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Molecular Mediator of Prostate Cancer Progression and Its Implication in Therapy
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam, Kaustubh Datta
In most occasions, prostate cancer contains very low level of somatic and germline mutations. Copy number variation or random gene fusion events are more frequent in primary prostate cancer. Epigenetic changes within the genetic environment has also played a strong role in development of prostate cancer [43, 44]. The genetic landscape of prostate cancer was intensely explored in the last few years with Next Generation Sequencing (NGS), whole genome expression analyses and analyses of epigenetic alterations. These findings, along with the results from genetically engineered mouse models (GEMM) for PCa initiation and progression, confirmed a number of features that define prostate cancer. These are: A relatively low rate of mutations in PCa compared to other tumors [45, 46].Prevalence of non-random copy number variations (CNV) in most PCa tumors involving well-known prostate oncogenes or tumor suppressors [47, 48].Recurrent chromosomal rearrangements involving ETS transcription factors, most frequently ERG, in ~50% of PCa. The genomic arrangements observed in PCa are complex and are thought to evolve in a punctuated manner with translocations and deletions occurring interdependently, via a process known as “chromoplexy” [49–56].Involvement of pathways that govern prostate embryonic development during the initiation and particularly during progression to CRPC [47, 57, 58].The importance of epigenetic changes such as chromatin remodeling, DNA methylation and histone acetylation [59, 60].The whole scale alterations in transcriptional programs, particularly those governed by androgen receptor (AR), and their prominent role in driving DNA rearrangements and co-opting developmental pathways [51, 55, 61, 62].
Therapeutic options in thymomas and thymic carcinomas
Published in Expert Review of Anticancer Therapy, 2022
Although TETs have been classified based on histological appearance using the WHO classification system, many studies on the molecular analysis of TETs have been conducted over the past 20 years [6]. According to the Cancer Genome Atlas project, types A and AB belong to the same spectrum of tumors, and there is little overlap with the spectrum of type B thymomas. Furthermore, the spectrum of thymic carcinomas is completely different from those of type A, AB, and B based on genomic hallmarks by RNA-seq [6]. The mutation in general transcription factor II was found in approximately 80% of patients with type A or AB thymomas and was correlated with better survival. In addition, a large miRNA cluster on chromosome 19q 13.42 is commonly overexpressed in types A and AB [6]. Loss-of-function mutation of tumor protein 53 is detected in 18.5%–26% of TETs (especially in thymic carcinomas) and is associated with poor overall survival (OS) [7]. RAS proteins are also frequently mutated in 7%–18.5% of TETs [7]. Furthermore, thymic carcinomas are characterized by the loss of chromosome 16q. In NUT carcinoma, single chromoplexy was discovered to cause the formation of NUT-fusion oncoproteins [8]. Further molecular analysis of TETs is expected to advance and contribute to the establishment of new classifications.
Mouse models for mesothelioma drug discovery and development
Published in Expert Opinion on Drug Discovery, 2021
Kenneth P. Seastedt, Nathanael Pruett, Chuong D. Hoang
The clinical approach to MPM is based on its histologic subtypes: epithelioid, biphasic (a mixture of histologic types), or sarcomatoid. The epithelioid subtype is most common, with the sarcomatoid subtype portending a poor prognosis [5]. Beyond these histologies, MPM tumors harbor diverse molecular heterogeneity and numerous chromosomal abnormalities (chromothripsis, chromoplexy, or both) [6]. The most frequently mutated tumor suppressor genes (TSGs) include BAP1, CDKN2A (encoding p16INK4A and p14ARF), and NF2, and to a lesser extent, include TP53, LATS2, and SETD2 [7]. Proto-oncogenes are rarely mutated in MPM; however, several pathways are consistently affected in MPM and, thus, the subject of targeted therapies. These include the PI3K-AKT-mTOR pathway, various metabolic vulnerabilities such as methylthioadenosine phosphorylase (MTAP) or argininosuccinate synthetase 1 (ASS1) loss, as well as targets of the tumor microenvironment such as cancer-associated fibroblasts [8].
Deep sequencing as an approach to understanding the complexity and improving the treatment of multiple myeloma
Published in Expert Review of Precision Medicine and Drug Development, 2020
Louis S. Williams, Jessica Caro, Beatrice Razzo, Eileen M. Boyle, Gareth J. Morgan
As large-scale sequencing of genomes in multiple myeloma has illuminated the variable evolutionary trajectories and mutational processes in the disease, attention has turned toward the role of reciprocal and complex structural variants located in the non-coding regions of the genome. These are common events which result in significant deregulation of gene expression and significantly impact prognosis. Of particular interest is the phenomena of chromothripsis, which entails the shattering and subsequent reconstruction of chromosomes secondary to the formation of micronuclei or chromatin bridging. Importantly, chromothripsis shatters a region of a chromosome in a single catastrophic event with the potential to deregulate multiple genes. A second complex structural event is chromoplexy, which generates chained rearrangement to form new chromosomal structures [64–66]. Investigators first described these events using WGS applied to multiple tumor types but initially focused on prostate cancer to chromoplexy [67].