Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-κB Regulation

Watt, Stephen A.; Purdie, Karin J.; Breems, Nicoline Y. den; Dimon, Michelle; Arron, Sarah T.; McHugh, Angela; Xue, Dylan J.; Dayal, Jasbani H.S.; Proby, Charlotte M.; Harwood, Catherine A.; Leigh, Irene M.; South, Andrew P.

doi:10.1016/j.ajpath.2015.05.018

Cited by 23 publications

(17 citation statements)

References 46 publications

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“…Targeted genetic analysis of all samples was undertaken using 454 pyrosequencing performed using the GS Junior system (Roche/454 Life Sciences, Branford, CT, United States) and Fluidigm (Fluidigm Corporation, San Francisco, CA, United States) PCR amplicon libraries as template. In addition to H, K , and NRAS , we also analyzed the genes NOTCH1, NOTCH2, TP53, CDKN2A, CARD11, CREBBP, TGFBR1 , and 2 , all of which our previous research has implicated in the pathogenesis of cSCC ( Brown et al, 2004 ; South et al, 2014 ; Cammareri et al, 2016 ; Watt et al, 2015 , 2016 ). Primers were designed and validated by Fluidigm (Fluidigm Corporation, San Francisco, CA, United States) as per recommended guidelines for Roche Titanium sequencing (Roche, Mannheim, Germany).…”

Section: Methodsmentioning

confidence: 99%

The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions

et al. 2018

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Background: Human papillomavirus (HPV) has long been proposed as a cofactor in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). More recently, the striking clinico-pathological features of cSCCs that complicate treatment of metastatic melanoma with inhibitors targeting BRAF mutations (BRAFi) has prompted speculation concerning a pathogenic role for oncogenic viruses. Here, we investigate HPV and human polyomaviruses (HPyV) and correlate with clinical, histologic, and genetic features in BRAFi-associated cSCC.Materials and Methods: Patients receiving BRAFi treatment were recruited at Barts Health NHS Trust. HPV DNA was detected in microdissected frozen samples using reverse line probe technology and degenerate and nested PCR. HPV immunohistochemistry was performed in a subset of samples. Quantitative PCR was performed to determine the presence and viral load of HPyVs with affinity for the skin (HPyV6, HPyV7, HPyV9, MCPyV, and TSPyV). These data were correlated with previous genetic mutational analysis of H, K and NRAS, NOTCH1/2, TP53, CDKN2A, CARD11, CREBBP, TGFBR1/2. Chromosomal aberrations were profiled using single nucleotide polymorphism (SNP) arrays.Results: Forty-five skin lesions from seven patients treated with single agent vemurafenib in 2012–2013 were analyzed: 12 cSCC, 19 viral warts (VW), 2 actinic keratosis (AK), 5 verrucous keratosis/other squamoproliferative (VK/SP) lesions, one melanocytic lesion and 6 normal skin samples. Significant histologic features of viral infection were seen in 10/12 (83%) cSCC. HPV DNA was detected in 18/19 (95%) VW/SP, 9/12 (75%) cSCC, 4/5 (80%) SP, and 3/6 (50%) normal skin samples and in 1/12 cases assessed by immunohistochemistry. HPyV was co-detected in 22/30 (73%) of samples, usually at low viral load, with MCPyV and HPyV7 the most common. SNP arrays confirmed low levels of chromosomal abnormality and there was no significant correlation between HPV or HPyV detection and individual gene mutations or overall mutational burden.Conclusion: Despite supportive clinicopathologic evidence, the role for HPV and HPyV infection in the pathogenesis of BRAFi-induced squamoproliferative lesions remains uncertain. Synergistic oncogenic mechanisms are plausible although speculative. Nonetheless, with the prospect of a significant increase in the adjuvant use of these drugs, further research is justified and may provide insight into the pathogenesis of other BRAFi-associated malignancies.

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Section: Methodsmentioning

confidence: 99%

The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions

et al. 2018

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“…Although the functions of statin-related protein remain to be fully elucidated, an anti-inflammatory activity via tumor necrosis factor-α reduction has been reported for the statin-related rosuvastatin protein (39). CARD proteins are scaffold proteins that function as key regulators of NF-κB signaling by providing a link between membrane receptors and NF-κB transcriptional subunits (40). CARD11 and CARD14-mediated alterations in NF-κB signaling are thought to be an early event in the development of cutaneous squamous cell carcinoma and psoriasis, respectively (40,41).…”

