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Clinical and pathologic spectrum of skin lesions. Noninflammatory cystic follicular lesions (A and E), inflamed follicular cysts: folliculitis with onset of perforation (B and F), perforating folliculitis (C and G), and keratoacanthoma (D and H).
Source publication
The emergence of skin tumors in patients treated with sorafenib or with more recent BRAF inhibitors is an intriguing and potentially serious event. We carried out a clinical, pathologic, and molecular study of skin lesions occurring in patients receiving sorafenib.
Thirty-one skin lesions from patients receiving sorafenib were characterized clinica...
Contexts in source publication
Context 1
... total of 22 lesions were excised and the pathologic examination with hematoxylin and eosin staining revealed a spectrum of lesions ( Fig. 1): (i) noninflammatory cystic hair follicles, (ii) cystic folliculitis and perforating folliculitis with rupture of the hair follicle wall and perifollicular infiltrates, (iii) KA defined as a crateriform epidermal neoplasm limited by sharp beaks with no cytologic atypia nor invasion, (iv) crateriform KA-like SCC defined as crateriform ...
Context 2
... folliculitis with rupture of the hair follicle wall and perifollicular infiltrates, (iii) KA defined as a crateriform epidermal neoplasm limited by sharp beaks with no cytologic atypia nor invasion, (iv) crateriform KA-like SCC defined as crateriform epidermal neoplasms with irregular budding borders, cytologic atypia, and invasive nests ( Fig. 1). Lymphatic metastatic embols were seen in one SCC (patient ...
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Citations
... skin cancer [17][18][19][20]. About 83% of our central nodes are present in the highest ranked cluster of the skin carcinoma network. ...
 Background: The basal-cell carcinoma (BCC) as one of the most common type of skin cancers reported to have an increasing trend during past years. Molecular approaches can be useful to advance diagnosis and treatment goals in this cancer.Materials and Methods: In this sense, one of the recent popular investigations, protein-protein interaction network analysis (PPI), was applied in this study to better facilitate molecular view of BCC.  Cytoscape v3.6.0 and its plug-ins analyzed and explored the topological and annotation features of the constructed network. Result: Among TP53, EGFR, AKT1, ERBB2, HRAS, and CCND1 as central agents of the network, five of them were also present in the first prominent cluster of the network in which considered for further analysis. It is suggested that there are significant related biological processes, actions, and expression changes for this highlighted cluster that may be related to BCC risk.  Conclusion: Therefore, the studied complex of proteins may worth considering for clinical studies and therapeutic interventions after validating by related tests. What is more, among these genes, EBBR2 has more to offer and consequently with additional values.  [GMJ.2018;7:e1271]
... 2,3 Deleterious mutations in genes such as TP63, TP53, RB1, CDKN2A, CCND1, MYC, FBXW7, HRAS, SOX2, NRF2, EP300, NOTCH-1, and RECQL4 may lead to the development of a variety of SCCs. 4,5 Mutations in cell cycle-regulated genes, such as CDKN2A, RB1, and TP53, were commonly reported in SCC. Moreover, mutations in some signaling pathway-related genes, including RAS, MAPK, and PI3K, could lead to different types of SCCs. ...
Squamous cell carcinoma (SCC) is the most common human solid tumor and the leading cause of cancer death. SCC of the breast is a very rare type of cancer that has not been well researched. Early identification of the genetic factors involved can lead to early diagnosis and targeted treatment. The present study was conducted in 2018 at Isfahan University of Medical Sciences (Isfahan, Iran). The proband was a 66-year-old woman with SCC of the breast and a positive family history of cancer. Blood DNA samples were used for whole-exome sequencing to identify germline pathogenic variants. Variant annotation and prioritization were done on variant call format files using bioinformatics software tools. The screened variants were confirmed using the Sanger sequencing method. Co-segregation analysis was performed on the blood DNA samples of the first- and second-degree relatives of the proband to assess the presence of the mutation. A novel germline pathogenic variant was identified in the RECQL4 gene of the family. RECQL4 is a known protein in DNA repair and replication. Considering its effect on other types of SCC, it may play an important role in SCC initiation and progression in the breast.
... PIK3CA was found to have genetic alterations, and amplification or mutations were found in 5% of clear cell renal cell carcinomas [27]. HRAS is a member of the RAS family, and normal or mutated forms of HRAS are overexpressed in various tumors [28][29][30][31]. QPCT (glutaminyl-peptide cyclotransferase) is bound to HRAS and improves the stability of HRAS by inhibiting its ubiquitination degradation, which can activate the ERK signaling pathway and lead to sunitinib resistance in renal cell cancer [32]. ...
