scholarly journals Genetic Alterations of Metastatic Colorectal Cancer

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 414
Author(s):  
Ugo Testa ◽  
Germana Castelli ◽  
Elvira Pelosi
Keyword(s):  
Tumor Development ◽  
Tumor Location ◽  
Genetic Alterations ◽  
Primary Tumors ◽  
Sequencing Studies ◽  
Microsatellite Stability ◽  
Tumor Types ◽  
Genetic Events ◽  
Metastatic Spreading

Genome sequencing studies have characterized the genetic alterations of different tumor types, highlighting the diversity of the molecular processes driving tumor development. Comprehensive sequencing studies have defined molecular subtypes of colorectal cancers (CRCs) through the identification of genetic events associated with microsatellite stability (MSS), microsatellite-instability-high (MSI-H), and hypermutation. Most of these studies characterized primary tumors. Only recent studies have addressed the characterization of the genetic and clinical heterogeneity of metastatic CRC. Metastatic CRC genomes were found to be not fundamentally different from primary CRCs in terms of the mutational landscape or of genes that drive tumorigenesis, and a genomic heterogeneity associated with tumor location of primary tumors helps to define different clinical behaviors of metastatic CRCs. Although CRC metastatic spreading was traditionally seen as a late-occurring event, growing evidence suggests that this process can begin early during tumor development and the clonal architecture of these tumors is consistently influenced by cancer treatment. Although the survival rate of patients with metastatic CRC patients improved in the last years, the response to current treatments and prognosis of many of these patients remain still poor, indicating the need to discover new improvements for therapeutic vulnerabilities and to formulate a rational prospective of personalized therapies.

Penile squamous cell carcinoma is genomically similar to other HPV-driven tumors.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 505-505 ◽  
Author(s):  
Jad Chahoud ◽  
Barrett Z. McCormick ◽  
Frederico Netto ◽  
Priya Rao ◽  
Curtis R. Pickering ◽  
...  
Keyword(s):  
Treatment Options ◽  
Tumor Development ◽  
Tumor Stage ◽  
Genetic Alterations ◽  
Lymph Node Status ◽  
Cancer Genes ◽  
Multiple Cancer ◽  
Primary Tumors ◽  
Md Anderson ◽  
Tumor Types

505 Background: PSCC is rare with limited treatment options for advanced disease. There have been no published genome-wide studies on the genetic alterations of PSCCs or on the differences between HPV (+) and HPV (−) PSCCs. We report the largest WES analysis of PSCC. Methods: We identified 34 pts diagnosed with PSCC, at MD Anderson, with primary tumors or metastatic lesions sufficient for WES. Patients, tumor and surgical characteristics were available through the MD Anderson prospective registry. Genomic DNAs from both Fresh frozen macrodissected tumors and paired-normal penile tissues were analyzed by WES. Results: Patients clinical characteristics are summarized in table 1. Eight of the most frequently mutated PSCC genes (NOTCH1 (35%), TP53 (35%), CDKN2A (24%), PIK3CA (21%), CASP8 (21%), FAT1 (18%), FBXW7 (15%) and EP300 (12%)) were significantly mutated in other SCC tumor types. Importantly, 8/8 and 5/8 genes were significant in head and neck SCC and cervical SCC, respectively, including 3 (CASP8, FXBW7, and EP300) genes that are only significant in these tumor types. TP53 mutations were associated with HPV (-) PSCC and were absent in HPV (+) SCC (P= 0.03). EP300 mutations were associated with advanced primary tumor stage. Of note we did not identify unique mutations associated with lymph node status. Conclusions: This is the largest systematic analyses of PSCC genomics uncovering the involvement of multiple cancer genes that are likely to be contributing to tumor development including; TP53, squamous differentiation, cell cycle, and chromatin regulation. PSCC are genomically similar to other HPV related SCC, and provide a therapeutic rationale for considering strategies successful in HPV related cancers. [Table: see text]

scholarly journals Multiregional genetic evolution of metastatic uveal melanoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Daniel A. Rodriguez ◽  
Jessica Yang ◽  
Michael A. Durante ◽  
Alexander N. Shoushtari ◽  
Stergios J. Moschos ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Tumor Development ◽  
Genetic Evolution ◽  
Metastatic Progression ◽  
Therapeutic Approaches ◽  
Primary Tumors ◽  
Early Tumor ◽  
Rapid Autopsy ◽  
Genetic Events ◽  
Novel Therapeutic

