scholarly journals Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine melanoma by integrated comparative genomic analysis

2017 ◽  
Author(s):  
W Hendricks ◽  
V Zismann ◽  
K Sivaprakasam ◽  
C Legendre ◽  
K Poorman ◽  
...  
Keyword(s):  
Human Melanoma ◽  
Integrated Analysis ◽  
Comparative Genomic ◽  
Putative Tumor Suppressor Gene ◽  
Pet Dogs ◽  
Genomic Landscape ◽  
Comparative Model ◽  
Melanoma Subtypes ◽  
Canine Melanoma ◽  
Genomic Basis

ABSTRACTCanine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases. No BRAF mutations were detected, but activating RAS mutations (24% of cases) occurred in conserved hotspots in all cutaneous and acral and 13% of mucosal subtypes. MDM2 amplifications (24%) and TP53 mutations (19%) were mutually exclusive. Additional low-frequency recurrent alterations were observed amidst low point mutation rates, an absence of ultraviolet light mutational signatures, and an abundance of copy number and structural alterations. Mutations that modulate cell proliferation and cell cycle control were common and highlight therapeutic axes such as MEK and MDM2 inhibition. This mutational landscape resembles that seen in BRAF wild-type and sun-shielded human melanoma subtypes. Overall, these data inform biological comparisons between canine and human melanoma while suggesting actionable targets in both species.AUTHOR SUMMARYMelanoma, an aggressive cancer arising from transformed melanocytes, commonly occurs in pet dogs. Unlike human melanoma, which most often occurs in sun-exposed cutaneous skin, canine melanoma typically arises in sun-shielded oral mucosa. Clinical features of canine melanoma resemble those of human melanoma, particularly the less common sun-shielded human subtypes. However, whereas the genomic basis of diverse human melanoma subtypes is well understood, canine melanoma genomics remain poorly defined. Similarly, although diverse new treatments for human melanoma based on a biologic disease understanding have recently shown dramatic improvements in outcomes for these patients, treatments for canine melanoma are limited and outcomes remain universally poor. Detailing the genomic basis of canine melanoma thus provides untapped potential for improving the lives of pet dogs while also helping to establish canine melanoma as a comparative model system for informing human melanoma biology and treatment. In order to better define the genomic landscape of canine melanoma, we performed multi-platform characterization of 37 tumors. Our integrated analysis confirms that these tumors commonly contain mutations in canine orthologs of human cancer genes such as RAS, MDM2, and TP53 as well mutational patterns that share important similarities with human melanoma subtypes. We have also found a new putative cancer gene, PTPRJ, frequently mutated in canine melanoma. These data will guide additional biologic and therapeutic studies in canine melanoma while framing the utility of comparative studies of canine and human cancers more broadly.

scholarly journals Canine Melanomas as Models for Human Melanomas: Clinical, Histological, and Genetic Comparison

Genes ◽  
2019 ◽  
Vol 10 (7) ◽  
pp. 501 ◽  
Author(s):  
Prouteau ◽  
André
Keyword(s):  
Human Melanoma ◽  
Translational Model ◽  
Comparative Oncology ◽  
Genetic Characteristics ◽  
Malignant Melanomas ◽  
Therapeutic Trials ◽  
Naturally Occurring ◽  
Preclinical Trials ◽  
Canine Models ◽  
Melanoma Subtypes

Despite recent genetic advances and numerous ongoing therapeutic trials, malignant melanoma remains fatal, and prognostic factors as well as more efficient treatments are needed. The development of such research strongly depends on the availability of appropriate models recapitulating all the features of human melanoma. The concept of comparative oncology, with the use of spontaneous canine models has recently acquired a unique value as a translational model. Canine malignant melanomas are naturally occurring cancers presenting striking homologies with human melanomas. As for many other cancers, dogs present surprising breed predispositions and higher frequency of certain subtypes per breed. Oral melanomas, which are much more frequent and highly severe in dogs and cutaneous melanomas with severe digital forms or uveal subtypes are subtypes presenting relevant homologies with their human counterparts, thus constituting close models for these human melanoma subtypes. This review addresses how canine and human melanoma subtypes compare based on their epidemiological, clinical, histological, and genetic characteristics, and how comparative oncology approaches can provide insights into rare and poorly characterized melanoma subtypes in humans that are frequent and breed-specific in dogs. We propose canine malignant melanomas as models for rare non-UV-induced human melanomas, especially mucosal melanomas. Naturally affected dogs offer the opportunity to decipher the genetics at both germline and somatic levels and to explore therapeutic options, with the dog entering preclinical trials as human patients, benefiting both dogs and humans.