The autoantibody in patients' serum can act as a biomarker for diagnosing cancer, and the differences in autoantibodies are significantly correlated with the changes in their target proteins. In this study, 16 renal cancer (RC) patients were assigned to the disease group, and 16 healthy people were assigned to the healthy control (HC) group. The human proteome microarray consisting of>19,500 proteins was used to examine the differences in IgG and IgM autoantibodies in sera between RC and HC. The comparative analysis of the microarray results shows that 101 types of IgG and 25 types of IgM autoantibodies are significantly higher in RC than in HC. Highly responsive autoantibodies can be candidate biomarkers (e.g., anti-KCNAB2 IgG and anti-RCN1 IgM). Extensive enzyme-linked immunosorbent assay (ELISA) was performed to screen sera in 72 RC patients and 66 healthy volunteers to verify the effectiveness of the new autoantibodies. The AUCs of anti-KCNAB2 IgG and anti-GAPDH IgG were 0.833 and 0.753, respectively. KCNAB2 achieves high protein expression, and its high mRNA level is confirmed to be an unfavorable prognostic marker in clear cell renal cell carcinoma (ccRCC) tissues. This study suggests that the high-throughput human proteome microarray can effectively screen autoantibodies in serum as candidate biomarkers, and their corresponding target proteins can lay a basis for the in-depth investigation into renal cancer.
... 324 A similar mechanism of paradoxical MAP kinase activation due to RAF inhibition has been reported in patients treated with the multikinase inhibitor sorafenib. [325][326][327] Activation of the MAP kinase pathway has also been proposed as a mechanism leading to secondary neoplasms by circumventing SHH signaling after SMO inhibition (see Figure S2). 328 Further investigation is necessary to determine if MAP kinase activation is also a possibly mechanisms with Notch inhibition. ...
Background:
Advances in molecular biology and genetics have contributed to breakthrough treatments directed at specific pathways associated with the development of cancer. Small-molecule inhibitors (Nibs) aimed at a variety of cellular pathways have been efficacious; however, they are associated with significant dermatologic toxicities.
Methods:
We conducted a comprehensive review of dermatologic toxicities associated with Nibs categorized into the following five groups: (a) MAP kinase; (b) growth factor/multi-tyrosine kinase; (c) cell division/DNA repair; (d) signaling associated with myeloproliferative neoplasms; and (e) other signaling pathways. Prospective phase I, II, or III clinical trials, retrospective literature reviews, systematic reviews/meta-analyses, and case reviews/reports were included for analysis.
Results:
Dermatologic toxicities reviewed were associated with every class of Nibs and ranged from mild to severe or life-threatening adverse skin reactions. Inflammatory reactions manifesting as maculopapular, papulopustular/acneiform, and eczematous lesions were frequent types of dermatologic toxicities seen with Nibs. Squamous cell carcinoma with keratoacanthoma-like features were associated with a subset of Nibs. Substantial overlap in dermatologic toxicities was found between Nibs.
Conclusions:
Dermatologic toxicities from Nibs are diverse and may overlap between classes of Nibs. Recognition of the various types of toxicities from Nibs is critical for patient care in the era of "oncodermatology/dermatopathology". This article is protected by copyright. All rights reserved.
... Since the approval of sorafenib, case reports and small series have described the onset of proliferative and inflammatory skin lesions (SL) in patients undergoing treatment, such as squamous cell carcinoma (SCC), keratoacanthoma (KA), actinic keratosis, cystic folliculitis and basal cell carcinoma (BCC) [10][11][12][13][14][15][16][17]. These lesions were predominantly reported in patients with renal cell carcinoma, while anecdotical cases have been described in HCC [11,12]. ...
... Our study also shows that a more exacerbated and early "skin response" evidenced a longer OS for those patients with eDAE and SL (median 26.5 months 95% CI In order to assess if sorafenib-treated group of patients were enduring a pro-proliferative stimulus for SL development due to a potential paradoxical increase in MAPK signaling pathway in skin cells, we checked mutational status for BRAF, KRAS, HRAS genes in our patients compared to mutational status for the same genes in a control group paired according to age, gender, type of skin lesions and demographics. Although none of our samples were positive for BRAF V600E mutation, the expression of pERK observed in a number of our samples are in line with the hypothetical paradoxical activation of the MAPK signaling in BRAF wild-type cells already described by other groups [15,20,21]. The concept that a targeted agent that blocks a pro-oncogenic mechanism in tumor cell has the potential to activate cell proliferation in a distinct tissue is well-known, not only in patients treated with sorafenib who develop skin cancer, but more frequently with BRAF inhibitors used in melanoma, such as vemurafenib, dabrafenib and encorafenib [22][23][24]. ...
Background/aim:
Dermatological adverse events (DAE) in hepatocellular carcinoma (HCC) patients treated with sorafenib predicts better outcome. Some turn into skin lesions (SL) requiring pathology examination. We describe incidence, characteristics and molecular profile of SL in HCC patients treated with sorafenib.
