scholarly journals Novel Finding of Copy Number Gains in GNAS and Loss of 10q in a Child With Malignant Transformation of Neurocutaneous Melanosis Syndrome

2021 ◽  
pp. 33-38
Author(s):  
Catherine Peterson ◽  
Stephanie A. Toll ◽  
Bradley Kolb ◽  
Janet M. Poulik ◽  
Miguel Reyes-Mugica ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Copy Number ◽  
Neurocutaneous Melanosis

scholarly journals Copy number abnormalities in new or progressive ‘neurocutaneous melanosis’ confirm it to be primary CNS melanoma

2016 ◽  
Vol 133 (2) ◽  
pp. 329-331 ◽  
Author(s):  
Veronica A. Kinsler ◽  
Satyamanaasa Polubothu ◽  
J. Eduardo Calonje ◽  
W. Kling Chong ◽  
Dominic Thompson ◽  
...  
Keyword(s):  
Copy Number ◽  
Neurocutaneous Melanosis

scholarly journals Genetic alterations associated with malignant transformation of sporadic vestibular schwannoma

2021 ◽  
Author(s):  
Aril Løge Håvik ◽  
Ove Bruland ◽  
Hrvoje Miletic ◽  
Lars Poulsgaard ◽  
David Scheie ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Malignant Transformation ◽  
Vestibular Schwannoma ◽  
Copy Number ◽  
Genetic Alterations ◽  
Whole Genome ◽  
Nerve Sheath Tumor ◽  
Copy Number Aberrations ◽  
Mutational Signature ◽  
Post Radiation

Abstract Introduction Malignant peripheral nerve sheath tumor of the vestibulocochlear nerve (VN-MPNST) is exceedingly rare and carries a poor prognosis. Little is known about its underlying genetics and in particular the process of malignant transformation. There is an ongoing debate on whether the transformation is initiated by ionizing radiation. We present here the analysis and comparison of two post-radiation VN-MPNST and one undergoing spontaneous transformation. Methods Four tumors from three patients (radiation-naïve vestibular schwannoma before (VS) and after (VN-MPNST) malignant transformation in addition to two post-radiation VN-MPNST) were subjected to DNA whole-genome microarray and whole-exome sequencing and tumor-specific mutations were called. Mutational signatures were characterized using MuSiCa. Results The tumor genomes were characterized predominantly by copy-number aberrations with 36–81% of the genome affected. Even the VS genome was grossly aberrated. The spontaneous malignant transformation was characterized by a near-total whole-genome doubling, disappearance of NF2 mutation and new mutations in three cancer-related genes (GNAQ, FOXO4 and PDGFRB). All tumors had homozygous loss of the tumor suppressor CDKN2A. Neither mutational signature nor copy number profile was associated with ionizing radiation. Conclusion The VN-MPNST genome in our cases is characterized by large copy-number aberrations and homozygous deletion of CDKN2A. Our study demonstrates a VS with genetic alterations similar to its malignant counterpart, suggesting the existence of premalignant VS. No consistent mutational signature was associated with ionizing radiation.

The relationship between leptin, leptin receptor, and FGFR1 in primary human breast tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13578-e13578
Author(s):  
Wyatt Shoemaker ◽  
Shreya Paithankar ◽  
Vanessa Benham ◽  
Bin Chen ◽  
Jamie Bernard
Keyword(s):  
Breast Cancer ◽  
Adipose Tissue ◽  
Malignant Transformation ◽  
Copy Number ◽  
Leptin Receptor ◽  
Gene Copy Number ◽  
Soft Agar ◽  
Normal Breast ◽  
Gene Copy ◽  
Jak2 Inhibitors

e13578 Background: General/overall obesity and visceral/central obesity are associated with increased breast cancer risk and poorer cancer outcomes; however, the precise etiology of these observations is not fully known. Our previous research suggests that adipose tissue-derived fibroblast growth factor 2 (FGF2) promotes malignant transformation of mammary epithelial cells through the activation of its primary receptor, fibroblast growth factor receptor 1 (FGFR1). Both FGF2 and leptin have been shown to be elevated in the serum in obesity (body mass index (BMI) > 25kg/m2). It is well established that elevated sera leptin promotes breast cancer through multiple mechanisms. Therefore, we hypothesized that tumors that express elevated FGFR1 and leptin receptor (LepR) may have a poorer prognosis in obese patients. Methods: Databases that house gene-sequenced breast cancer tumors and normal breast tissue were analyzed to discern relationships between gene copy number and mRNA levels of leptin, leptin receptor, FGFR1 and janus kinase 2 (Jak2), as Jak2 was shown to be a common downstream mediator of both FGFR1 and leptin receptor activation by Cytoscape network analysis. Furthermore, we tested the efficacy of Jak2 inhibitors for preventing mammary epithelial cell malignant transformation using our well-established models of adipose tissue-stimulated growth in soft agar. The anchorage-independent growth in soft agar is a surrogate marker for malignant transformation. Results: A much stronger significant relationship exists between FGFR1 mRNA and leptin mRNA in primary breast cancer (p = 3.17*10−9) compared with normal breast epithelium (p = 0.0013). In primary breast tumors, gene copy number of FGFR1 positively correlates with leptin copy number (p = 8.956*10−8, r = 0.19). Moreover, two separate Jak2 inhibitors attenuated both leptin+FGF2-stimulated and mouse adipose tissue-stimulated MCF-10A cell transformation. Conclusions: Taken together, these results suggest that elevated sera FGF2 and leptin in obese patients may promote breast tumorigenesis in tumors that express elevated FGFR1 and LepR and that Jak2 inhibitors may be a novel therapeutic option for adiposity-driven breast cancers. Future work will examine the relationship between FGFR1/leptin receptor expression and survival and how these relationships are influenced by BMI status.

