Distinct transcriptomic landscapes of cutaneous basal cell carcinomas and squamous cell carcinomas

The majority of non-melanoma skin cancer (NMSC) is cutaneous basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), which are also called keratinocyte carcinomas, as both of them originate from keratinocytes. The incidence of keratinocyte carcinomas is over 5 million per year in the US, three-fold higher than the total incidence of all other types of cancer combined. While there are several reports on gene expression profiling of BCC and SCC, there are significant variations in the reported gene expression changes in different studies. One reason is that tumor-adjacent normal skin specimens were not included in many studies as matched controls. Furthermore, while numerous studies of skin stem cells in mouse models have been reported, their relevance to human skin cancer remains unknown. In this report, we analyzed gene expression profiles of paired specimens of keratinocyte carcinomas with their matched normal skin tissues as the control. Among several novel findings, we discovered a significant number of zinc finger encoding genes up-regulated in human BCC. In BCC, a novel link was found between hedgehog signaling, Wnt signaling, and the cilium. While the SCC cancer-stem-cell gene signature is shared between human and mouse SCCs, the hair follicle stem-cell signature of mice was not highly represented in human SCC. Differential gene expression (DEG) in human BCC shares gene signature with both bulge and epidermal stem cells. We have also determined that human BCCs and SCCs have distinct gene expression patterns, and some of them are not fully reflected in current mouse models

Signal peptide cleavage is essential for surface expression of a regulatory T cell surface protein, leucine rich repeat containing 32 (LRRC32)

<p>Abstract</p> <p>Background</p> <p>Elevated numbers of regulatory T cells (T_regs) have been implicated in certain cancers. Depletion of T_regshas been shown to increase anti-tumor immunity. T_regsalso play a critical role in the suppression of autoimmune responses. The study of T_regshas been hampered by a lack of adequate surface markers. Leucine Rich Repeat Containing 32 (LRRC32), also known as Glycoprotein A Repetitions Predominant (GARP), has been postulated as a novel surface marker of activated T_regs. However, there is limited information regarding the processing of LRRC32 or the regulatory phenotype and functional activity of T_regsexpressing LRRC32.</p> <p>Results</p> <p>Using naturally-occurring freshly isolated T_regs, we demonstrate that low levels of LRRC32 are present intracellularly prior to activation and that freshly isolated LRRC32⁺T_regsare distinct from LRRC32^-T_regswith respect to the expression of surface CD62L. Using LRRC32 transfectants of HEK cells, we demonstrate that the N-terminus of LRRC32 is cleaved prior to expression of the protein at the cell surface. Furthermore, we demonstrate using a construct containing a deleted putative signal peptide region that the presence of a signal peptide region is critical to cell surface expression of LRRC32. Finally, mixed lymphocyte assays demonstrate that LRRC32⁺T_regsare more potent suppressors than LRRC32^-T_regs.</p> <p>Conclusions</p> <p>A cleaved signal peptide site in LRRC32 is necessary for surface localization of native LRRC32 following activation of naturally-occurring freshly-isolated regulatory T cells. LRRC32 expression appears to alter the surface expression of activation markers of T cells such as CD62L. LRRC32 surface expression may be useful as a marker that selects for more potent T_regpopulations. In summary, understanding the processing and expression of LRRC32 may provide insight into the mechanism of action of T_regsand the refinement of immunotherapeutic strategies aimed at targeting these cells.</p

Higher susceptibility to sunburn is associated with decreased plasma glutamine and increased plasma glutamate levels among US women: An analysis of the Nurses' Health Study I and II

To the Editor: The metabolism of glutamine and glutamate, 2 important amino acids synthesized in the human body, may have an etiologic role in melanoma, an aggressive skin malignancy. 1 , 2 Preclinical experiments and clinical trials have found that metabotropic glutamate receptor 1 blocker and glutamate release inhibitor (eg, Riluzole) can suppress melanoma cell migration, invasion, and proliferation. 2 Additionally, inhibiting glutaminase, the enzyme that converts glutamine to glutamate, further reduced glutamate bioavailability and suppressed tumor progression. 1 Susceptibility to sunburn, a pigmentary trait, is a well-known risk factor for melanoma. 3 However, it is unclear whether plasma glutamate and glutamine are affected by this host factor even before cancer onset

Enhanced metastatic risk assessment in cutaneous squamous cell carcinoma with the 40-gene expression profile test

Aim: To clinically validate the 40-gene expression profile (40-GEP) test for cutaneous squamous cell carcinoma patients and evaluate coupling the test with individual clinicopathologic risk factor-based assessment methods. Patients & methods: In a 33-site study, primary tumors with known patient outcomes were assessed under clinical testing conditions (n = 420). The 40-GEP results were integrated with clinicopathologic risk factors. Kaplan–Meier and Cox regression analyses were performed for metastasis. Results: The 40-GEP test demonstrated significant prognostic value. Risk classification was improved via integration of 40-GEP results with clinicopathologic risk factor-based assessment, with metastasis rates near the general cutaneous squamous cell carcinoma population for Class 1 and ≥50% for Class 2B. Conclusion: Combining molecular profiling with clinicopathologic risk factor assessment enhances stratification of cutaneous squamous cell carcinoma patients and may inform decision-making for risk-appropriate management strategies