AbstractUveal melanoma (UM) is the most common primary intraocular malignancy in adults and leads to deadly metastases for which there is no approved treatment. Genetic events driving early tumor development are well-described, but those occurring later during metastatic progression remain poorly understood. We performed multiregional genomic sequencing on 22 tumors collected from two patients with widely metastatic UM who underwent rapid autopsy. We observed multiple seeding events from the primary tumors, metastasis-to-metastasis seeding, polyclonal seeding, and late driver variants in ATM, KRAS, and other genes previously unreported in UM. These findings reveal previously unrecognized temporal and anatomic complexity in the genetic evolution of metastatic uveal melanoma, and they highlight the distinction between early and late phases of UM genetic evolution with implications for novel therapeutic approaches.

Tumor subtypes associated with prostate cancer (PCa) both as first and second primary tumors: A registry-based analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17528-e17528
Author(s):  
Andrew Wellen ◽  
David J. Peace
Keyword(s):  
Tumor Development ◽  
Myelogenous Leukemia ◽  
Second Primary ◽  
Extrinsic Factors ◽  
Primary Tumors ◽  
Tumor Subtypes ◽  
Period 2 ◽  
Geographical Regions ◽  
Second Primary Tumors ◽  
Tumor Types

e17528 Background: First primary tumors (FPT) generally are associated with decreased survival and, thus, reduced risk of second primary tumors (SPT). A greater than expected incidence of SPT may indicate causal factors shared in common with a particular FPT, especially if the converse also is observed, i.e. if incidence is also greater than expected when tumor sequence is reversed. We analyzed the Surveillance, Epidemiology, and End Results (SEER) cancer registry to identify tumors with higher than expected incidence in relation to PCa, both as FPT and SPT. Methods: We searched the SEER18 cancer database covering 18 geographical regions of the U.S. from 2000 to 2016. SEER*Stat software v.8.3.6 was used to calculate standardized incidence ratios (SIR) of various SPT after defined FPT. SIR compare the incidence of a particular cancer within subsets of the registry population as a ratio to the expected incidence from a comparable matched group derived from the general population. 813,712 men with prostatic FPT (1° PCa) were included in the analysis for SIR of any SPT, while 2,554,835 men with any FPT were included in the analysis for SIR of prostatic SPT (2° PCa). Results were stratified by race and latency. Reciprocal SIR (1° PCa; 2° PCa) for values with p < 0.05 are reported. Results: Aggregate analysis of all tumors demonstrated lower than expected SIR for SPT, both for any SPT after 1° PCa and for 2° PCa after any FPT (0.69; 0.53). By contrast, six tumor subtypes – small intestine (1.17; 1.19), melanoma (1.05; 1.23), bladder (1.14; 2.02), kidney (1.22; 1.36), thyroid (1.27; 1.36), and chronic myelogenous leukemia (1.10; 1.15) – had bidirectionally increased secondary SIR in relation to PCa. The reciprocal increases were detected across racial subgroups for bladder, kidney and thyroid cancers. SIR tended to be highest in the early post-FPT period (2-11 mo.) with significant increases for bladder (1.49; 6.75), kidney (2.66; 1.87), and thyroid (1.61; 1.65) cancers. These three tumor types retained bidirectional increases in relation to PCa over intermediate latencies (12-119 mo.), but not beyond 120 mo. Conclusions: Overall, FPT were associated with lower than expected incidence of SPT, most likely as a result of shortened life expectancy. However, several tumors were identified that 1). occurred with higher than expected incidence after 1° PCa and 2). were associated with higher than expected incidence of 2° PCa. Further examination of the relationship of these tumors with PCa may identify mutual intrinsic or extrinsic factors that contribute to tumor development.

