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18 pages, 2714 KiB

Open AccessArticle

Checkpoint Kinase 1 (CHK1) Functions as Both a Diagnostic Marker and a Regulator of Epithelial-to-Mesenchymal Transition (EMT) in Triple-Negative Breast Cancer

by Hyo-Jin Kim, Bo-Gyeong Seo, Eun-Chan Seo, Kwang-Min Lee and Cheol Hwangbo

Curr. Issues Mol. Biol. 2022, 44(12), 5848-5865; https://doi.org/10.3390/cimb44120398 - 23 Nov 2022

Cited by 4 | Viewed by 1942

Abstract

Triple-negative breast cancer (TNBC) is more difficult to treat and has a higher mortality rate than other subtypes. Although hormone receptor-targeted therapy is an effective treatment to increase survival rate in breast cancer patients, it is not suitable for TNBC patients. To address [...] Read more.

Triple-negative breast cancer (TNBC) is more difficult to treat and has a higher mortality rate than other subtypes. Although hormone receptor-targeted therapy is an effective treatment to increase survival rate in breast cancer patients, it is not suitable for TNBC patients. To address the issues, differentially expressed genes (DEGs) in TNBC patients from the Gene Expression Omnibus (GEO) database were analyzed. A total of 170 genes were obtained from three Genomic Spatial Events (GSEs) using the intersection of each GSE dataset and 61 DEGs were identified after validation with the gene enrichment analysis. We combined this with the degree scores from the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) network, of which 7 genes were correlated with survival rate. Finally, a proteomics database revealed that only the CHK1 protein level was differently expressed in basal-like compared with other subtypes. We demonstrated that CHK1 expression was higher in TNBC cell lines compared with non-TNBC cell lines, and CHK1 promotes epithelial to mesenchymal transition (EMT) as well as migration and invasion ability. Our study provides new insight into the TNBC subnetwork that may be useful in the prognosis and treatment of TNBC patients. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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18 pages, 1912 KiB

Open AccessArticle

MicroRNA and mRNA Expression Changes in Glioblastoma Cells Cultivated under Conditions of Neurosphere Formation

by Maya A. Dymova, Natalia S. Vasileva, Elena V. Kuligina, Yulya I. Savinovskaya, Nikita D. Zinchenko, Alisa B. Ageenko, Sergey V. Mishinov, Grigory A. Stepanov, Vladimir A. Richter and Dmitry V. Semenov

Curr. Issues Mol. Biol. 2022, 44(11), 5294-5311; https://doi.org/10.3390/cimb44110360 - 30 Oct 2022

Cited by 3 | Viewed by 2568

Abstract

Glioblastoma multiforme (GBM) is one of the most highly metastatic cancers. The study of the pathogenesis of GBM, as well as the development of targeted oncolytic drugs, require the use of actual cell models, in particular, the use of 3D cultures or neurospheres [...] Read more.

Glioblastoma multiforme (GBM) is one of the most highly metastatic cancers. The study of the pathogenesis of GBM, as well as the development of targeted oncolytic drugs, require the use of actual cell models, in particular, the use of 3D cultures or neurospheres (NS). During the formation of NS, the adaptive molecular landscape of the transcriptome, which includes various regulatory RNAs, changes. The aim of this study was to reveal changes in the expression of microRNAs (miRNAs) and their target mRNAs in GBM cells under conditions of NS formation. Neurospheres were obtained from both immortalized U87 MG and patient-derived BR3 GBM cell cultures. Next generation sequencing analysis of small and long RNAs of adherent and NS cultures of GBM cells was carried out. It was found that the formation of NS proceeds with an increase in the level of seven and a decrease in the level of 11 miRNAs common to U87 MG and BR3, as well as an increase in the level of 38 and a decrease in the level of 12 mRNA/lncRNA. Upregulation of miRNAs hsa-miR: -139-5p; -148a-3p; -192-5p; -218-5p; -34a-5p; and -381-3p are accompanied by decreased levels of their target mRNAs: RTN4, FLNA, SH3BP4, DNPEP, ETS2, MICALL1, and GREM1. Downregulation of hsa-miR: -130b-5p, -25-5p, -335-3p and -339-5p occurs with increased levels of mRNA-targets BDKRB2, SPRY4, ERRFI1 and TGM2. The involvement of SPRY4, ERRFI1, and MICALL1 mRNAs in the regulation of EGFR/FGFR signaling highlights the role of hsa-miR: -130b-5p, -25-5p, -335-3p, and -34a-5p not only in the formation of NS, but also in the regulation of malignant growth and invasion of GBM. Our data provide the basis for the development of new approaches to the diagnosis and treatment of GBM. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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13 pages, 600 KiB

Open AccessArticle

SOD2 Gene Variants (rs4880 and rs5746136) and Their Association with Breast Cancer Risk

by Martha P. Gallegos-Arreola, Ramiro Ramírez-Patiño, Josefina Y. Sánchez-López, Guillermo M. Zúñiga-González, Luis E. Figuera, Jorge I. Delgado-Saucedo, Belinda C. Gómez-Meda, Mónica A. Rosales-Reynoso, Ana M. Puebla-Pérez, María L. Lemus-Varela, Asbiel F. Garibaldi-Ríos, Nayely A. Marín-Domínguez, Diana P. Pacheco-Verduzco and Emaan A. Mohamed-Flores

Curr. Issues Mol. Biol. 2022, 44(11), 5221-5233; https://doi.org/10.3390/cimb44110355 - 26 Oct 2022

Cited by 11 | Viewed by 3595

Abstract

The superoxide dismutase (SOD) is the principal antioxidant defense system in the body that is activated by a reactive oxygen species. Some variants of the SOD2 gene have been associated with cancer. The rs4880 variant was determined by PCR real-time and the rs5746136 [...] Read more.