Materials and methods:
SL were prospectively collected in 311 HCC patients who started sorafenib. SL from sorafenib cohort were compared to those from a control patient group selected to match SL type and demographics. HRAS, KRAS and BRAF mutations were analyzed by CAST-PCR, mutated p53 and MAPK pathway activation by immunohistochemistry and immune infiltration by hematoxylin-eosin staining.
Results:
Eighty-eight out of 311 patients developed DAE and 7.4% SL required histological assessment. Most frequent lesions were keratoacanthomas (n = 4), squamous-cell carcinomas (SCC)(n = 5), basal-cell carcinomas (BCC)(n = 3) and seborrheic keratosis (n = 5). HRAS and KRAS mutations were detected in 4 SL, while no mutations showed in control SL. Nuclear pERK immunostaining was identified in 33.3% of cases versus 5.3% of controls. Most SL (90%) from patients with DAE were proliferative with intense immune infiltration (73%).
Conclusions:
The onset of SL and their molecular profile did not impact negatively on patient's prognosis, but intense proliferation of SL may reflect compensatory activation of MAPK pathway and warrants their close monitoring.
... PIK3CA was identi ed with genetic alteration, and ampli cation or mutations were 5% in clear cell renal cell carcinoma [27]. HRAS is a member of the RAS family, and normal or mutated forms of HRAS are overexpressed in multiple tumors [28][29][30][31]. QPCT (Glutaminyl peptide cyclotransferase) is bound to HRAS and increases the stability of HRAS by reducing its ubiquitination degradation, thus activating the ERK signaling pathway and leading to sunitinib resistance in renal cell cancer [32]. ...
Background: The autoantibody in the patient's serum can be used as a marker for the diagnosis of cancer, and the differences of autoantibodies are closely related to the changes of their target proteins. The human proteome microarray platform can be used for the screening of autoantibodies.
Methods: In this study, 16 renal cancer (RC) patients were taken as a disease group, and the same number of healthy people was selected as a healthy control (HC) group. The protein microarray containing 16,152 proteins was used to detect the possible differences of autoantibodies IgG and IgM in the sera between the RC group and HC group. The screening criteria for autoantibodies and their target proteins are: fold change > 1.2, p-value < 0.05, positive ratio of RC > 30% and positive ratio of HC < 10%. Then the screened target proteins were used for cluster analysis of functions and pathways by PANTHER, DAVID and STRING.
Results: Through the comparative analysis of the microarray results, there were 139 types of IgG and 43 types of IgM autoantibody significantly higher in RC than in the HC, and the highly responsive autoantibodies can be candidate biomarkers, such as anti-BCAS4-IgG and anti-RCN1-IgM. There were 159 IgG and 261 IgM autoantibodies that were significantly changed between the RC and the HC. The target proteins BCAS4 and RCN1 may be RC-related antigen and proteins such as GAP43 and CCT8 may be RC-related or RC-specific antigen. The functional clustering results showed those target proteins were mainly directed against the MAPK signaling pathway, Antigen processing: ubiquitination & proteasome degradation, Cargo recognition for clathrin-mediated endocytosis, etc.
Conclustions: The high-content human proteome microarray platform can effectively screen autoantibodies in serum as candidate markers for renal cancer, and their corresponding target proteins can lay the foundation for the study of renal cancer.
... Melanoma patients treated with the BRAF inhibitor sorafenib are in high risk of developing UV-induced squamous cell carcinoma during the course of their treatment. (96,97). Sorafenib is known to have strong off-target effect against ZAK (61), and was reported to suppress UVinduced and ZAK-dependent apoptosis in cultured keratinocytes (76). ...
Cells rely on stress response pathways to uphold cellular homeostasis and limit the negative effects of harmful environmental stimuli. The stress- and mitogen-activated protein (MAP) kinases, p38 and JNK, are at the nexus of numerous stress responses, among these the ribotoxic stress response (RSR). Ribosomal impairment is detrimental to cell function as it disrupts protein synthesis, increase inflammatory signaling and, if unresolved, lead to cell death. In this review, we offer a general overview of the three main translation surveillance pathways; the RSR, Ribosome-associated Quality Control (RQC) and the Integrated Stress Response (ISR). We highlight recent advances made in defining activation mechanisms for these pathways and discuss their commonalities and differences. Finally, we reflect on the physiological role of the RSR and consider the therapeutic potential of targeting the sensing kinase ZAKα for treatment of ribotoxin exposure.
... SCCs. 30,31 Significantly mutations could also be found in in a subset of early precursors that were infundibulocystic supporting an oncogenic pathway with increased mutational burden. In general, these papular keratotic tumors appear rapidly but are often indolent, have not been destructive or metastasized and can regress. ...