scholarly journals Epigenetic Alterations in Bladder Cancer and Their Potential Clinical Implications

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Han Han ◽  
Erika M. Wolff ◽  
Gangning Liang
Keyword(s):  
Bladder Cancer ◽  
Genetic Alterations ◽  
High Rate ◽  
Epigenetic Therapy ◽  
Future Research ◽  
Epigenetic Alterations ◽  
Pharmacological Interventions ◽  
Genetic Abnormalities ◽  
Tumor Types

Urothelial carcinoma (UC), the most common type of bladder cancer, is one of the most expensive malignancies to treat due to its high rate of recurrence. The characterization of the genetic alterations associated with UC has revealed the presence of two mutually exclusive molecular pathways along which distinct genetic abnormalities contribute to the formation of invasive and noninvasive tumors. Here, we focus on the epigenetic alterations found in UC, including the presence of an epigenetic field defect throughout bladders with tumors. A distinct hypomethylation pattern was found in noninvasive tumors, whereas widespread hypermethylation was found in invasive tumors, indicating the two pathways given rise to two tumor types also differ epigenetically. Since certain epigenetic alterations precede histopathological changes, they can serve as excellent markers for the development of diagnostic, prognostic, and surveillance tools. In addition, their dynamic nature and reversibility with pharmacological interventions open new and exciting avenues for therapies. The epigenetic abnormalities associated with UC would make it an excellent target for epigenetic therapy, which is currently approved for the treatment of a few hematological malignancies. Future research is needed to address efficacy and potential toxicity issues before it can be implemented as a therapeutic strategy for solid tumors.

scholarly journals Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2048
Author(s):  
Antónia Afonso Póvoa ◽  
Elisabete Teixeira ◽  
Maria Rosa Bella-Cueto ◽  
Rui Batista ◽  
Ana Pestana ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Patient Outcomes ◽  
Genetic Alterations ◽  
Papillary Thyroid ◽  
Tissue Samples ◽  
Primary Tumors ◽  
Persistent Disease ◽  
Increased Risk ◽  
Structural Disease

Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002–2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTpmut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAFwt/TERTpmut (HR = 6.8, p = 0.003), BRAFmut/TERTpmut (HR = 3.2, p = 0.056) and BRAFmut/TERTpwt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAFwt/TERTpmut (HR = 24.2, p < 0.001) and BRAFmut/TERTpmut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTpmut regardless of BRAF status (BRAFmut/TERTpmut, log-rank p < 0.001; BRAFwt/TERTpmut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients’ outcome. BRAFmut/TERTpwt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTpmut tumors were predisposed to recurrent structural disease and DSM.

scholarly journals Multi-Omics Characterization of Inflammatory Bowel Disease-Induced Hyperplasia/Dysplasia in the Rag2−/−/Il10−/− Mouse Model

2020 ◽  
Vol 22 (1) ◽  
pp. 364
Author(s):  
Qiyuan Han ◽  
Thomas J. Y. Kono ◽  
Charles G. Knutson ◽  
Nicola M. Parry ◽  
Christopher L. Seiler ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Gastrointestinal Disease ◽  
Tumor Development ◽  
Proximal Colon ◽  
Helicobacter Hepaticus ◽  
Reduced Representation ◽  
Reduced Representation Bisulfite Sequencing ◽  
Inflammatory Bowel

Epigenetic dysregulation is hypothesized to play a role in the observed association between inflammatory bowel disease (IBD) and colon tumor development. In the present work, DNA methylome, hydroxymethylome, and transcriptome analyses were conducted in proximal colon tissues harvested from the Helicobacter hepaticus (H. hepaticus)-infected murine model of IBD. Reduced representation bisulfite sequencing (RRBS) and oxidative RRBS (oxRRBS) analyses identified 1606 differentially methylated regions (DMR) and 3011 differentially hydroxymethylated regions (DhMR). These DMR/DhMR overlapped with genes that are associated with gastrointestinal disease, inflammatory disease, and cancer. RNA-seq revealed pronounced expression changes of a number of genes associated with inflammation and cancer. Several genes including Duox2, Tgm2, Cdhr5, and Hk2 exhibited changes in both DNA methylation/hydroxymethylation and gene expression levels. Overall, our results suggest that chronic inflammation triggers changes in methylation and hydroxymethylation patterns in the genome, altering the expression of key tumorigenesis genes and potentially contributing to the initiation of colorectal cancer.