The superoxide dismutase (SOD) is the principal antioxidant defense system in the body that is activated by a reactive oxygen species. Some variants of the SOD2 gene have been associated with cancer. The rs4880 variant was determined by PCR real-time and the rs5746136 variant by PCR-RFLP in healthy subjects and in breast cancer (BC) patients. The rs4880 and rs5746136 variants were associated with BC susceptibility when BC patients and the control group were compared for the CT, TT, CTCC, and the T alleles (p < 0.05). The CT genotype of the rs4880 variant showed significant statistical differences in patients and controls aged ≤ 45 years old, and with hormonal consumption (p < 0.05). The rs4880 variant was associated with BC patients with CTTT genotype and obesity, the presence of DM2-SAH, and a non-chemotherapy response (p < 0.05). Additionally, the rs5746136 variant was associated with susceptibility to BC with Ki-67 (≥20%), luminal A type BC, and a chemotherapy partial response (p < 0.05) in BC patients who carry TT, TC, and CTTT genotypes, respectively. The haplotype T/T (OR 1.98; 95% CI 1.20–3.26, p = 0.005) was observed to be a risk factor for BC. The rs4880 and rs5746136 variants in the SOD2 gene were associated with BC susceptibility. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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13 pages, 1330 KiB

Open AccessArticle

Human Melanoma Cells Differentially Express RNASEL/RNase-L and miR-146a-5p under Sex Hormonal Stimulation

by Elisa Orlandi, Elisa De Tomi, Rachele Campagnari, Francesca Belpinati, Monica Rodolfo, Elisabetta Vergani, Giovanni Malerba, Macarena Gomez-Lira, Marta Menegazzi and Maria Grazia Romanelli

Curr. Issues Mol. Biol. 2022, 44(10), 4790-4802; https://doi.org/10.3390/cimb44100326 - 11 Oct 2022

Cited by 1 | Viewed by 2093

Abstract

Polymorphisms in the ribonuclease L (RNASEL) coding gene and hsa-miR-146a-5p (miR-146a) have been associated with melanoma in a sex-specific manner. We hypothesized that RNASEL and miR-146a expression could be influenced by sex hormones playing a role in the female advantages observed in melanoma [...] Read more.

Polymorphisms in the ribonuclease L (RNASEL) coding gene and hsa-miR-146a-5p (miR-146a) have been associated with melanoma in a sex-specific manner. We hypothesized that RNASEL and miR-146a expression could be influenced by sex hormones playing a role in the female advantages observed in melanoma incidence and survival. Thus, we explored the effects of testosterone and 17β-estradiol on RNASEL and miR-146a expression in LM-20 and A375 melanoma cell lines. Direct targeting of miR-146a to the 3′ untranslated region (3′UTR) of RNASEL was examined using a luciferase reporter system. Our results indicate that RNASEL is a direct target of miR-146a in both melanoma cell lines. Trough qPCR and western blot analyses, we explored the effect of miR-146a mimic transfection in the presence of each hormone either on RNASEL mRNA level or on protein expression of RNase-L, the enzyme codified by RNASEL gene. In the presence of testosterone or 17β-estradiol, miR-146a overexpression did not influence RNASEL transcript level in LM-20 cell line, but it slightly induced RNASEL mRNA level in A375 cells. Remarkably, miR-146a overexpression was able to repress the protein level of RNase-L in both LM-20 and A375 cells in the presence of each hormone, as well as to elicit high expression levels of the activated form of the extracellular signal-regulated kinases (ERK)1/2, hence confirming the pro-tumorigenic role of miR-146a overexpression in melanoma. Thereafter, we assessed if the administration of each hormone could affect the endogenous expression of RNASEL and miR-146a genes in LM-20 and A375 cell lines. Testosterone exerted no significant effect on RNASEL gene expression in both cell lines, while 17β-estradiol enhanced RNASEL transcript level at least in LM-20 melanoma cells. Conversely, miR-146a transcript augmented only in the presence of testosterone in either melanoma cell line. Importantly, each hormone acted quite the opposite regarding the RNase-L protein expression, i.e., testosterone significantly decreased RNase-L expression, whereas 17β-estradiol increased it. Overall, the data show that, in melanoma cells treated with 17β-estradiol, RNase-L expression increased likely by transcriptional induction of its gene. Testosterone, instead, decreased RNase-L expression in melanoma cell lines with a post-transcriptional mechanism in which miR-146a could play a role. In conclusion, the pro-tumor activity of androgen hormone in melanoma cells could be exacerbated by both miR-146a increase and RNase-L downregulation. These events may contribute to the worse outcome in male melanoma patients. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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14 pages, 2818 KiB

Open AccessArticle

Identification of Age-Associated Transcriptomic Changes Linked to Immunotherapy Response in Primary Melanoma

by Nehal Farid El-Helbawy and Ahmed Ezat El Zowalaty

Curr. Issues Mol. Biol. 2022, 44(9), 4118-4131; https://doi.org/10.3390/cimb44090282 - 7 Sep 2022

Viewed by 2482

Abstract

Melanoma is a lethal form of skin cancer. Immunotherapeutic agents such as anti-PD-1 (pembrolizumab and nivolumab) and anti-CTLA-4 (ipilimumab) have revolutionized melanoma treatment; however, drug resistance is rapidly acquired. Several studies have reported an increase in melanoma rates in older patients. Thus, the [...] Read more.

Melanoma is a lethal form of skin cancer. Immunotherapeutic agents such as anti-PD-1 (pembrolizumab and nivolumab) and anti-CTLA-4 (ipilimumab) have revolutionized melanoma treatment; however, drug resistance is rapidly acquired. Several studies have reported an increase in melanoma rates in older patients. Thus, the impact of ageing on transcriptional profiles of melanoma and response to immunotherapy is essential to understand. In this study, the bioinformatic analysis of RNA seq data of old and young melanoma patients receiving immunotherapy identifies the significant upregulation of extra-cellular matrix and cellular adhesion genes in young cohorts, while genes involved in cell proliferation, inflammation, non-canonical Wnt signaling and tyrosine kinase receptor ROR2 are significantly upregulated in the old cohort. Several Treg signature genes as well as transcription factors that are associated with dysfunctional T cell tumor infiltration are differentially expressed. The differential expression of several genes involved in oxidative phosphorylation, glycolysis and glutamine metabolism is also observed. Taken together, this study provides novel findings on the impact of ageing on transcriptional changes in melanoma, and novel therapeutic targets for future studies. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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21 pages, 2507 KiB

Open AccessArticle

Multigene Panel Sequencing Reveals Cancer-Specific and Common Somatic Mutations in Colorectal Cancer Patients: An Egyptian Experience

by Amira Salah El-Din Youssef, Mohamed A. Abdel-Fattah, Mai M. Lotfy, Auhood Nassar, Mohamed Abouelhoda, Ahmed O. Touny, Zeinab K. Hassan, Mohammed Mohey Eldin, Abeer A. Bahnassy, Hussein Khaled and Abdel Rahman N. Zekri

Curr. Issues Mol. Biol. 2022, 44(3), 1332-1352; https://doi.org/10.3390/cimb44030090 - 18 Mar 2022

Cited by 7 | Viewed by 4848

Abstract

This study aims at identifying common pathogenic somatic mutations at different stages of colorectal carcinogenesis in Egyptian patients. Our cohort included colonoscopic biopsies collected from 120 patients: 20 biopsies from patients with inflammatory bowel disease, 38 from colonic polyp patients, and 62 from [...] Read more.

