Is the presence of Merkel cell polyomavirus and human papillomavirus DNA in keratinocyte cancers and precancers associated with HIV status? A case-control study.

The epidemiology and potential pathogenic roles of human papillomavirus (HPV) and Merkel cell polyomavirus (MCV) in keratinocyte cancers (KCs) arising in people living with HIV (PLWH) compared with HIV-negative individuals are poorly understood. These issues were investigated by a case-control study in which the presence of MCV and HPV DNA was identified by polymerase chain reaction in microdissected formalin-fixed paraffin-embedded tissue from PLWH and HIV-negative individuals. The samples comprised 190 cutaneous and genital KCs/precancers (actinic keratoses, n = 43; cutaneous squamous cell carcinoma (cSCC) in situ, n = 24; basal cell carcinoma, n = 78; cSCC, n = 34; penile carcinoma in situ, n = 9; penile SCC, n = 2 from 104 individuals (PLWH, n = 51; HIV-negative, n = 53).

The Genomic Landscape of Actinic Keratosis.

Actinic keratoses (AKs) are lesions of epidermal keratinocyte dysplasia and are precursors for invasive cutaneous squamous cell carcinoma (cSCC). Identifying the specific genomic alterations driving the progression from normal skin to skin with AK to skin with invasive cSCC is challenging because of the massive UVR-induced mutational burden characteristic at all stages of this progression. In this study, we report the largest AK whole-exome sequencing study to date and perform a mutational signature and candidate driver gene analysis on these lesions.

A Unique Panel of Patient-Derived Cutaneous Squamous Cell Carcinoma Cell Lines Provides a Preclinical Pathway for Therapeutic Testing.

Background: Cutaneous squamous cell carcinoma (cSCC) incidence continues to rise with increasing morbidity and mortality, with limited treatment options for advanced disease. Future improvements in targeted therapy will rely on advances in genomic/transcriptomic understanding and the use of model systems for basic research. We describe here the panel of 16 primary and metastatic cSCC cell lines developed and characterised over the past three decades in our laboratory in order to provide such a resource for future preclinical research and drug screening.

Epigenetic Regulation of iASPP-p63 Feedback Loop in Cutaneous Squamous Cell Carcinoma.

Keratinocyte skin cancer, comprising cutaneous squamous (cSCC) and basal cell carcinoma, is the most common malignancy in the United Kingdom. P53 is frequently mutated in cSCC. iASPP is a key inhibitor of p53 and NF-κB signaling pathways and has been documented as highly expressed in several types of human cancer.

The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature.

Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes.

Reduced SMAD2/3 activation independently predicts increased depth of human cutaneous squamous cell carcinoma.

The incidence of cutaneous squamous cell carcinoma (cSCC) is rising. Whilst the majority are cured surgically, aggressive metastatic cSCC carry a poor prognosis. Inactivating mutations in transforming growth factor beta (TGF-β) receptors have been identified amongst genetic drivers of sporadic tumours and murine models of cSCC, suggesting a tumour suppressor function for TGF-β in normal skin.

Whole-Exome Sequencing Validates a Preclinical Mouse Model for the Prevention and Treatment of Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies. Solar UV radiation is the major factor in the etiology of cSCC. Whole-exome sequencing of 18 microdissected tumor samples (cases) derived from SKH-1 hairless mice that had been chronically exposed to solar-simulated UV (SSUV) radiation showed a median point mutation (SNP) rate of 155 per Mb.

Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma.

Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation. Here we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin.

HLA Immunogenotype Determines Persistent Human Papillomavirus Virus Infection in HIV-Infected Patients Receiving Antiretroviral Treatment.

A proportion of human immunodeficiency virus (HIV)-infected patients develop persistent, stigmatizing human papillomavirus (HPV)-related cutaneous and genital warts and anogenital (pre)cancer. This is the first study to investigate immunogenetic variations that might account for HPV susceptibility and the largest to date to categorize the HPV types associated with cutaneous warts in HIV-positive patients. The HLA class I and II allele distribution was analyzed in 49 antiretroviral (ART)-treated HIV-positive patients with persistent warts, 42 noninfected controls, and 46 HIV-positive controls.

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

NF-κB signaling plays a crucial role in regulating proliferation and differentiation in the epidermis. Alterations in the NF-κB pathway can lead to skin pathologies with a significant burden to human health such as psoriasis and cutaneous squamous cell carcinoma (cSCC). Caspase recruitment domain (CARD)-containing scaffold proteins are key regulators of NF-κB signaling by providing a link between membrane receptors and NF-κB transcriptional subunits.

NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis.

Cutaneous SCC (cSCC) is the most frequently occuring skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here, we use massively parallel exome and targeted level sequencing of 132 sporadic cSCCs and of 39 squamoproliferative lesions and cSCCs arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples, to identify NOTCH1 mutation as an early event in squamous cell carcinogenesis. Bisected vemurafenib-induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC, suggesting polyclonal origin.