scholarly journals The cellular origin and malignant transformation of Waldenström macroglobulinemia

Blood ◽  
2015 ◽  
Vol 125 (15) ◽  
pp. 2370-2380 ◽  
Author(s):  
Bruno Paiva ◽  
Luis A. Corchete ◽  
Maria-Belen Vidriales ◽  
Ramón García-Sanz ◽  
Jose J. Perez ◽  
...  
Keyword(s):  
B Cells ◽  
Malignant Transformation ◽  
Copy Number ◽  
Molecular Signatures ◽  
Waldenström Macroglobulinemia ◽  
Cellular Origin ◽  
Waldenstrom Macroglobulinemia ◽  
Key Points

Key Points Benign (ie, IgM MGUS and smoldering WM) clonal B cells already harbor the phenotypic and molecular signatures of the malignant WM clone. Multistep transformation from benign (ie, IgM MGUS and smoldering WM) to malignant WM may require specific copy number abnormalities.

Copy number variations as potential diagnostic and prognostic markers for CNS melanocytic neoplasms in neurocutaneous melanosis

2016 ◽  
Vol 133 (2) ◽  
pp. 333-335 ◽  
Author(s):  
Adriana C. H. van Engen-van Grunsven ◽  
Katrin Rabold ◽  
Heidi V. N. Küsters-Vandevelde ◽  
Jos Rijntjes ◽  
Melika Djafarihamedani ◽  
...  
Keyword(s):  
Copy Number ◽  
Prognostic Markers ◽  
Copy Number Variations ◽  
Neurocutaneous Melanosis

Identification of a LOH Region on Chromosome 9p Associated with a Specific Gene Expression Signature in Adult B-Lineage ALL through Integration of High Density Microarray Expression and SNP Analyses.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1119-1119
Author(s):  
Sabina Chiaretti ◽  
Xiaochun Li ◽  
Robert Gentleman ◽  
Cheng Li ◽  
Antonella Vitale ◽  
...  
Keyword(s):  
Gene Expression ◽  
Malignant Transformation ◽  
Copy Number ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
High Density ◽  
Snp Analysis ◽  
Molecular Abnormalities ◽  
Chromosome 9P ◽  
B Lineage

Abstract Acute lymphoblastic leukemia (ALL) is characterized by the presence of specific rearrangements associated with distinct gene expression signatures defined by high density microarray. Rearrangements of MLL, E2A/PBX1, BCR/ABL and TEL/AML1 are examples of this phenomenon, which also provide insights into the mechanisms of malignant transformation in these cases. Nevertheless, many cases of ALL do not carry known molecular abnormalities and do not exhibit unique gene expression profiles. In these cases, the mechanisms of malignant transformation remain unknown. Our goal was to develop an integrated genetic approach to discover new mechanisms of transformation in ALL and to define patterns of expression associated with these genetic abnormalities. Gene expression profiles were determined in B-lineage ALL from 95 adult patients using Affymetrix U95Av2 GeneChips. Within this group, high density SNP analysis was performed on 16 paired samples of normal and leukemia cells from the same patient using Affymetrix Mapping 10K Arrays. SNP analysis of normal and ALL DNA based on chromosome copy number interference revealed the presence of several regions of amplification, the most frequent involving chromosome X (3 samples, plus 1 Klinefelter syndrome, minimal amplified region: Xp22.31 to Xp11.1) and chromosome 21 (3 samples plus 1 Down syndrome, minimal amplified regions 21q223.13 to 21q22.2). Further analysis showed a frequent occurrence of LOH on chromosome 3, 6, and 21. Remarkably, this analysis revealed the presence of LOH in a portion of chromosome 9p (9p13.3 to 9p24.3) in 25% of cases. FISH analysis confirmed the presence of a homozygous deletion at 9p21 in 2 of these samples, whereas the 2 remaining cases showed a normal copy number, suggesting that in these 2 patients a deletion followed by duplication occurred. Analysis of gene expression based on genes located in this deleted region identified two genes with reduced expression: tropomyosin 2, a putative tumor suppressor gene and a transcript whith an unknown function. Analysis of gene expression in these cases revealed differential expression of 124 genes: of these, only 25 were highly expressed in the “9p LOH cases”. The use of this gene set in a heat map of all the cases without molecular abnormalities revealed a cluster that included 10 cases. 5 have known 9p abnormalities involving p15 and/or p16, 2 have 9p LOH by SNP analysis and 2 did not have sufficient material for further analysis. Given these results, we evaluated to what extent there was an overlap between these two phenomena. This revealed 34 transcripts that were consistently selected, suggesting that these genes represent a unique signature reflecting leukemic transformation involving the 9p region. These results demonstrate that integrated analysis of gene expression and SNP-based comparison of leukemia and normal cells can identify previously unknown groups of tumors with distinct genetic profiles. Further studies can now be undertaken to better define the mechanisms of transformation in these leukemias.

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