This study aims at identifying common pathogenic somatic mutations at different stages of colorectal carcinogenesis in Egyptian patients. Our cohort included colonoscopic biopsies collected from 120 patients: 20 biopsies from patients with inflammatory bowel disease, 38 from colonic polyp patients, and 62 from patients with colorectal cancer. On top of this, the cohort included 20 biopsies from patients with non-specific mild to moderated colitis. Targeted DNA sequencing using a customized gene panel of 96 colorectal related genes running on the Ion Torrent NGS technology was used to process the samples. Our results revealed that 69% of all cases harbored at least one somatic mutation. Fifty-seven genes were found to carry 232 somatic non-synonymous variants. The most frequently pathogenic somatic mutations were localized in TP53, APC, KRAS, and PIK3CA. In total, 16 somatic mutations were detected in the CRC group and in either the IBD or CP group. In addition, our data showed that 51% of total somatic variants were CRC-specific variants. The average number of CRC-specific variants per sample is 2.4. The top genes carrying CRC-specific mutations are APC, TP53, PIK3CA, FBXW7, ATM, and SMAD4. It seems obvious that TP53 and APC genes were the most affected genes with somatic mutations in all groups. Of interest, 85% and 28% of the APC and TP53 deleterious somatic mutations were located in Exon 14 and Exon 3, respectively. Besides, 37% and 28% of the total somatic mutations identified in APC and TP53 were CRC-specific variants, respectively. Moreover, we identified that, in 29 somatic mutations in 21 genes, their association with CRC patients was unprecedented. Ten detected variants were likely to be novel: six in PIK3CA and four variants in FBXW7. The detected P53, Wnt/βcatenin, Angiogenesis, EGFR, TGF-β and Interleukin signaling pathways were the most altered pathways in 22%, 16%, 12%, 10%, 9% and 9% of the CRC patients, respectively. These results would contribute to a better understanding of the colorectal cancer and in introducing personalized therapies for Egyptian CRC patients. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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22 pages, 3995 KiB

Open AccessArticle

Functional Screenings Identify Regulatory Variants Associated with Breast Cancer Susceptibility

by Naixia Ren, Yingying Li, Yulong Xiong, Panfeng Li, Yutian Ren and Qilai Huang

Curr. Issues Mol. Biol. 2021, 43(3), 1756-1777; https://doi.org/10.3390/cimb43030124 - 26 Oct 2021

Cited by 2 | Viewed by 4359

Abstract

Genome-wide association studies (GWAS) have identified more than 2000 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility, most of which are located in the non-coding region. However, the causal SNPs functioning as gene regulatory elements still remain largely undisclosed. Here, we applied [...] Read more.

Genome-wide association studies (GWAS) have identified more than 2000 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility, most of which are located in the non-coding region. However, the causal SNPs functioning as gene regulatory elements still remain largely undisclosed. Here, we applied a Dinucleotide Parallel Reporter sequencing (DiR-seq) assay to evaluate 288 breast cancer risk SNPs in nine different breast cancer cell lines. Further multi-omics analysis with the ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing), DNase-seq (DNase I hypersensitive sites sequencing) and histone modification ChIP-seq (Chromatin Immunoprecipitation sequencing) nominated seven functional SNPs in breast cancer cells. Functional investigations show that rs4808611 affects breast cancer progression by altering the gene expression of NR2F6. For the other site, rs2236007, the alteration promotes the binding of the suppressive transcription factor EGR1 and results in the downregulation of PAX9 expression. The downregulated expression of PAX9 causes cancer malignancies and is associated with the poor prognosis of breast cancer patients. Our findings contribute to defining the functional risk SNPs and the related genes for breast cancer risk prediction. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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19 pages, 6060 KiB

Open AccessArticle

MC1R Is a Prognostic Marker and Its Expression Is Correlated with MSI in Colorectal Cancer

by Lixiong Peng, Jiang Chang, Xilin Liu, Shiying Lu, Honglin Ren, Xiaoshi Zhou, Zengshan Liu and Pan Hu

Curr. Issues Mol. Biol. 2021, 43(3), 1529-1547; https://doi.org/10.3390/cimb43030108 - 11 Oct 2021

Cited by 9 | Viewed by 3947

Abstract

Melanocortin 1 receptor (MC1R) is thought to be a marker of poor prognosis and a potential target for the treatment of melanoma. Studies have found that MC1R promotes several tumor behaviors, including cell proliferation and differentiation, pigment formation, and genome damage [...] Read more.

Melanocortin 1 receptor (MC1R) is thought to be a marker of poor prognosis and a potential target for the treatment of melanoma. Studies have found that MC1R promotes several tumor behaviors, including cell proliferation and differentiation, pigment formation, and genome damage repair. Some single-nucleotide polymorphisms (SNPs) of MC1R are involved in the occurrence and development of melanoma. A few studies have reported a relationship between MC1R and colorectal cancer (CRC). In this research, our objective was to examine MC1R expression and MC1R SNPs and investigate their correlation with the clinicopathological features of human CRC tissues. We evaluated MC1R mRNA expression by performing bioinformatic analyses on human CRC expression datasets. We used Western blotting and RT-qPCR to compare MC1R expression in CRC tissues with that in normal tissues, and MC1R SNPs in CRC tissues were detected by PCR-direct sequencing (DS). The expression of MC1R was significantly decreased in CRC tissues compared with normal tissue, and its expression was negatively associated with P53 expression, MLH1 expression, and PMS2 expression, and high MC1R expression was significantly associated with microsatellite instability (MSI). MC1R SNPs were also associated with the clinicopathological characteristics of CRC; for example, the rs2228479 locus genotype was correlated with Ki67 status, and the rs885479 locus genotype was correlated with age and T stage. In conclusion, MC1R plays a crucial role in the progression of CRC and may be a marker of poor prognosis in CRC. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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17 pages, 1751 KiB

Open AccessArticle

Multiplexed DNA Methylation Analysis in Colorectal Cancer Using Liquid Biopsy and Its Diagnostic and Predictive Value

by Walter Pulverer, Kristi Kruusmaa, Silvia Schönthaler, Jasmin Huber, Marko Bitenc, Thomas Bachleitner-Hofmann, Jagdeep Singh Bhangu, Rudolf Oehler, Gerda Egger and Andreas Weinhäusel

Curr. Issues Mol. Biol. 2021, 43(3), 1419-1435; https://doi.org/10.3390/cimb43030100 - 3 Oct 2021

Cited by 15 | Viewed by 4370

Abstract

Early diagnosis of colorectal cancer (CRC) is of high importance as prognosis depends on tumour stage at the time of diagnosis. Detection of tumour-specific DNA methylation marks in cfDNA has several advantages over other approaches and has great potential for solving diagnostic needs. [...] Read more.

