Figure 1.
(A). Ocular melanoma and cutaneous melanoma cohorts used in this study. (B). Fam-562 pedigree and clinical images of two nevoid melanoma-like melanocytic proliferations (NEMMPs) diagnosed in Fam729. (C). Fam-729 pedigree. One carrier had a Spitz nevus, which has been reported to harbor somatic BAP1 mutations [4]. Abbreviations: M, mutation carrier; wt, wildtype germline sequence; Ob, obligate carrier; OCMEL, ocular melanoma; MEL, cutaneous melanoma; NEMMPs, nevoid melanoma-like melanocytic proliferations; BR, breast cancer; CHL, cholangiocarcinoma; LG, lung cancer; KID, kidney cancer; UNP, melanoma of unknown primary site; CNS, central nervous system tumor; LK, leukemia. Crosses indicate CM with a nevoid pattern. The numbers next to the “MEL” indicate ages of diagnosis. For the sake of confidentiality, the pedigrees have been masked for some non-affected individuals and siblings. Nonessential gender information has also been disguised by a diamond; the number of individuals collapsed into the diamond is indicated.
Table 1.
BAP1 Mutations Identified In Study.
Figure 2.
Histologic and molecular analyses of tumors from Fam-562.
(A)–(F): Histology of 2 distinct NEMMPs. (A) Scanning view of the first lesion showing two expansile dermal nodules (H&E, 2×,) with a (B) benign nevoid appearance (H&E, 10×). (C) Atypical cytological features including nuclear pleomorphism and prominent nucleoli and a dermal mitotic figure (arrow) (H&E, 40×) along with focal increases in Ki67 staining (inset). (D) In the second lesion, there is an expansile dermal proliferation (H&E, 4×). (E) Detail of a field populated by dermal nevic cells with bland nuclear features (H&E,20×). (F) A proliferative area showing marked nuclear atypia and hyperchromasia along with elevated Ki 67 staining (inset). Biallelic inactivation of BAP1 in two tumors through (G) loss of the wildtype allele in a nevoid melanoma (ie. LOH; arrow) or (H) a secondary mutation (p.Ser123Lysfs*3) in a NEMMP that did not exhibit LOH.
Figure 3.
Distribution of BAP1 mutations.
Inactivating germline mutations identified in this study are indicated by the red arrows. Reported somatic missense mutations (blue bars) and indels (blue arrows) from ocular melanoma specimens (COSMIC database; http://www.sanger.ac.uk/genetics/CGP/cosmic/) and germline variants (blue lines) from other families are also shown. Half of the germline variants occur in the terminal 150 amino acids while the somatic changes are more scattered.