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Although cutaneous squamous cell carcinoma (cSCC) is treatable in the majority of cases, deadly invasive and metastatic cases do occur. To date there are neither reliable predictive biomarkers of disease progression nor FDA-approved targeted therapies as standard of care. To address these issues, we screened patient-derived primary cultured cells from invasive/metastatic cSCC with 107 small-molecule inhibitors. In-house bioinformatics tools were used to cross-analyze drug responses and DNA mutations in tumors detected by whole-exome sequencing (WES). Aberrations in molecular pathways with evidence of potential drug targets were identified, including the Eph-ephrin and neutrophil degranulation signaling pathways. Using a screening panel of siRNAs, we identified EPHA6 and EPHA7 as targets within the Eph-ephrin pathway responsible for mitigating decreased cell viability. These studies form a plausible foundation for detecting biomarkers of high-risk progressive disease applicable in dermatopathology and for patient-specific therapeutic options for invasive/metastatic cSCC.Parkes Weber syndrome is associated with autosomal dominant inheritance, caused by germline heterozygous inactivating changes in the RASA1 gene, characterized by multiple micro arteriovenous fistulas and segmental overgrowth of soft tissue and skeletal components. The focal nature and variable expressivity associated with this disease has led to the hypothesis that somatic "second hit" inactivating changes in RASA1 are necessary for disease development. We report a 2-yr-old male with extensive capillary malformation and segmental overgrowth of his lower left extremity. Ultrasound showed subcutaneous phlebectasia draining the capillary malformation; magnetic resonance imaging showed overgrowth of the extremity with prominence of fatty tissues, fatty infiltration, and enlargement of all the major muscle groups. Germline RASA1 testing was normal. Later somatic testing from affected tissue showed two pathogenic variants in RASA1 consistent with the c.934_938del, p.(Glu312Argfs*14) and the c.2925del, p.(Asn976Metfs*20) with variant allele fractions of 3.6% and 4.2%, respectively. The intrafamilial variability of Parkes Weber syndrome involving segmental overgrowth of soft tissue, endothelium, and bone is strongly suggestive of a somatic second-hit model. There are at least two reports of confirmed second somatic hits in RASA1 To our knowledge, this is the first report of an individual with two somatic pathogenic variants in the RASA1 gene in DNA from a vascular lesion.Pathogenic variants in the XPC complex subunit, DNA damage recognition, and repair factor (XPC) are the cause of xeroderma pigmentosum, group C (MIM 278720). Xeroderma pigmentosum is an inherited condition characterized by hypersensitivity to ultraviolet (UV) irradiation and increased risk of skin cancer due to a defect in nucleotide excision repair (NER). Here we describe an individual with a novel missense variant and deletion of exons 14-15 in XPC presenting with a history of recurrent melanomas. The proband is a 39-yr-old female evaluated through the Mayo Clinic Department of Clinical Genomics. Prior to age 36, she had more than 60 skin biopsies that showed dysplastic nevi, many of which had atypia. At age 36 she presented with her first melanoma in situ, and since then has had more than 10 melanomas. The proband underwent research whole-exome sequencing (WES) through the Mayo Clinic's Center for Individualized Medicine and a novel heterozygous variant of uncertain significance (VUS) in XPC (c.1709T > G, p.Val570Gly) was identified. Clinical confirmation pursued via XPC gene sequencing and deletion/duplication analysis of XPC revealed a pathogenic heterozygous deletion of ∼1 kb within XPC, including exons 14 and 15. BI-D1870 supplier Research studies determined the alterations to be in trans Although variants in XPC generally result in early-onset skin cancer in childhood, the proband is atypical in that she did not present with her first melanoma until age 36. Review of the patient's clinical, pathological, and genetic findings points to a diagnosis of delayed presentation of xeroderma pigmentosum.Within histone H3, lysine 27 (H3K27) is one of the residues that functions as a molecular switch, by virtue of being subject to mutually exclusive post-translational modifications that have reciprocal effects on gene expression. Whereas acetylation of H3K27 is associated with transcriptional activation, methylation at this residue causes transcriptional silencing; these two modifications are mutually exclusive. Establishment of these epigenetic marks is important in defining cellular identity and for maintaining normal cell function, as evidenced by rare genetic disorders of epigenetic writers involved in H3K27 post-translational modification. Polycomb repressive complex (PRC2)-related overgrowth and Rubinstein-Taybi syndrome (RSTS) are respectively associated with impaired H3K27 methylation and acetylation. Whereas these syndromes share commonalities like intellectual disability and susceptibility to cancers, they are generally divergent in their skeletal growth phenotypes, potentially through dysregulation of their opposing H3K27 writer functions. In this review, we discuss the requirement of H3K27 modifications for successful embryogenesis, highlighting data from relevant mouse knockout studies. Although such gene ablation studies are integral for defining fundamental biological roles of methyl- and acetyltransferase function in vivo, studies of partial loss-of-function models are likely to yield more meaningful translational insight into progression of PRC2-related overgrowth or RSTS. Thus, modeling of rare human PRC2-related overgrowth and RSTS variants in mice is needed to fully understand the causative role of aberrant H3K27 modification in the pathophysiology of these syndromes.Although BRAF inhibition has demonstrated activity in BRAF V600 -mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAF V600 -mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.