Early diagnosis of colorectal cancer (CRC) is of high importance as prognosis depends on tumour stage at the time of diagnosis. Detection of tumour-specific DNA methylation marks in cfDNA has several advantages over other approaches and has great potential for solving diagnostic needs. We report here the identification of DNA methylation biomarkers for CRC and give insights in our methylation-sensitive restriction enzyme coupled qPCR (MSRE-qPCR) system. Targeted microarrays were used to investigate the DNA methylation status of 360 cancer-associated genes. Validation was done by qPCR-based approaches. A focus was on investigating marker performance in cfDNA from 88 patients (44 CRC, 44 controls). Finally, the workflow was scaled-up to perform 180plex analysis on 110 cfDNA samples, to identify a DNA methylation signature for advanced colonic adenomas (AA). A DNA methylation signature (n = 44) was deduced from microarray experiments and confirmed by quantitative methylation-specific PCR (qMSP) and by MSRE-qPCR, providing for six genes’ single areas under the curve (AUC) values of >0.85 (WT1, PENK, SPARC, GDNF, TMEFF2, DCC). A subset of the signatures can be used for patient stratification and therapy monitoring for progressed CRC with liver metastasis using cfDNA. Furthermore, we identified a 35-plex classifier for the identification of AAs with an AUC of 0.80. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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9 pages, 7141 KiB

Open AccessArticle

Contribution of Neuropilin-1 in Radiation-Survived Subclones of NSCLC Cell Line H1299

by Kaori Tsutsumi, Ayaka Chiba, Yuta Tadaki, Shima Minaki, Takahito Ooshima and Haruka Takahashi

Curr. Issues Mol. Biol. 2021, 43(3), 1203-1211; https://doi.org/10.3390/cimb43030085 - 22 Sep 2021

Cited by 1 | Viewed by 2448

Abstract

Non-small cell lung cancer (NSCLC) is an aggressive lung cancer accounting for approximately 85% of all lung cancer patients. For the patients with Stages IIIA, IIIB, and IIIC, the 5-year survival is low though with the combination with radiotherapy and chemotherapy. In addition, [...] Read more.

Non-small cell lung cancer (NSCLC) is an aggressive lung cancer accounting for approximately 85% of all lung cancer patients. For the patients with Stages IIIA, IIIB, and IIIC, the 5-year survival is low though with the combination with radiotherapy and chemotherapy. In addition, the occurrence of tumor cells (repopulated tumors) that survive irradiation remains a challenge. In our previous report, we subcloned the radiation-surviving tumor cells (IR cells) using the human NSCLC cell line, H1299, and found that the expression of neuropilin-1 (NRP-1) was upregulated in IR cells by the microarray analysis. Here, we investigated the contribution of neuropilin-1 to changes in the characteristics of IR cells. Although there were no differences in angiogenic activity in the tube formation assay between parental and IR cells, the cell motility was increased in IR cells compared to parental cells in the cell migration assay. This enhanced cell motility was suppressed by pretreatment with anti-NRP-1 antibody. Although further studies are necessary to identify other molecules associated with NRP-1, the increase in cellular motility in IR cells might be due to the contribution of NRP-1. Inhibition of NRP-1 would help control tumor malignancy in radiation-surviving NSCLC. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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10 pages, 827 KiB

Open AccessArticle

Chromosomal Location of Genes Differentially Expressed in Tumor Cells Surviving High-Dose X-ray Irradiation: A Preliminary Study on Radio-Fragile Sites

by Kaori Tsutsumi, Moe Masuda and Hiroyuki Date

Curr. Issues Mol. Biol. 2021, 43(2), 1133-1141; https://doi.org/10.3390/cimb43020080 - 8 Sep 2021

Viewed by 2552

Abstract

Altered gene expression is a common feature of tumor cells after irradiation. Our previous study showed that this phenomenon is not only an acute response to cytotoxic stress, instead, it was persistently detected in tumor cells that survived 10 Gy irradiation (IR cells). [...] Read more.

Altered gene expression is a common feature of tumor cells after irradiation. Our previous study showed that this phenomenon is not only an acute response to cytotoxic stress, instead, it was persistently detected in tumor cells that survived 10 Gy irradiation (IR cells). The current understanding is that DNA double-strand breaks (DSBs) are recognized by the phosphorylation of histone H2AX (H2AX) and triggers the ataxia-telangiectasia mutated (ATM) protein or the ATM- and Rad3-related (ATR) pathway, which activate or inactivate the DNA repair or apoptotic or senescence related molecules and causes the expression of genes in many instances. However, because changes in gene expression persist after passaging in IR cells, it may be due to the different pathways from these transient intracellular signaling pathways caused by DSBs. We performed microarray analysis of 30,000 genes in radiation-surviving cells (H1299-IR and MCF7-IR) and found an interesting relation between altered genes and their chromosomal loci. These loci formed a cluster on the chromosome, especially on 1q21 and 6p21-p22 in both irradiated cell lines. These chromosome sites might be regarded as “radio-fragile” sites. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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20 pages, 2343 KiB

Open AccessArticle

Application of Combined Long Amplicon Sequencing (CoLAS) for Genetic Analysis of Neurofibromatosis Type 1: A Pilot Study

by Sumihito Togi, Hiroki Ura and Yo Niida

Curr. Issues Mol. Biol. 2021, 43(2), 782-801; https://doi.org/10.3390/cimb43020057 - 23 Jul 2021

Cited by 10 | Viewed by 3126

Abstract

Elaborate analyses of the status of gene mutations in neurofibromatosis type 1 (NF1) are still difficult nowadays due to the large gene sizes, broad mutation spectrum, and the various effects of mutations on mRNA splicing. These problems cannot be solved simply by sequencing [...] Read more.

