Molecular testing in metastatic basal cell carcinoma

Background: Metastatic basal cell carcinoma (mBCC) is a very rare entity, and diagnosis can be challenging. Therapeutic options are limited, and response to targeted therapy is poor. Objective: To demonstrate a clonal relationship between BCCs and their metastases and to explore which hedgehog pathway-related mutations are involved in mBCC. Methods: Genetic analysis was conducted in 10 primary BCCs and their metastases. Genes relevant for BCC development were analyzed in tumor and metastasis material with small molecule molecular inversion probes (smMIPs) for PTCH1, PTCH2, SMO, SUFU, GLI2, and TP53 or with targeted next generation sequencing of the same genes and CDKN2A, CDKN2B, CIC, DAXX, DDX3X, FUBP1, NF1, NF2, PTEN, SETD2, TRAF7, and the TERT promoter. Results: In 8 of 10 patients, identical gene mutations could be demonstrated in the primary tumors and their metastases. A broad spectrum of mutations was found. Four patients had SMO mutations in their tumor or metastasis, or both. All SMO mutations found were known to cause resistance to targeted therapy with vismodegib. Limitations: In 2 patients there was insufficient qualitative DNA available for genetic analysis. Conclusions: Molecular testing can help to identify the origin of a BCC metastasis and may be of prognostic and therapeutic value

Immunohistochemical analysis of the mechanistic target of rapamycin and hypoxia signalling pathways in basal cell carcinoma and trichoepithelioma

Background: Basal cell carcinoma (BCC) is the most common cancer in Caucasians. Trichoepithelioma (TE) is a benign neoplasm that strongly resembles BCC. Both are hair follicle (HF) tumours. HFs are hypoxic microenvironments, therefore we hypothesized that hypoxia-induced signalling pathways could be involved in BCC and TE as they are in other human malignancies. Hypoxia-inducible factor 1 (HIF1) and mechanistic/mammalian target of rapamycin (mTOR) are key players in these pathways. Objectives: To determine whether HIF1/mTOR signalling is involved in BCC and TE. Methods: We used immunohistochemical staining of formalin-fixed paraffin-embedded BCC (n = 45) and TE (n = 35) samples to assess activity of HIF1, mTORC1 and their most important target genes. The percentage positive tumour cells was assessed manually in a semi-quantitative manner and categorized (0%, 80%). Results: Among 45 BCC and 35 TE examined, expression levels were respectively 81% and 57% (BNIP3), 73% and 75% (CAIX), 79% and 86% (GLUT1), 50% and 19% (HIF1 alpha), 89% and 88% (pAKT), 55% and 61% (pS6), 15% and 25% (pMTOR), 44% and 63% (PHD2) and 44% and 49% (VEGF-A). CAIX, Glut1 and PHD2 expression levels were significantly higher in TE when only samples with at least 80% expression were included. Conclusions: HIF and mTORC1 signalling seems active in both BCC and TE. There are no appreciable differences between the two with respect to pathway activity. At this moment immunohistochemical analyses of HIF, mTORC1 and their target genes does not provide a reliable diagnostic tool for the discrimination of BCC and TE

Corporate governance and management earnings forecast behaviour:Evidence from a low private litigation environment

Purpose The purpose of our study is to examine the influence of three external corporate governance mechanisms (continuous disclosure regulatory reform, analyst following and ownership concentration) and one internal corporate governance mechanism (board structure) on the likelihood, frequency, horizon, precision and accuracy of management earnings forecasts in the low private litigation environment of New Zealand. Design/methodology/approach The authors use a sample of 1,082 management earnings forecasts issued by 125 firms listed on the New Zealand Exchange during the 1998-2007 financial reporting periods. The authors effectively control the self-selection bias problem inherent in management earnings forecasts. Findings The findings provide strong evidence that corporate governance significantly influences management earnings forecast behaviour. Firms with effective corporate governance tend to forecast earnings and provide these earnings forecasts more frequently and precisely. Earnings forecasts issued by firms with more non-executive directors on the board are less optimistically biased. A possible interpretation of the findings is that effective corporate governance mechanisms are able to substitute for a private enforcement alternative. Originality/value The findings have value in informing governance choices in the absence of external disciplinary mechanisms such as private litigation

Molecular testing in metastatic basal cell carcinoma

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a very rare entity, and diagnosis can be challenging. Therapeutic options are limited, and response to targeted therapy is poor. OBJECTIVE: To demonstrate a clonal relationship between BCCs and their metastases and to explore which hedgehog pathway-related mutations are involved in mBCC. METHODS: Genetic analysis was conducted in 10 primary BCCs and their metastases. Genes relevant for BCC development were analyzed in tumor and metastasis material with small molecule molecular inversion probes (smMIPs) for PTCH1, PTCH2, SMO, SUFU, GLI2, and TP53 or with targeted next generation sequencing of the same genes and CDKN2A, CDKN2B, CIC, DAXX, DDX3X, FUBP1, NF1, NF2, PTEN, SETD2, TRAF7, and the TERT promoter. RESULTS: In 8 of 10 patients, identical gene mutations could be demonstrated in the primary tumors and their metastases. A broad spectrum of mutations was found. Four patients had SMO mutations in their tumor or metastasis, or both. All SMO mutations found were known to cause resistance to targeted therapy with vismodegib. LIMITATIONS: In 2 patients there was insufficient qualitative DNA available for genetic analysis. CONCLUSIONS: Molecular testing can help to identify the origin of a BCC metastasis and may be of prognostic and therapeutic value

Immunohistochemical stains for hypoxia inducible factor 1α (HIF1α), phosphorylated mechanistic/mammalian target of rapamycin (pmTOR) and their target genes in basal cell carcinoma (BCC).

<p>BCL-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) (<b>a</b>); carbonic anhydrase IX (CAIX) (<b>b</b>); glucose transporter 1 (GLUT1) (<b>c</b>); HIF1α (<b>d</b>); phosphorylated protein kinase B (pAKT) (<b>e</b>);phosphorylated ribosomal protein S6 (pS6) (<b>f</b>); pmTOR (<b>g</b>); prolyl hydroxylase domain protein 2 (PHD2) (<b>h</b>); vascular endothelial growth factor (VEGF-A) (<b>i</b>). Original magnification: (a–i) x 200.</p

Tumour characteristics.

<p>*Date are presented as n (%).</p><p>Tumour characteristics.</p

Low levels of nuclear ß-catenin coincide with high levels of E-cadherin in BCC.

<p><b>A.</b> Microphotographs of selected sample of ß-catenin, showing nuclear staining only at the periphery or the tumor. Bar = 200 µm. <b>B.</b> Microphotographs of selected sample of E-cadherin showing lowered expression of the tumor compared with the normal epidermis.</p