Somatic Activation of KIT in Distinct Subtypes of Melanoma

2006 ◽  
Vol 24 (26) ◽  
pp. 4340-4346 ◽  
Author(s):  
John A. Curtin ◽  
Klaus Busam ◽  
Daniel Pinkel ◽  
Boris C. Bastian
Keyword(s):  
Map Kinase ◽  
Copy Number ◽  
Significant Proportion ◽  
Therapeutic Benefit ◽  
Comparative Genomic ◽  
Protein Levels ◽  
Hybridization Data ◽  
Exposed Skin ◽  
Mitogen Activated Protein ◽  
Melanoma Subtypes

Purpose Melanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogen-activated protein (MAP) kinase pathway commonly mutated in melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS. Patients and Methods We analyzed array comparative genomic hybridization data from 102 primary melanomas (38 from mucosa, 28 from acral skin, and 18 from skin with and 18 from skin without chronic sun-induced damage) for DNA copy number aberrations specific to melanoma subtypes where mutations in BRAF and NRAS are infrequent. A narrow amplification on 4q12 was found, and candidate genes within it were analyzed. Results Oncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary melanomas found mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels. Conclusion KIT is an important oncogene in melanoma. Because the majority of the KIT mutations we found in melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global melanoma burden.

scholarly journals Widespread selection and gene flow shape the genomic landscape during a radiation of monkeyflowers

2018 ◽  
Author(s):  
Sean Stankowski ◽  
Madeline A. Chase ◽  
Allison M. Fuiten ◽  
Murillo F. Rodrigues ◽  
Peter L. Ralph ◽  
...  
Keyword(s):  
Gene Flow ◽  
Local Density ◽  
Background Selection ◽  
Deleterious Mutations ◽  
Evolutionary Processes ◽  
Genome Wide ◽  
Genomic Landscape ◽  
Genome Features ◽  
Genomic Studies ◽  
Genomic Basis

AbstractSpeciation genomic studies aim to interpret patterns of genome-wide variation in light of the processes that give rise to new species. However, interpreting the genomic ‘landscape’ of speciation is difficult, because many evolutionary processes can impact levels of variation. Facilitated by the first chromosome-level assembly for the group, we use whole-genome sequencing and simulations to shed light on the processes that have shaped the genomic landscape during a recent radiation of monkeyflowers. After inferring the phylogenetic relationships among the nine taxa in this radiation, we show that highly similar diversity (π) and differentiation (FST) landscapes have emerged across the group. Variation in these landscapes was strongly predicted by the local density of functional elements and the recombination rate, suggesting that the landscapes have been shaped by widespread natural selection. Using the varying divergence times between pairs of taxa, we show that the correlations between FST and genome features arose almost immediately after a population split and have become stronger over time. Simulations of genomic landscape evolution suggest that background selection (i.e., selection against deleterious mutations) alone is too subtle to generate the observed patterns, but scenarios that involve positive selection and genetic incompatibilities are plausible alternative explanations. Finally, tests for introgression among these taxa reveal widespread evidence of heterogeneous selection against gene flow during this radiation. Thus, combined with existing evidence for adaptation in this system, we conclude that the correlation in FST among these taxa informs us about the genomic basis of adaptation and speciation in this system.Author summaryWhat can patterns of genome-wide variation tell us about the speciation process? The answer to this question depends upon our ability to infer the evolutionary processes underlying these patterns. This, however, is difficult, because many processes can leave similar footprints, but some have nothing to do with speciation per se. For example, many studies have found highly heterogeneous levels of genetic differentiation when comparing the genomes of emerging species. These patterns are often referred to as differentiation ‘landscapes’ because they appear as a rugged topography of ‘peaks’ and ‘valleys’ as one scans across the genome. It has often been argued that selection against deleterious mutations, a process referred to as background selection, is primarily responsible for shaping differentiation landscapes early in speciation. If this hypothesis is correct, then it is unlikely that patterns of differentiation will reveal much about the genomic basis of speciation. However, using genome sequences from nine emerging species of monkeyflower coupled with simulations of genomic divergence, we show that it is unlikely that background selection is the primary architect of these landscapes. Rather, differentiation landscapes have probably been shaped by adaptation and gene flow, which are processes that are central to our understanding of speciation. Therefore, our work has important implications for our understanding of what patterns of differentiation can tell us about the genetic basis of adaptation and speciation.