Elaborate analyses of the status of gene mutations in neurofibromatosis type 1 (NF1) are still difficult nowadays due to the large gene sizes, broad mutation spectrum, and the various effects of mutations on mRNA splicing. These problems cannot be solved simply by sequencing the entire coding region using next-generation sequencing (NGS). We recently developed a new strategy, named combined long amplicon sequencing (CoLAS), which is a method for simultaneously analysing the whole genomic DNA region and, also, the full-length cDNA of the disease-causative gene with long-range PCR-based NGS. In this study, CoLAS was specifically arranged for NF1 genetic analysis, then applied to 20 patients (five previously reported and 15 newly recruited patients, including suspicious cases) for optimising the method and to verify its efficacy and benefits. Among new cases, CoLAS detected not only 10 mutations, including three unreported mutations and one mosaic mutation, but also various splicing abnormalities and allelic expression ratios quantitatively. In addition, heterozygous mapping by polymorphisms, including introns, showed copy number monitoring of the entire NF1 gene region was possible in the majority of patients tested. Moreover, it was shown that, when a chromosomal level microdeletion was suspected from heterozygous mapping, it could be detected directly by breakpoint-specific long PCR. In conclusion, CoLAS not simply detect the causative mutation but accurately elucidated the entire structure of the NF1 gene, its mRNA expression, and also the splicing status, which reinforces its high usefulness in the gene analysis of NF1. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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13 pages, 1312 KiB

Open AccessArticle

Evaluating the Effect of 3′-UTR Variants in DICER1 and DROSHA on Their Tissue-Specific Expression by miRNA Target Prediction

by Dmitrii S. Bug, Artem V. Tishkov, Ivan S. Moiseev and Natalia V. Petukhova

Curr. Issues Mol. Biol. 2021, 43(2), 605-617; https://doi.org/10.3390/cimb43020044 - 6 Jul 2021

Cited by 6 | Viewed by 2730

Abstract

Untranslated gene regions (UTRs) play an important role in controlling gene expression. 3′-UTRs are primarily targeted by microRNA (miRNA) molecules that form complex gene regulatory networks. Cancer genomes are replete with non-coding mutations, many of which are connected to changes in tumor gene [...] Read more.

Untranslated gene regions (UTRs) play an important role in controlling gene expression. 3′-UTRs are primarily targeted by microRNA (miRNA) molecules that form complex gene regulatory networks. Cancer genomes are replete with non-coding mutations, many of which are connected to changes in tumor gene expression that accompany the development of cancer and are associated with resistance to therapy. Therefore, variants that occurred in 3′-UTR under cancer progression should be analysed to predict their phenotypic effect on gene expression, e.g., by evaluating their impact on miRNA target sites. Here, we analyze 3′-UTR variants in DICER1 and DROSHA genes in the context of myelodysplastic syndrome (MDS) development. The key features of this analysis include an assessment of both “canonical” and “non-canonical” types of mRNA-miRNA binding and tissue-specific profiling of miRNA interactions with wild-type and mutated genes. As a result, we obtained a list of DICER1 and DROSHA variants likely altering the miRNA sites and, therefore, potentially leading to the observed tissue-specific gene downregulation. All identified variants have low population frequency consistent with their potential association with pathology progression. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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15 pages, 2083 KiB

Open AccessArticle

Identification and Characterization of Cancer Stem-Like Cells in ALK-Positive Anaplastic Large Cell Lymphoma Using the SORE6 Reporter

by Jing Li, Moinul Haque, Chuquan Shang, Bardes Hassan, Dongzhe Liu, Will Chen and Raymond Lai

Curr. Issues Mol. Biol. 2021, 43(2), 543-557; https://doi.org/10.3390/cimb43020041 - 2 Jul 2021

Cited by 5 | Viewed by 3157 | Correction

Abstract

Transcription factors Sox2 and Oct4 are essential in maintaining the pluripotency of embryonic stem cells and conferring stemness in cancer stem-like (CSL) cells. SORE6, an in-vitro reporter system, was designed to quantify the transcription activity of Sox2/Oct4 and identify CSL cells in non-hematologic [...] Read more.

Transcription factors Sox2 and Oct4 are essential in maintaining the pluripotency of embryonic stem cells and conferring stemness in cancer stem-like (CSL) cells. SORE6, an in-vitro reporter system, was designed to quantify the transcription activity of Sox2/Oct4 and identify CSL cells in non-hematologic cancers. Using SORE6, we identified and enriched CSL cells in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). Two ALK + ALCL cell lines, SupM2 and UCONN-L2, contained approximately 20% of SORE6+ cells, which were purified based on their expression of green fluorescent protein. We then performed functional studies using single-cell clones derived from SORE6− and SORE6+ cells. Compared to SORE6− cells, SORE6+ cells were significantly more chemoresistant and clonogenic in colony-formation assays. Sox2/Oct4 are directly involved in conferring these CSL properties, since the shRNA knockdown of Sox2 in SORE6+ significantly lowered their chemoresistance, while enforced expression of Sox2/Oct4 in SORE6− cells produced opposite effects. Using Western blots, we found that the expression and subcellular localization of Sox2/Oct4 were similar between SORE6− and SORE6+ cells. However, in SORE6+ but not SORE6− cells, Sox2 and Oct4 abundantly bound to a probe containing the SORE6 consensus sequence. c-Myc, previously shown to regulate cancer stemness in ALK + ALCL, regulated the SORE6 activity. In conclusion, SORE6 is useful in identifying/enriching CSL cells in ALK + ALCL. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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14 pages, 2099 KiB

Open AccessArticle

Anti-Inflammatory Effect of Pineapple Rhizome Bromelain through Downregulation of the NF-B- and MAPKs-Signaling Pathways in Lipopolysaccharide (LPS)-Stimulated RAW264.7 Cells

by Orapin Insuan, Phornphimon Janchai, Benchaluk Thongchuai, Rujirek Chaiwongsa, Supaporn Khamchun, Somphot Saoin, Wimonrut Insuan, Peraphan Pothacharoen, Waraporn Apiwatanapiwat, Antika Boondaeng and Pilanee Vaithanomsat

Curr. Issues Mol. Biol. 2021, 43(1), 93-106; https://doi.org/10.3390/cimb43010008 - 7 May 2021

Cited by 21 | Viewed by 6441

Abstract

Bromelain is a mixture of proteolytic enzymes derived from pineapple (Ananas comosus) fruit and stem possessing several beneficial properties, particularly anti-inflammatory activity. However, the molecular mechanisms underlying the anti-inflammatory effects of bromelain are unclear. This study investigated the anti-inflammatory effects and [...] Read more.

