A novel AKT3 mutation in melanoma tumours and cell lines.

Recently, a rare activating mutation of AKT1 (E17K) has been reported in breast, ovarian, and colorectal cancers. However, analogous activating mutations in AKT2 or AKT3 have not been identified in any cancer lineage. To determine the prevalence of AKT E17K mutations in melanoma, the most aggressive form of skin cancer, we analysed 137 human melanoma specimens and 65 human melanoma cell lines for the previously described activating mutation of AKT1, and for analogous mutations in AKT2 and AKT3. We identified a single AKT1 E17K mutation. Remarkably, a previously unidentified AKT3 E17K mutation was detected in two melanomas (from one patient) as well as two cell lines. The AKT3 E17K mutation results in activation of AKT when expressed in human melanoma cells. This represents the first report of AKT mutations in melanoma, and the initial identification of an AKT3 mutation in any human cancer lineage. We have also identified the first known human cell lines with naturally occurring AKT E17K mutations.

Desmoid tumor: a disease opportune for molecular insights.

Desmoid tumors are monoclonal proliferations that fall within a broad histologic spectrum of fibrous mesenchymal tumors that ranges from benign proliferations of scar tissue to high-grade fibrosarcomas. These low-grade tumors are extremely infiltrative locally, but lack the ability to metastasize systemically. While they are only rarely a direct cause of mortality, using current therapeutic modalities, these tumors have a high rate of local recurrence that can result in significant treatment related morbidity. Sporadic desmoids are usually associated with somatic mutations in codons 41 or 45 of exon 3 of beta-catenin (CTNNB1). Desmoid tumors occurring in the background of familial adenomatous polyposis (FAP) usually contain inactivating germline mutations in the adenomatous polyposis coli (APC) gene. CTNNB1 and APC are part of the Wnt signaling pathway and mutations in either gene result in stabilization of the beta-catenin protein and allow nuclear translocation and binding of beta-catenin to the T-cell factor/lymphoid enhancer factor (TCF/Lef) family of transcription factors, resulting in activation of target genes which may underlie desmoid tumor biology and clinical behavior. In an era of molecularly targeted therapeutics there is a real need to better grasp the molecular mechanisms behind desmoid tumorigenesis and progression. This knowledge will eventually result in the development of patient and tumor tailored therapies and assist in the control and eradication of this disease.

Characteristic Ber-EP4 and EMA expression in sebaceoma is immunohistochemically distinct from basal cell carcinoma.

AIMS: There is considerable overlap between the histological features of sebaceoma and basal cell carcinoma (BCC). The distinction between these two tumours is important due to the often more locally aggressive nature of BCC and the association of sebaceoma with the Muir-Torre syndrome. The aim of this study was to describe the immunohistochemical reactivity of the cells in sebaceoma to Ber-EP4 and epithelial membrane antigen (EMA) and investigate the utility of this panel to differentiate sebaceoma from basal cell carcinoma. METHODS AND RESULTS: Immunohistochemistry of 25 sebaceomas for Ber-EP4 and EMA revealed unequivocal negative expression of Ber-EP4 in 24 of 25 sebaceomas. A single case exhibited focal weak Ber-EP4 staining, predominantly in mature sebocytes and in < 10% of the tumour cells. EMA was not expressed in the germinative cells of sebaceoma, but was expressed strongly in approximately 50% of mature sebocytes in all cases and highlighted the cytoplasmic vacuoles. We reviewed the immunoreactivity of 51 cases of nodular BCCs and found moderate or strong BerEP4 expression in all cases with never less than 20% of the tumour staining. Expression of EMA was uncommon in BCC (moderate or strong in 8%) and was confined to keratotic or squamoid areas. CONCLUSION: The use of Ber-EP4 in combination with EMA, both widely used immunomarkers in histopathology, is a helpful aid in distinguishing sebaceoma from nodular BCC.

Sebaceous neoplasia and Torre-Muir syndrome.

Sebaceous tumours include hyperplasia, adenoma, sebaceoma and carcinoma. Importantly, the latter three are potential markers of Torre-Muir syndrome; the hereditary association of sebaceous neoplasia and internal malignancy, most commonly colorectal carcinoma. The diagnostic features, differential diagnosis, molecular diagnostics and recent advances in pathogenesis of this rare group of tumours are discussed along with Torre-Muir syndrome and recommendations for screening for this important association.