Keratoacanthomas (KAs) are distinctive tumors that are defined by their clinical and histopathological features. Their relationship and distinction from squamous cell carcinoma (SCC) however remain controversial. All cytogenic and immunohistochemical markers that have been applied in this quest have failed. A close relationship of KAs to hair follicles has been recognized. The descriptive term infundibulocystic or infundibular SCC was introduced to define a more broad‐based pathway encompassing KAs. The follicular infundibulum roles in respect to neoplasia and wound healing are important elements in understanding the pathogenesis of KAs. Mouse models for KA have provided insights into the relationship of KA to follicles and SCCs. These advances and together with the diverse clinical and histopathological aspects of KA have contributed to the formulation of a conceptual pathway. The central element is that ultraviolet (UV)‐mutated or activated committed infundibular stem cells are driven by the combination of a mutated oncogenic RAS pathway linked with the Wnt/beta‐catenin pathway responsible for stem cell maintenance, hair follicle development, wound healing and driving keratoacanthoma proliferation and terminal keratinisation. The existence and activation of this mutated pathway may form the basis of the paradoxical emergence of KAs and SCCs in patients receiving BRAF and PD‐1 inhibitor therapy. This article is protected by copyright. All rights reserved.
... This routine vigilant screening has been successful thus far, and all reported cases of MKI-induced secondary cutaneous malignancy have been early-stage disease that is easily managed with surgical excision or local destruction. 41 ...
Over the past 2 decades, rapid advancement in systemic anticancer therapeutics has led to astounding improvement in survival rates of patients with cancer. However, this celebrated progress has brought with it an evolving spectrum of drug toxicities that limit their prodigious capabilities. Cutaneous adverse events are of the most frequent of these toxicities, with substantial impact on quality of life and commonly resulting in dose reduction or change in therapy. Thus, familiarity with the array of dermatologic manifestations caused by these drugs is prudent for patient treatment. As such, the advent of dedicated oncodermatologists, and their introduction into multidisciplinary cancer care, has been crucial in optimizing treatment through therapeutic achievement and overall well-being. This review will address the epidemiology, clinical presentations, and management strategies of the major dermatologic adverse events of systemic anticancer agents, including cytotoxic chemotherapy, targeted therapy, and immunotherapy.
... When the non-activated HRAS is stimulated by certain factors, the GDP turns into GTP; thus, HRAS changes into its activated form, promoting the activation of downstream signalling pathways [58,59]. Normal or mutated forms of HRAS are overexpressed in multiple tumours [60][61][62][63][64][65]. In our study, we found that QPCT bound to HRAS and increased the stability of HRAS by reducing its ubiquitination degradation, thus activating the ERK signalling pathway and leading to sunitinib resistance in RCC. ...
Rationale: Although sunitinib has been shown to improve the survival rate of advanced renal cell carcinoma (RCC) patients, poor drug response is a major challenge that reduces patient benefit. It is important to elucidate the underlying mechanism so that the therapeutic response to sunitinib can be restored.
Methods: We used an Illumina HumanMethylation 850K microarray to find methylation-differentiated CpG sites between sunitinib-nonresponsive and -responsive RCC tissues and Sequenom MassARRAY methylation analysis to verify the methylation chip results. We verified glutaminyl peptide cyclotransferase (QPCT) expression in sunitinib-nonresponsive and -responsive RCC tissues via qRT-PCR, western blot and immunohistochemical assays. Then, cell counting kit 8 (CCK-8), plate colony formation and flow cytometric assays were used to verify the function of QPCT in RCC sunitinib resistance after QPCT intervention or overexpression. Chromatin immunoprecipitation (ChIP) was performed to clarify the upstream regulatory mechanism of QPCT. A human proteome microarray assay was used to identify downstream proteins that interact with QPCT, and co-immunoprecipitation (co-IP) and confocal laser microscopy were used to verify the protein chip results.
Results: We found that the degree of methylation in the QPCT promoter region was significantly different between sunitinib-nonresponsive and -responsive RCC tissues. In the sunitinib-nonresponsive tissues, the degree of methylation in the QPCT promoter region was significantly reduced, and the expression of QPCT was upregulated, which correlated with a clinically poor response to sunitinib. A knockdown of QPCT conferred sunitinib sensitivity traits to RCC cells, whereas an overexpression of QPCT restored sunitinib resistance in RCC cells. Mechanistically, reducing the methylation degree of the QPCT promoter region by 5-aza-2'-deoxycytidine (decitabine) in RCC cells could increase the expression of QPCT and NF-κB (p65) bound to the QPCT promoter region, positively regulating its expression, while the hypermethylation in the QPCT promoter region could inhibit the binding of NF-κB (p65). QPCT could bind to HRAS and attenuate the ubiquitination of HRAS, thus increasing its stability and leading to the activation of the ERK pathway in RCC cells.
Conclusion: QPCT may be a novel predictor of the response to sunitinib therapy in RCC patients and a potential therapeutic target.