Bromelain is a mixture of proteolytic enzymes derived from pineapple (Ananas comosus) fruit and stem possessing several beneficial properties, particularly anti-inflammatory activity. However, the molecular mechanisms underlying the anti-inflammatory effects of bromelain are unclear. This study investigated the anti-inflammatory effects and inhibitory molecular mechanisms of crude and purified rhizome bromelains on lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells. RAW264.7 cells were pre-treated with various concentrations of crude bromelain (CB) or purified bromelain (PB), and then treated with LPS. The production levels of pro-inflammatory cytokines and mediators, including nitric oxide (NO), interleukin (IL)-6, and tumor necrosis factor (TNF)- were determined by Griess and ELISA assays. The expressions of inducible nitric oxide synthetase (iNOS), cyclooxygenase (COX)-2, nuclear factor kappa B (NF-B), and mitogen-activated protein kinases (MAPKs)-signaling pathway-related proteins were examined by western blot analysis. The pre-treatment of bromelain dose-dependently reduced LPS-induced pro-inflammatory cytokines and mediators, which correlated with downregulation of iNOS and COX-2 expressions. The inhibitory potency of PB was stronger than that of CB. PB also suppressed phosphorylated NF-B (p65), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha, extracellular signal-regulated kinases, c-Jun amino-terminal kinases, and p38 proteins in LPS-treated cells. PB then exhibited potent anti-inflammatory effects on LPS-induced inflammatory responses in RAW264.7 cells by inhibiting the NF-B and MAPKs-signaling pathways. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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19 pages, 9576 KiB

Open AccessArticle

Comprehensive Analysis of Prognostic and Genetic Signatures for General Transcription Factor III (GTF3) in Clinical Colorectal Cancer Patients Using Bioinformatics Approaches

by Gangga Anuraga, Wan-Chun Tang, Nam Nhut Phan, Hoang Dang Khoa Ta, Yen-Hsi Liu, Yung-Fu Wu, Kuen-Haur Lee and Chih-Yang Wang

Curr. Issues Mol. Biol. 2021, 43(1), 2-20; https://doi.org/10.3390/cimb43010002 - 27 Apr 2021

Cited by 20 | Viewed by 5187

Abstract

Colorectal cancer (CRC) has the fourth-highest incidence of all cancer types, and its incidence has steadily increased in the last decade. The general transcription factor III (GTF3) family, comprising GTF3A, GTF3B, GTF3C1, and GTFC2, were stated to be linked with the expansion of [...] Read more.

Colorectal cancer (CRC) has the fourth-highest incidence of all cancer types, and its incidence has steadily increased in the last decade. The general transcription factor III (GTF3) family, comprising GTF3A, GTF3B, GTF3C1, and GTFC2, were stated to be linked with the expansion of different types of cancers; however, their messenger (m)RNA expressions and prognostic values in colorectal cancer need to be further investigated. To study the transcriptomic expression levels of GTF3 gene members in colorectal cancer in both cancerous tissues and cell lines, we first performed high-throughput screening using the Oncomine, GEPIA, and CCLE databases. We then applied the Prognoscan database to query correlations of their mRNA expressions with the disease-specific survival (DSS), overall survival (OS), and disease-free survival (DFS) status of the colorectal cancer patient. Furthermore, proteomics expressions of GTF3 family members in clinical colorectal cancer specimens were also examined using the Human Protein Atlas. Finally, genomic alterations of GTF3 family gene expressions in colorectal cancer and their signal transduction pathways were studied using cBioPortal, ClueGO, CluePedia, and MetaCore platform. Our findings revealed that GTF3 family members’ expressions were significantly correlated with the cell cycle, oxidative stress, WNT/β-catenin signaling, Rho GTPases, and G-protein-coupled receptors (GPCRs). Clinically, high GTF3A and GTF3B expressions were significantly correlated with poor prognoses in colorectal cancer patients. Collectively, our study declares that GTF3A was overexpressed in cancer tissues and cell lines, particularly colorectal cancer, and it could possibly step in as a potential prognostic biomarker. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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Review

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17 pages, 1260 KiB

Open AccessReview

CDKN2A/B Homozygous Deletions in Astrocytomas: A Literature Review

by Alexander Yuile, Laveniya Satgunaseelan, Joe Q. Wei, Michael Rodriguez, Michael Back, Nick Pavlakis, Amanda Hudson, Marina Kastelan, Helen R. Wheeler and Adrian Lee

Curr. Issues Mol. Biol. 2023, 45(7), 5276-5292; https://doi.org/10.3390/cimb45070335 - 22 Jun 2023

Cited by 7 | Viewed by 4952

Abstract

Genomic alterations of CDKN2A and CDKN2B in astrocytomas have been an evolving area of study for decades. Most recently, there has been considerable interest in the effect of CDKN2A and/or CDKN2B (CDKN2A/B) homozygous deletions (HD) on the prognosis of isocitrate dehydrogenase [...] Read more.

Genomic alterations of CDKN2A and CDKN2B in astrocytomas have been an evolving area of study for decades. Most recently, there has been considerable interest in the effect of CDKN2A and/or CDKN2B (CDKN2A/B) homozygous deletions (HD) on the prognosis of isocitrate dehydrogenase (IDH)-mutant astrocytomas. This is highlighted by the adoption of CDKN2A/B HD as an essential criterion for astrocytoma and IDH-mutant central nervous system (CNS) WHO grade 4 in the fifth edition of the World Health Organisation (WHO) Classification of Central Nervous System Tumours (2021). The CDKN2A and CDKN2B genes are located on the short arm of chromosome 9. CDKN2A encodes for two proteins, p14 and p16, and CDKN2B encodes for p15. These proteins regulate cell growth and angiogenesis. Interpreting the impact of CDKN2A/B alterations on astrocytoma prognosis is complicated by recent changes in tumour classification and a lack of uniform standards for testing CDKN2A/B. While the prognostic impact of CDKN2A/B HD is established, the role of different CDKN2A/B alterations—heterozygous deletions (HeD), point mutations, and promoter methylation—is less clear. Consequently, how these alternations should be incorporated into patient management remains controversial. To this end, we reviewed the literature on different CDKN2A/B alterations in IDH-mutant astrocytomas and their impact on diagnosis and management. We also provided a historical review of the changing impact of CDKN2A/B alterations as glioma classification has evolved over time. Through this historical context, we demonstrate that CDKN2A/B HD is an important negative prognostic marker in IDH-mutant astrocytomas; however, the historical data is challenging to interpret given changes in tumour classification over time, variation in the quality of evidence, and variations in the techniques used to identify CDKN2A/B deletions. Therefore, future prospective studies using uniform classification and detection techniques are required to improve the clinical interpretation of this molecular marker. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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15 pages, 1019 KiB

Open AccessReview

Cellular and Genetic Background of Osteosarcoma

by Inga Urlić, Marijana Šimić Jovičić, Karla Ostojić and Alan Ivković

Curr. Issues Mol. Biol. 2023, 45(5), 4344-4358; https://doi.org/10.3390/cimb45050276 - 15 May 2023

Cited by 8 | Viewed by 2491

Abstract

Osteosarcoma describes a tumor of mesenchymal origin with an annual incidence rate of four to five people per million. Even though chemotherapy treatment has shown success in non-metastatic osteosarcoma, metastatic disease still has a low survival rate of 20%. A targeted therapy approach [...] Read more.

