumor predisposition syndrome (OMIM 614327) with increased risk of uveal and cutaneous melanomas, cutaneous atypical and epithelioid melanocytic lesions, lung adenocarcinoma, clear cell renal cell carcinoma, and other tumors.
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.
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%).
In uveal melanoma, monosomy 3 is the most common genetic alteration and somatic mutations of BAP1, a tumor suppressor gene, have been reported in nearly 50% of primary uveal melanomas.
Inherited loss-of-function mutations in the BAP1 oncosuppressor gene are responsible for an inherited syndrome with predisposition to malignant mesothelioma (MM), uveal and keratinocytic melanoma, and other malignancies.
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.