scholarly journals TMOD-02. A MODEL OF THE INITIATION AND GENOMIC LANDSCAPE OF GLIOBLASTOMA (GBM)

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi262-vi263
Author(s):  
Alexandra Bohm ◽  
Jessica DePetro ◽  
Carmen Binding ◽  
Cameron Grisdale ◽  
Matthaeus Ware ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ex Vivo ◽  
Striking Similarity ◽  
Transformed Cells ◽  
Comparative Genomic ◽  
Molecular Heterogeneity ◽  
Detailed Knowledge ◽  
Ex Vivo Model ◽  
Genomic Landscape ◽  
Human Gbm

Abstract IDH-wildtype GBM is the most common variant of this cancer and occurs in older adults. Unfortunately patients’ tumors are either inherently resistant to standard treatment, which includes radio- and chemo-therapy, or acquire resistance during the therapeutic process. Additionally, although effective in other cancers, targeted therapies have yielded disappointing results in GBM, perhaps because the fully developed disease has significant cellular and molecular heterogeneity, allowing the tumour to adapt to treatments. Better insight into managing GBM might result from a detailed knowledge of its initiating events, which have not yet been elucidated. With this in mind, we developed a mouse model of GBM in which the earliest stages can be studied. This ex vivo model recreates GBM by culturing subventricular zone (SVZ) cells, the putative ‘cell of origin’ of GBM in platelet-derived growth factor A (PDGFA). Under this condition SVZ cells from p53 null mice transform, becoming exogenous growth factor independent and tumorigenic in immune-competent mice. In contrast, wildtype SVZ cells do not proliferate in PDGFA and null cells in EGF/FGF do not transform. To discover why p53 null SVZ cells uniquely transform in PDGFA, we performed array comparative genomic hybridization (aCGH) on cells before and after transformation in PDGFA and whole genome sequencing (WGS) on transformed cells and tumours generated from PDGFA-transformed cells. aCGH and WGS revealed that the genomic landscape of transformed cells displayed a striking similarity to that observed in primary human GBM. Specifically, these studies showed that chromosomal alterations are a hallmark of culturing SVZ cells in PDGFA, an intriguing finding considering GBM is also characterized by a specific landscape of copy number alterations. This model may resemble the pathogenesis of human GBM and be leveraged to investigate the early stages of tumorigenesis, further leading to the development of preventative strategies and novel therapeutics.

Targeting Src/Stat3 pathway in malignant melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8025-8025
Author(s):  
J. Homsi ◽  
J. Messina ◽  
C. Cubutt ◽  
S. Maunglay ◽  
L. Scalf ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Topoisomerase I ◽  
Chemotherapeutic Agents ◽  
Human Melanoma ◽  
Variable Expression ◽  
Src Inhibitor ◽  
Melanoma Subtypes ◽  
Chemotherapy Agents ◽  
Melanoma Cell Lines

8025 Background: The Src/Stat 3 pathway has been implicated in the pathogenesis of several malignancies including melanoma. In the current study we evaluated the prevalence of Src and Stat3 activation in human melanoma and the effect of Src inhibitors alone or in combination with chemotherapeutic agents on melanoma cell lines. Methods: Activation of Src was measured by staining for Src-phosphotyrosine 416 (P-Src) and Stat3 by phosphotyrosine 705 Stat3 (P-Stat3). Immunohistochemistry was performed with anti-pStat3-Y705 and anti-pSrc-Y416 antibodies (Cell Signaling, Beverly, MA) on 3 melanoma subtypes. Staining of tumor cells for P-Stat3 was scored by percentage of stained cells as follows: 0 (no staining), 1 (1–25%), 2 (26–50%), 3 (>50%), and intensity 0–3 (0: absent, 1: low, 2: moderate, and 3: high). The sum of these was the composite P-Stat3 score: 0 (0), 1 (1–2), 2 (3–4), and 3 (5–6). P-Src staining was scored by intensity. Melanoma cell lines, A-375, SK-Mel-5 and SK-Mel-28 were exposed to Src inhibitors, SKI-606, PD 180970 and BMS 354825 alone or in combination with standard chemotherapy agents and IC-50 was determined by MTT assay at 24 and 72 hours. Results: 35 biopsies were stained. Median age was 66 years (range 23–90); 60% were women. 48% of all melanoma stained express P-Src; all samples express pStat3. We found a positive correlation between P-Src and P-Stat3 (Spearman coefficient=0.346, p=0.042). 46% stained only for pStat3 and 6% did not stain for either P-Src or P-Stat3. Most positively stained biopsies stained weakly for P-Src and moderately or strongly for pStat3. Src inhibitors inhibited the proliferation of melanoma cell lines; furthermore Src inhibitor treatment synergized with platinum and topoisomerase I inhibitors but not temozolomide. Conclusions: 1) Immunohistochemistry shows variable expression of P-Src and P-Stat3 in human melanoma 2) All tumors staining for P-Src also stain for P-Stat3 and the strength of staining is significantly related. 3) This data may be useful in planning future clinical trials with Src inhibitors in melanoma. [Table: see text] [Table: see text]