Section: Discussionmentioning

confidence: 99%

“…CARD proteins are scaffold proteins that function as key regulators of NF-κB signaling by providing a link between membrane receptors and NF-κB transcriptional subunits (40). CARD11 and CARD14-mediated alterations in NF-κB signaling are thought to be an early event in the development of cutaneous squamous cell carcinoma and psoriasis, respectively (40,41). CARD9 in macrophages mediates necrotic smooth muscle cell-induced inflammation by activating NF-κB (42).…”

Section: Discussionmentioning

confidence: 99%

Label-free LC-MS/MS shotgun proteomics to investigate the anti-inflammatory effect of rCC16

Pang

Bai

et al. 2016

Molecular Medicine Reports

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Clara cell protein (CC16) is an anti-inflammatory protein, which is expressed in the airway epithelium. It is involved in the development of airway inflammatory diseases, including chronic obstructive pulmonary disease and asthma. However, the exact molecular mechanism underlying its anti-inflammatory action remains to be fully elucidated. The aim of the present study was to define the protein profiles of the anti-inflammatory effect of CC16 in lipopolysaccharide (LPS)-treated rat tracheal epithelial (RTE) cells using shotgun proteomics. Protein extracts were obtained from control RTE cells, RTE cells treated with LPS and RTE cells treated with LPS and recombinant CC16 (rCC16). Subsequent label-free quantification and bioinformatics analyses identified 12 proteins that were differentially expressed in the three treatment groups as a cluster of five distinct groups according to their molecular functions. Five of the twelve proteins were revealed to be associated with the cytoskeleton: Matrix metalloproteinase-9, myosin heavy chain 10, actin-related protein-3 homolog, elongation factor 1-α-1 (EF-1-α-1), and acidic ribosomal phosphoprotein P0. Five of the twelve proteins were associated with cellular proliferation: DNA-dependent protein kinase catalytic subunit, EF-1-α-1, tyrosine 3-monooxygenase, caspase recruitment domain (CARD) protein 12 and adenosylhomocysteinase (SAHH) 3. Three proteins were associated with gene regulation: EF-1-α-1, SAHH 3 and acidic ribosomal phosphoprotein P0. Three proteins were associated with inflammation: Tyrosine 3-monooxygenase, CARD protein 12 and statin-related protein. ATPase (H+-transporting, V1 subunit A, isoform 1) was revealed to be associated with energy metabolism, and uridine diphosphate glycosyltransferase 1 family polypeptide A8 with drug metabolism and detoxification. The identified proteins were further validated using reverse transcription-quantitative polymerase chain reaction. These protein profiles, and their interacting protein network, may facilitate the elucidation of the molecular mechanisms underlying the anti-inflammatory effects of CC16.

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“…Further investigation of tumor antigens involved in cSCC pathogenesis is necessary, especially given that there is currently no targeted treatment option for cSCC widely in use [65]. Some cSCC tumor antigens in immunocompetent patients have been identified, such as mutated TP53 , HRAS , CDKN2A , PTCH, KNSTRN , CARD11 , NOTCH1 , and NOTCH2 gene products, overexpressed HER-2 , MUC-1 , EGFR, Fyn , and Ep-CAM gene products, as well as cancer-testis antigens [34,35,53,65–68]. Additional tumor antigens in cSCC driver genes have been described among immunosuppressed patients, including FAT1 [69,70].…”

Section: Limitations and Future Workmentioning

confidence: 99%

Cutaneous squamous cell cancer (cSCC) risk and the human leukocyte antigen (HLA) system

et al. 2017

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Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer among Caucasians in the United States, with rising incidence over the past decade. Treatment for non-melanoma skin cancer, including cSCC, in the United States was estimated to cost $4.8 billion in 2014. Thus, an understanding of cSCC pathogenesis could have important public health implications. Immune function impacts cSCC risk, given that cSCC incidence rates are substantially higher in patients with compromised immune systems. We report a systematic review of published associations between cSCC risk and the human leukocyte antigen (HLA) system. This review includes studies that analyze germline class I and class II HLA allelic variation as well as HLA cell-surface protein expression levels associated with cSCC risk. We propose biological mechanisms for these HLA-cSCC associations based on known mechanisms of HLA involvement in other diseases. The review suggests that immunity regulates the development of cSCC and that HLA-cSCC associations differ between immunocompetent and immunosuppressed patients. This difference may reflect the presence of viral co-factors that affect tumorigenesis in immunosuppressed patients. Finally, we highlight limitations in the literature on HLA-cSCC associations, and suggest directions for future research aimed at understanding, preventing and treating cSCC.

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Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-κB Regulation

Cited by 23 publications

References 46 publications

The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions

The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions

Label-free LC-MS/MS shotgun proteomics to investigate the anti-inflammatory effect of rCC16

Cutaneous squamous cell cancer (cSCC) risk and the human leukocyte antigen (HLA) system

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