BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition.

Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in ∼30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy.

Long-term outcome of Spitz-type melanocytic tumors.

OBJECTIVE: Despite recent advances in our molecular understanding of Spitz-type tumors, the clinical behavior of these lesions remains unclear. We thus set out to define the clinical outcome of classic Spitz nevi, atypical Spitz tumors (ASTs), and spitzoid melanomas. DESIGN: From 1987 through 2002, data on all lesions containing the term "Spitz" or "Spitz" [AND] "melanoma" were retrieved from the pathology database at Massachusetts General Hospital, and the cases were followed up for their outcome. SETTING: The study was performed at a university-affiliated tertiary health care center in Boston, Massachusetts. PATIENTS: A total of 157 patients with Spitz-type melanocytic lesions and follow-up information were identified. MAIN OUTCOME MEASURES: Sentinel lymph node biopsy results, metastases, or fatality were assessed. RESULTS: There were 68 classic Spitz nevi, 76 ASTs, 10 spitzoid melanomas, and 3 melanomas that arose in Spitz nevi. Spitz nevi were diagnosed at a younger age than ASTs (mean age, 26.4 years vs 33.7 years) (P = .01), though both occurred earlier than melanomas (mean age, 50.4 years, P < .001). Sentinel lymph node biopsy findings were positive in 1 of 6 and 4 of 8 patients with ASTs and spitzoid melanomas, respectively. After a median follow-up of 9.1 years, only 1 patient with an AST, who had a separate intermediate-thickness melanoma, developed distant metastasis. There were 6 documented invasive melanomas among 144 patients with classic Spitz nevi or ASTs (observed/expected ratio, 8.03) (P = .01). CONCLUSIONS: Atypical Spitz tumors are associated with minimal lethal potential, an increased melanoma risk, and a moderate risk of metastasis to regional nodes. It makes clinical sense to minimize aggressive treatment but to offer careful surveillance for rare relapses and subsequent melanomas.

The classification of cutaneous melanoma.

Forty years ago, a clinical and histological classification scheme and prognostic factors were described for cutaneous melanoma. This scheme included the subtypes superficial spreading, nodular and lentigo maligna, and prognostic factors including tumor thickness, ulceration, and mitotic activity. There have been some tweaks to the classification scheme, but these basic findings form the foundation for melanoma diagnosis and staging today. Currently, no molecular marker or target has proved reliably useful in the staging or treatment of melanoma. Measurement with a simple ruler serves as the basis for the staging of primary cutaneous melanoma, while the recognition of primary tumor mitotic activity and ulceration also remain significant factors. Recently, mutational analysis has revealed a correlation of activating mutations with the morphological descriptors from decades ago. Future classification schemes may have more power in predicting response to therapy by integrating specific genomic and intra-tumoral expression profiles with histologic findings.