Osteosarcoma describes a tumor of mesenchymal origin with an annual incidence rate of four to five people per million. Even though chemotherapy treatment has shown success in non-metastatic osteosarcoma, metastatic disease still has a low survival rate of 20%. A targeted therapy approach is limited due to high heterogeneity of tumors, and different underlying mutations. In this review, we will summarize new advances obtained by new technologies, such as next generation sequencing and single-cell sequencing. These new techniques have enabled better assessment of cell populations within osteosarcoma, as well as an understanding of the molecular pathogenesis. We also discuss the presence and properties of osteosarcoma stem cells—the cell population within the tumor that is responsible for metastasis, recurrence, and drug resistance. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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16 pages, 566 KiB

Open AccessReview

The Landscape and Therapeutic Targeting of BRCA1, BRCA2 and Other DNA Damage Response Genes in Pancreatic Cancer

by Ioannis A. Voutsadakis and Antonia Digklia

Curr. Issues Mol. Biol. 2023, 45(3), 2105-2120; https://doi.org/10.3390/cimb45030135 - 3 Mar 2023

Cited by 3 | Viewed by 2213

Abstract

Genes participating in the cellular response to damaged DNA have an important function to protect genetic information from alterations due to extrinsic and intrinsic cellular insults. In cancer cells, alterations in these genes are a source of genetic instability, which is advantageous for [...] Read more.

Genes participating in the cellular response to damaged DNA have an important function to protect genetic information from alterations due to extrinsic and intrinsic cellular insults. In cancer cells, alterations in these genes are a source of genetic instability, which is advantageous for cancer progression by providing background for adaptation to adverse environments and attack by the immune system. Mutations in BRCA1 and BRCA2 genes have been known for decades to predispose to familial breast and ovarian cancers, and, more recently, prostate and pancreatic cancers have been added to the constellation of cancers that show increased prevalence in these families. Cancers associated with these genetic syndromes are currently treated with PARP inhibitors based on the exquisite sensitivity of cells lacking BRCA1 or BRCA2 function to inhibition of the PARP enzyme. In contrast, the sensitivity of pancreatic cancers with somatic BRCA1 and BRCA2 mutations and with mutations in other homologous recombination (HR) repair genes to PARP inhibitors is less established and the subject of ongoing investigations. This paper reviews the prevalence of pancreatic cancers with HR gene defects and treatment of pancreatic cancer patients with defects in HR with PARP inhibitors and other drugs in development that target these molecular defects. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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18 pages, 1614 KiB

Open AccessReview

The Role of WRAP53 in Cell Homeostasis and Carcinogenesis Onset

by Renan Brito Gadelha, Caio Bezerra Machado, Flávia Melo Cunha de Pinho Pessoa, Laudreísa da Costa Pantoja, Igor Valentim Barreto, Rodrigo Monteiro Ribeiro, Manoel Odorico de Moraes Filho, Maria Elisabete Amaral de Moraes, André Salim Khayat and Caroline Aquino Moreira-Nunes

Curr. Issues Mol. Biol. 2022, 44(11), 5498-5515; https://doi.org/10.3390/cimb44110372 - 4 Nov 2022

Cited by 2 | Viewed by 2509

Abstract

The WD repeat containing antisense to TP53 (WRAP53) gene codifies an antisense transcript for tumor protein p53 (TP53), stabilization (WRAP53α), and a functional protein (WRAP53β, WDR79, or TCAB1). The WRAP53β protein functions as a scaffolding protein that is important [...] Read more.

The WD repeat containing antisense to TP53 (WRAP53) gene codifies an antisense transcript for tumor protein p53 (TP53), stabilization (WRAP53α), and a functional protein (WRAP53β, WDR79, or TCAB1). The WRAP53β protein functions as a scaffolding protein that is important for telomerase localization, telomere assembly, Cajal body integrity, and DNA double-strand break repair. WRAP53β is one of many proteins known for containing WD40 domains, which are responsible for mediating a variety of cell interactions. Currently, WRAP53 overexpression is considered a biomarker for a diverse subset of cancer types, and in this study, we describe what is known about WRAP53β’s multiple interactions in cell protein trafficking, Cajal body formation, and DNA double-strand break repair and its current perspectives as a biomarker for cancer. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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15 pages, 1223 KiB

Open AccessReview

Current and Future Perspectives of Cell-Free DNA in Liquid Biopsy

by Shicai Liu and Jinke Wang

Curr. Issues Mol. Biol. 2022, 44(6), 2695-2709; https://doi.org/10.3390/cimb44060184 - 10 Jun 2022

Cited by 15 | Viewed by 5174

Abstract

A liquid biopsy is a minimally invasive or non-invasive method to analyze a range of tumor material in blood or other body fluids, including circulating tumor cells (CTCs), cell-free DNA (cfDNA), messenger RNA (mRNA), microRNA (miRNA), and exosomes, which is a very promising [...] Read more.

A liquid biopsy is a minimally invasive or non-invasive method to analyze a range of tumor material in blood or other body fluids, including circulating tumor cells (CTCs), cell-free DNA (cfDNA), messenger RNA (mRNA), microRNA (miRNA), and exosomes, which is a very promising technology. Among these cancer biomarkers, plasma cfDNA is the most widely used in clinical practice. Compared with a tissue biopsy of traditional cancer diagnosis, in assessing tumor heterogeneity, a liquid biopsy is more reliable because all tumor sites release cfDNA into the blood. Therefore, a cfDNA liquid biopsy is less invasive and comprehensive. Moreover, the development of next-generation sequencing technology makes cfDNA sequencing more sensitive than a tissue biopsy, with higher clinical applicability and wider application. In this publication, we aim to review the latest perspectives of cfDNA liquid biopsy clinical significance and application in cancer diagnosis, treatment, and prognosis. We introduce the sequencing techniques and challenges of cfDNA detection, analysis, and clinical applications, and discuss future research directions. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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8 pages, 3834 KiB

Open AccessCase Report

Recurrent PIK3CA H1047R-Mutated Congenital Infiltrative Facial Lipomatosis: A Case Report and Review of Literature

by Kei Shing Oh, Hisham F. Bahmad, Kalin Veselinov Stoyanov, Ibrahim H. Amjad and Carole Brathwaite

Curr. Issues Mol. Biol. 2023, 45(2), 1712-1719; https://doi.org/10.3390/cimb45020110 - 17 Feb 2023

Cited by 4 | Viewed by 1934

Abstract

Congenital infiltrating lipomatosis of the face (CILF) is a rare, congenital, nonhereditary facial overgrowth due to post-zygomatic activating mutations in PIK3CA gene. It is unilateral and involves hypertrophy of both the soft and hard tissue structures on the affected side of the face. [...] Read more.

