Purpose: Extramammary Paget disease (EMPD) is an uncommon skin malignancy whose genetic alterations are poorly characterized. Previous reports identified mutations in chromatin remodeling genes and . In order to unambiguously determine driver mutations in EMPD, we analyzed 87 EMPD samples using exome sequencing in combination with targeted sequencing.
Experimental Design: First, we analyzed 37 EMPD samples that were surgically resected using whole-exome sequencing. Based on several analysis, we built a custom capture panel of putative driver genes and analyzed 50 additional formalin-fixed, paraffin-embedded samples using target sequencing. expression was evaluated by HER2 immunohisotochemistry. Select samples were further analyzed by fluorescence hybridization.
Results: A median of 92 mutations/sample was identified in exome analysis. A union of driver detection algorithms identified , and as likely driver mutations. Copy-number alteration analysis showed regions spanning as recurrently deleted, and as recurrently amplified. , and amplification/mutation showed tendency toward mutual exclusivity. Copy-number alteration load was associated with likelihood to recur. Mutational signatures were dominated by aging and APOBEC activation and lacked evidence of ultraviolet radiation. HER2 IHC/fluorescence analysis validated amplification but was underpowered to detect mutations. Tumor heterogeneity in terms of amplification status was observed in some cases.
Conclusions: Our comprehensive, unbiased analysis shows EMPD is characterized by alterations involving the PI3K-AKT pathway. EMPD is distinct from other skin cancers in both molecular pathways altered and etiology behind mutagenesis.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3205 | DOI Listing |
Nat Commun
January 2025
NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Mutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kα and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, although the structural details of this interaction remain unclear.
View Article and Find Full Text PDFMol Biol Evol
December 2024
Computational Biology and Bioinformatics, Université Libre de Bruxelles, 1050 Brussels, Belgium.
Determining the impact of mutations on the thermodynamic stability of proteins is essential for a wide range of applications such as rational protein design and genetic variant interpretation.Since protein stability is a major driver of evolution, evolutionary data are often used to guide stability predictions. Many state-of-the-art stability predictors extract evolutionary information from multiple sequence alignments (MSA) of proteins homologous to a query protein, and leverage it to predict the effects of mutations on protein stability.
View Article and Find Full Text PDFWhite matter hyperintensities (WMH) are areas of increased lucency visualized on T2-weighted magnetic resonance imaging (MRI), including fluid attenuated inversion recovery (FLAIR) sequences. Over the past 15 years we have been examining WMH in studies of cognitive aging among clinical, community-based, and populations at genetic risk to understand the role of vascular brain injury in Alzheimer's disease (AD) onset, symptom progression, and pathogenesis. Our findings suggest that regional WMH, particularly when distributed in posterior areas, increase risk for clinical AD and contribute to the clinical course of the disease, even among genetic population with relatively low rates of vascular risk factor, like adults with Down syndrome and with autosomal dominant genetic mutations for AD.
View Article and Find Full Text PDFBackground: Autosomal Dominant Alzheimer's Disease (ADAD) is a rare and early-onset form of Alzheimer's disease with a familial pattern of inheritance. While the pathological features of ADAD, such as amyloid plaques and neurofibrillary tangles, have been extensively studied, the involvement of white matter (WM) neuroinflammation is not well-explored. In sporadic AD, the hindered ratio (HR) derived from diffusion basis spectrum imaging (DBSI) has been used to study neuroinflammation in WM.
View Article and Find Full Text PDFExpert Rev Anticancer Ther
January 2025
Royal Marsden Hospital, London.
Introduction: BRAF mutations are the most common driver mutation in cutaneous melanoma, present in 40% of cases. Rationally-designed BRAF targeted therapy (TT) has been developed in response to this, and alongside immune checkpoint inhibitors (ICI), forms the backbone of systemic therapy options for BRAF-mutant melanoma. Various therapeutic approaches have been studied in the neoadjuvant, adjuvant and advanced settings, and there is a wealth of information to guide clinicians managing these patients.
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