Common acquired melanocytic nevi are benign neoplasms that are composed of small uniform melanocytes and typically present as flat or slightly elevated, pigmented lesions on the skin. We describe two families with a new autosomal dominant syndrome characterized by multiple skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected patients developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of the BAP1 gene. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histologic similarities to the familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.

Hereditary Rb predisposes to a variety of new cancers over time, with radiotherapy further enhancing the risk of tumors arising in the radiation field.

Retinoblastoma is a rare cancer of the infant retina, which forms when both RB1 alleles mutate in a susceptible retinal cell, likely a cone photoreceptor precursor. Loss of the tumour suppressor functions of the retinoblastoma protein, pRB, leads to uncontrolled cell division and recurrent genomic changes during tumour progression. Although pRB is expressed in virtually all tissues, cone precursors have biochemical and molecular features that may sensitize to RB1 loss to enable tumourigenesis. Retinoblastoma is diagnosed in ~8,000 children each year worldwide. Patient survival is >95% in high-income countries, but <30% globally. However, outcomes are improving through increasing awareness for earlier diagnosis, new guidelines and sharing of expertise. Intra-arterial and intravitreal chemotherapy have emerged as promising methods to salvage eyes. Ongoing international collaborations will replace the multiple different classifications of eye involvement with standardized definitions to consistently assess eligibility, efficacy and safety of treatment options. Life-long follow-up is warranted since survivors of heritable retinoblastoma are at risk for developing second cancers. Defining the molecular consequences of RB1 loss in diverse tissues may open new avenues for treatment and prevention of retinoblastoma as well as second cancers in patients with germline RB1 mutations.

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SUMMARY Retinoblastomas develop due to the loss of the Rb protein, yet the cell type in which Rb suppresses retinoblastoma, and the cellular circuitry that underlies the need for Rb are undefined. Here, we show that retinoblastoma cells express markers of post-mitotic cone precursors, but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is specifically needed to suppress ARF-induced apoptosis in cultured retinoblastoma cells. Interestingly, retinoblastoma cell MDM2 expression was regulated by the cone-specific RXRγ transcription factor and a human-specific RXRγ consensus binding site, and proliferation required RXRγ as well as the cone-specific thyroid hormone receptor-β2. These findings provide support for a cone precursor origin of retinoblastoma and suggest that human cone-specific signaling circuitry sensitizes to the oncogenic effects of RB1 mutations.

Importance Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in MAPK pathway activation. Objective To assess the efficacy of selumetinib, a selective, non-ATP competitive inhibitor of MEK1 and MEK2, in uveal melanoma. Design Randomized open-label phase II clinical trial comparing selumetinib versus chemotherapy. Those receiving chemotherapy could receive selumetinib at the time of radiographic progression. Setting Fifteen academic oncology centers. Participants 120 patients with metastatic uveal melanoma. Interventions 101 patients were randomized on a 1:1 ratio to selumetinib 75 mg orally twice daily on a continual basis (n=50) or chemotherapy (temozolomide 150 mg/m2 orally daily for 5 of every 28 days or DTIC 1000 mg/m2 intravenously every 21 days; investigator choice; n=51) until disease progression, death, intolerable toxicity, or withdrawal of consent. Following primary outcome analysis, enrollment continued in a non-randomized fashion to the superior therapy. Main Outcomes Final analysis of progression-free survival, the primary endpoint, was assessed as of April 22, 2013. Additional endpoints, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. Results Median progression-free survival for those randomized to chemotherapy and selumetinib was 7 (95% CI, 4.3 – 8.4; median treatment duration of 8 weeks (IQR, 4.3–16)) and 15.9 weeks (95% CI, 8.4 – 21.1; median treatment duration of 16.1 weeks (IQR, 8.1–25.3)), respectively (hazard ratio 0.46; 95% CI, 0.30 – 0.71; p < 0.001). Median overall survival was 9.1 (95% CI, 6.1 – 11.1) and 11.8 months (95% CI, 9.8 – 15.7) for those randomized to chemotherapy and selumetinib, respectively (hazard ratio 0.66; 95% CI, 0.41–1.06; p=0.09). No objective responses were observed with chemotherapy. 49% of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% patients treated with selumetinib, with 37% requiring at least one dose reduction. Conclusions and Relevance In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high adverse event rate.

A substantial subset of patients with metastatic uveal melanoma survive more than 4 years with metastatic disease. Data on variates of survival and site of first metastasis may guide strategies for screening patients, although our data failed to show a survival advantage in discovering asymptomatic metastatic disease.

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