Abstract 3417: The genomic landscape of canine melanoma reveals broad mutational heterogeneity and recurrent patterns of structural variation

2014 ◽  
Author(s):  
William P. Hendricks ◽  
Victoria Zismann ◽  
Berry Button ◽  
Christophe Legendre ◽  
Waibhav Tembe ◽  
...  
Keyword(s):  
Structural Variation ◽  
Genomic Landscape ◽  
Canine Melanoma ◽  
Recurrent Patterns

scholarly journals Magellan: A Web Based System for the Integrated Analysis of Heterogeneous Biological Data and Annotations; Application to DNA Copy Number and Expression Data in Ovarian Cancer

2006 ◽  
Vol 2 ◽  
pp. 117693510600200 ◽  
Author(s):  
Chris B. Kingsley ◽  
Wen-Lin Kuo ◽  
Daniel Polikoff ◽  
Andy Berchuck ◽  
Joe W. Gray ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Analytical Methods ◽  
Patient Survival ◽  
Biological Data ◽  
Integrated Analysis ◽  
Comparative Genomic ◽  
Expression Data ◽  
Data Set ◽  
Web Based ◽  
Web Based System

Recent advances in high throughput biological methods allow researchers to generate enormous amounts of data from a single experiment. In order to extract meaningful conclusions from this tidal wave of data, it will be necessary to develop analytical methods of sufficient power and utility. It is particularly important that biologists themselves be able to perform many of these analyses, such that their background knowledge of the experimental system under study can be used to interpret results and direct further inquiries. We have developed a web-based system, Magellan, which allows the upload, storage, and analysis of multivariate data and textual or numerical annotations. Data and annotations are treated as abstract entities, to maximize the different types of information the system can store and analyze. Annotations can be used in analyses/visualizations, as a means of subsetting data to reduce dimensionality, or as a means of projecting variables from one data type or data set to another. Analytical methods are deployed within Magellan such that new functionalities can be added in a straightforward fashion. Using Magellan, we performed an integrated analysis of genome-wide comparative genomic hybridization (CGH), mRNA expression, and clinical data from ovarian tumors. Analyses included the use of permutation-based methods to identify genes whose mRNA expression levels correlated with patient survival, a nearest neighbor classifier to predict patient survival from CGH data, and curated annotations such as genomic position and derived annotations such as statistical computations to explore the quantitative relationship between CGH and mRNA expression data.

scholarly journals Analysis of the Coptis chinensis genome reveals the diversification of protoberberine-type alkaloids

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yifei Liu ◽  
Bo Wang ◽  
Shaohua Shu ◽  
Zheng Li ◽  
Chi Song ◽  
...  
Keyword(s):  
Genome Duplication ◽  
Comparative Genomic ◽  
Specific Gene ◽  
Coptis Chinensis ◽  
Phylogenetic Placement ◽  
Genomic Landscape ◽  
Genomic Analyses ◽  
Early Diverging Eudicots ◽  
Functional Versatility ◽  
Tandem Duplications

AbstractChinese goldthread (Coptis chinensis Franch.), a member of the Ranunculales, represents an important early-diverging eudicot lineage with diverse medicinal applications. Here, we present a high-quality chromosome-scale genome assembly and annotation of C. chinensis. Phylogenetic and comparative genomic analyses reveal the phylogenetic placement of this species and identify a single round of ancient whole-genome duplication (WGD) shared by the Ranunculaceae. We characterize genes involved in the biosynthesis of protoberberine-type alkaloids in C. chinensis. In particular, local genomic tandem duplications contribute to member amplification of a Ranunculales clade-specific gene family of the cytochrome P450 (CYP) 719. The functional versatility of a key CYP719 gene that encodes the (S)-canadine synthase enzyme involved in the berberine biosynthesis pathway may play critical roles in the diversification of other berberine-related alkaloids in C. chinensis. Our study provides insights into the genomic landscape of early-diverging eudicots and provides a valuable model genome for genetic and applied studies of Ranunculales.