Key differences identified between actinic keratosis and cutaneous squamous cell carcinoma by transcriptome profiling.

Background: Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair-skinned populations worldwide and its incidence is increasing. Despite previous observations of multiple genetic abnormalities in cSCC, the oncogenic process remains elusive. The purpose of this study was to elucidate key molecular events associated with progression from premalignant actinic keratoses (AKs) to invasive cSCC by transcriptome profiling.

The telomere profile distinguishes two classes of genetically distinct cutaneous squamous cell carcinomas.

The incidence of skin cancer is increasing worldwide and cutaneous squamous cell carcinomas (SCCs) are associated with considerable morbidity and mortality, particularly in immunosuppressed individuals ('carcinomatous catastrophy'). Yet, molecular mechanisms are still insufficiently understood. Besides ultraviolet (UV)-indicative mutations, chromosomal aberrations are prominent.

Exploiting FOXM1-orchestrated molecular network for early squamous cell carcinoma diagnosis and prognosis.

Histopathological discordance with molecular phenotype of many human cancers poses clinically challenging tasks for accurate cancer diagnosis, which impacts on treatment strategy and patient outcome. Hence, an objective, accurate and quantitative method is needed. A quantitative Malignancy Index Diagnostic System (qMIDS) was developed based on 14 FOXM1 (isoform B)-associated genes implicated in the regulation of the cell cycle, differentiation, ageing, genomic stability, epigenetic and stem cell renewal, and two reference genes.

AKT1 loss correlates with episomal HPV16 in vulval intraepithelial neoplasia.

Anogenital malignancy has a significant association with high-risk mucosal alpha-human papillomaviruses (alpha-PV), particularly HPV 16 and 18 whereas extragenital SCC has been linked to the presence of cutaneous beta and gamma-HPV types. Vulval skin may be colonised by both mucosal and cutaneous (beta-, mu-, nu- and gamma-) PV types, but there are few systematic studies investigating their presence and their relative contributions to vulval malignancy. Dysregulation of AKT, a serine/threonine kinase, plays a significant role in several cancers.

NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity.

Background: Novel prognostic biomarkers and therapeutic strategies are urgently required for malignant melanoma. Ecto-5-prime-nucleotidase (NT5E; CD73) overexpression has been reported in several human cancers. The mechanism(s) underlying deregulated expression and the clinical consequences of changes in expression are not known.

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of nonmelanoma skin cancer (NMSC), and its incidence is increasing rapidly. Metastatic cSCC accounts for the majority of deaths associated with NMSC, but the genetic basis for cSCC progression remains poorly understood. A previous study identified small deletions (typically <1 Mb) in the protein tyrosine phosphatase receptor Type D (PTPRD) gene that segregated with more aggressive cSCC.

Clinically significant human papilloma virus in squamous cell carcinoma of the head and neck in UK practice.

Aims: The association between squamous cell carcinoma of the head and neck (HNSCC) and infection with human papilloma viruses (HPV) has created considerable interest. Rates of primary oropharyngeal cancers have shown increasing incidence and declining age at presentation over the last decade, believed to relate to infection with oncogenic or high-risk subtypes of HPV (HR-HPV). HR-HPV-associated tumours have reportedly improved outcomes when compared with HPV-negative cancers.

Cutaneous squamous cell carcinoma (SCC) and the DNA damage response: pATM expression patterns in pre-malignant and malignant keratinocyte skin lesions.

Recent evidence suggests that an initial barrier to the emergence of tumours is a DNA damage response that evokes a counter-response which arrests the growth of, or eliminates, damaged cells. Early precursor lesions express markers of an activated DNA damage response in several types of tumour, with a diminishing response in more advanced cancers. An important marker of DNA damage is ATM which becomes phosphorylated (pATM) upon activation.

Integrative mRNA profiling comparing cultured primary cells with clinical samples reveals PLK1 and C20orf20 as therapeutic targets in cutaneous squamous cell carcinoma.

Identifying therapeutic targets for cancer treatment relies on consistent changes within particular types or sub-types of malignancy. The ability to define either consistent changes or sub-types of malignancy is often masked by tumor heterogeneity. To elucidate therapeutic targets in cutaneous squamous cell carcinoma (cSCC), the most frequent skin neoplasm with malignant potential, we have developed an integrated approach to gene expression profiling beginning with primary keratinocytes in culture.

Feeder layers: co-culture with nonneoplastic cells.

Maintenance of a mitotically inactive feeder layer which is able to provide extracellular matrix and growth factors can be critical in establishing and maintaining primary tumor cells. How feeder cells are handled and processed is crucial for providing trouble-free support for primary tumor cells and spontaneously immortalized lines.