scholarly journals MiR-7 in Cancer Development

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 325
Author(s):  
Petra Korać ◽  
Mariastefania Antica ◽  
Maja Matulić
Keyword(s):  
Cell Fate ◽  
Dominant Role ◽  
Tumor Development ◽  
Mrna Translation ◽  
Cell Types ◽  
Fine Tuning ◽  
Non Coding Rna ◽  
Tumor Types ◽  
Different Cell Types ◽  
The Brain

MicroRNAs (miRNAs) are short non-coding RNA involved in the regulation of specific mRNA translation. They participate in cellular signaling circuits and can act as oncogenes in tumor development, so-called oncomirs, as well as tumor suppressors. miR-7 is an ancient miRNA involved in the fine-tuning of several signaling pathways, acting mainly as tumor suppressor. Through downregulation of PI3K and MAPK pathways, its dominant role is the suppression of proliferation and survival, stimulation of apoptosis and inhibition of migration. Besides these functions, it has numerous additional roles in the differentiation process of different cell types, protection from stress and chromatin remodulation. One of the most investigated tissues is the brain, where its downregulation is linked with glioblastoma cell proliferation. Its deregulation is found also in other tumor types, such as in liver, lung and pancreas. In some types of lung and oral carcinoma, it can act as oncomir. miR-7 roles in cell fate determination and maintenance of cell homeostasis are still to be discovered, as well as the possibilities of its use as a specific biotherapeutic.

scholarly journals Molecular and Pharmacological Characterization of the Interaction between Human Geranylgeranyltransferase Type I and Ras-Related Protein Rap1B

2021 ◽  
Vol 22 (5) ◽  
pp. 2501
Author(s):  
Sonja Hinz ◽  
Dominik Jung ◽  
Dorota Hauert ◽  
Hagen S. Bachmann
Keyword(s):  
Protein Function ◽  
Tumor Development ◽  
Cysteine Residue ◽  
Type I ◽  
Pharmacological Characterization ◽  
Anti Cancer ◽  
And Function ◽  
Caax Motif ◽  
Important Drug

Geranylgeranyltransferase type-I (GGTase-I) represents an important drug target since it contributes to the function of many proteins that are involved in tumor development and metastasis. This led to the development of GGTase-I inhibitors as anti-cancer drugs blocking the protein function and membrane association of e.g., Rap subfamilies that are involved in cell differentiation and cell growth. In the present study, we developed a new NanoBiT assay to monitor the interaction of human GGTase-I and its substrate Rap1B. Different Rap1B prenylation-deficient mutants (C181G, C181S, and ΔCQLL) were designed and investigated for their interaction with GGTase-I. While the Rap1B mutants C181G and C181S still exhibited interaction with human GGTase-I, mutant ΔCQLL, lacking the entire CAAX motif (defined by a cysteine residue, two aliphatic residues, and the C-terminal residue), showed reduced interaction. Moreover, a specific, peptidomimetic and competitive CAAX inhibitor was able to block the interaction of Rap1B with GGTase-I. Furthermore, activation of both Gαs-coupled human adenosine receptors, A2A (A2AAR) and A2B (A2BAR), increased the interaction between GGTase-I and Rap1B, probably representing a way to modulate prenylation and function of Rap1B. Thus, A2AAR and A2BAR antagonists might be promising candidates for therapeutic intervention for different types of cancer that overexpress Rap1B. Finally, the NanoBiT assay provides a tool to investigate the pharmacology of GGTase-I inhibitors.

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