scholarly journals The genome of the plague-resistant great gerbil reveals species-specific duplication of an MHCII gene

2018 ◽  
Author(s):  
Pernille Nilsson ◽  
Monica H. Solbakken ◽  
Boris V. Schmid ◽  
Russell J. S. Orr ◽  
Ruichen Lv ◽  
...  
Keyword(s):  
Adaptive Immune Response ◽  
Gene Families ◽  
Comparative Genomic ◽  
Immune Gene ◽  
Gene Repertoire ◽  
Great Gerbil ◽  
Genomic Landscape ◽  
A Genome ◽  
Natural Hosts ◽  
Species Specific

AbstractThe great gerbil (Rhombomys opimus) is a social rodent living in permanent, complex burrow systems distributed throughout Central Asia, where it serves as the main host of several important vector-borne infectious diseases and is defined as a key reservoir species for plague (Yersinia pestis). Studies from the wild have shown that the great gerbil is largely resistant to plague but the genetic basis for resistance is yet to be determined. Here, we present a highly contiguous annotated genome assembly of great gerbil, covering over 96 % of the estimated 2.47 Gb genome. Comparative genomic analyses focusing on the immune gene repertoire, reveal shared gene losses within TLR gene families (i.e. TLR8, TLR10 and all members of TLR11-subfamily) for the Gerbillinae lineage, accompanied with signs of diversifying selection of TLR7 and TLR9. Most notably, we find a great gerbil-specific duplication of the MHCII DRB locus. In silico analyses suggest that the duplicated gene provides high peptide binding affinity for Yersiniae epitopes. The great gerbil genome provides new insights into the genomic landscape that confers immunological resistance towards plague. The high affinity for Yersinia epitopes could be key in our understanding of the high resistance in great gerbils, putatively conferring a faster initiation of the adaptive immune response leading to survival of the infection. Our study demonstrates the power of studying zoonosis in natural hosts through the generation of a genome resource for further comparative and experimental work on plague survival and evolution of host-pathogen interactions.

scholarly journals Inhibitory Effects of Euphorbia tirucalli Lineu (Euphorbiaceae) Diluted Latex on Human and Canine Melanoma Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Diego Pinha Alves da Paz ◽  
Márcia Kazumi Nagamine ◽  
Murilo Penteado Del Grande ◽  
João Vitor Pereira Leite ◽  
Flavia Mendonça Gonçalves Sobreira ◽  
...  
Keyword(s):  
Melanoma Cells ◽  
Human Melanoma ◽  
Control Group ◽  
Inhibitory Effects ◽  
Euphorbia Tirucalli ◽  
Human Melanoma Cells ◽  
Standard Solution ◽  
Canine Melanoma ◽  
Shape Curve ◽  
Toxic Plant

Euphorbia tirucalli Lineu (Euphorbiaceae) is a tropical and subtropical ornamental and toxic plant. E. tirucalli produces a latex that is commonly used to treat neoplasms. This study aimed to evaluate the effects of diluted E. tirucalli latex (DETL) on human (SK-MEL-28) and canine (CBMY) melanoma cells. SK-MEL-28 (3 × 103 cells/well) and CBMY (6 × 103 cells/well) were cultivated in 96-well plates. The cells were treated with 50 μl/well of dilutions (1/2, 1/4, 1/8, 1/16, 1/32, 1/64, 1/128, 1/256, and 1/512) of a standard solution containing 1 mg/mL of the E. tirucalli latex (ETL) in DMEM. Control group cells received 50 μl/well of DMEM. After 24, 48, and 72 h of treatment, cell viability was assessed by the MTT assay. There was a significant decrease in viability at 48 and 72 hours after treatment for human melanoma cells and at 24, 48, and 72 hours for canine cells, mainly in higher dilutions of ETL. Human melanoma cells presented a typical U shape curve, characteristic of hormesis. To our knowledge, this is the first study showing inhibitory effects of DETL on canine melanoma cells. Therefore, DETL is a potentially new antineoplastic drug.

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