Congenital infiltrating lipomatosis of the face (CILF) is a rare, congenital, nonhereditary facial overgrowth due to post-zygomatic activating mutations in PIK3CA gene. It is unilateral and involves hypertrophy of both the soft and hard tissue structures on the affected side of the face. This commonly results in early eruption of the teeth, hypertrophy of the facial bones, macroglossia, and proliferation of the parotid gland. Less than 80 cases of CILF have been reported in the literature so far. Treatment modalities include liposuction and surgical excision. However, since the hallmark of CILF is mutation in the PIK3CA gene, PI3K inhibitors may play a therapeutic role in CILF. We report a case of an 8-year-old boy with recurrent CILF of the scalp and nose, with PIK3CA H1047R mutation. We discuss the differential diagnoses, clinical outcomes, and management of this rare entity. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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9 pages, 7318 KiB

Open AccessCase Report

PIK3R1, HRAS and AR Gene Alterations Associated with Sclerosing Polycystic Adenoma of the Parotid Gland

by Hisham F. Bahmad, Gina Elhammady, Jennifer M. Gass, Juan C. Paramo, Robert Poppiti and John Alexis

Curr. Issues Mol. Biol. 2023, 45(2), 954-962; https://doi.org/10.3390/cimb45020061 - 19 Jan 2023

Cited by 2 | Viewed by 1826

Abstract

Sclerosing polycystic adenoma (SPA) is a rare neoplasm occurring in the salivary glands, mainly the parotid gland. Although it was originally thought to represent a non-neoplastic process, recent genetic data have proven its monoclonality, supporting its neoplastic origin. We report a case of [...] Read more.

Sclerosing polycystic adenoma (SPA) is a rare neoplasm occurring in the salivary glands, mainly the parotid gland. Although it was originally thought to represent a non-neoplastic process, recent genetic data have proven its monoclonality, supporting its neoplastic origin. We report a case of a 73-year-old woman who presented with left neck swelling and pain. A 3 cm hypoechoic, heterogeneous, solid mass was identified on neck ultrasonography within the left parotid gland. Fine needle aspiration revealed benign acinar cells and lymphocytes. Left partial superficial parotidectomy was performed and a diagnosis of SPA was made. Targeted next-generation sequencing (NGS) revealed three clinically significant alterations in the PIK3R1, HRAS, and AR genes. Alterations in the PIK3R1 gene have been previously reported in cases of SPA; however, this study is the first to report two novel clinically significant genomic alterations in the HRAS and AR genes. AR protein expression by immunohistochemistry was strongly and diffusely positive in the neoplastic epithelial cells compared to the adjacent normal salivary gland tissue, which was dead negative for AR. This molecular profile will enhance our understanding of the molecular pathways underlying the development of this tumor. Although this entity was initially thought to be a reactive process, evidence from our case and similar cases strongly support the notion that it is neoplastic due to the presence of specific genetic alterations linked to it. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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9 pages, 796 KiB

Open AccessPerspective

Implications of Concurrent IDH1 and IDH2 Mutations on Survival in Glioma—A Case Report and Systematic Review

by Alexander Yuile, Laveniya Satgunaseelan, Joe Wei, Marina Kastelan, Michael F. Back, Maggie Lee, Heng Wei, Michael E. Buckland, Adrian Lee and Helen R. Wheeler

Curr. Issues Mol. Biol. 2022, 44(10), 5117-5125; https://doi.org/10.3390/cimb44100348 - 21 Oct 2022

Cited by 5 | Viewed by 3793

Abstract

Both IDH1 (isocitrate dehydrogenase 1) and IDH2 (isocitrate dehydrogenase 2) mutations play a vital role in the development of gliomas through disruption of normal cellular metabolic processes. Here we describe a case of a patient with an IDH-mutant astrocytoma, in which both IDH1 [...] Read more.

Both IDH1 (isocitrate dehydrogenase 1) and IDH2 (isocitrate dehydrogenase 2) mutations play a vital role in the development of gliomas through disruption of normal cellular metabolic processes. Here we describe a case of a patient with an IDH-mutant astrocytoma, in which both IDH1 and IDH2 mutations were detected within the same tumour. The patient remains disease-free, nine and a half years after her initial diagnosis. Interrogation of cancer genomic databases and a systematic review was undertaken, demonstrating the rarity of the co-occurrence of IDH1 and IDH2 mutations in a variety of cancer types, and in glioma specifically. Due to the favourable outcome observed in this patient, the potential effect of concurrent IDH1 and IDH2 mutations on survival was also investigated. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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10 pages, 5341 KiB

Open AccessCase Report

Case Report: Genetic Alterations Associated with the Progression of Carotid Paraganglioma

by Vladislav Pavlov, Anastasiya Snezhkina, Dmitry Kalinin, Alexander Golovyuk, Anastasiya Kobelyatskaya, Ildar Bakhtogarimov, Nadezhda Volchenko, George Krasnov and Anna Kudryavtseva

Curr. Issues Mol. Biol. 2021, 43(3), 2266-2275; https://doi.org/10.3390/cimb43030159 - 17 Dec 2021

Cited by 3 | Viewed by 2637

Abstract

Paragangliomas (PGLs) are rare neuroendocrine tumors that can develop from any paraganglion across the body. The carotid body is the most often location of PGLs in the head and neck region. Carotid PGLs (CPGLs) are characterized by predominantly non-aggressive behavior; however, all tumors [...] Read more.

Paragangliomas (PGLs) are rare neuroendocrine tumors that can develop from any paraganglion across the body. The carotid body is the most often location of PGLs in the head and neck region. Carotid PGLs (CPGLs) are characterized by predominantly non-aggressive behavior; however, all tumors have the potential to metastasize. To date, molecular mechanisms of paraganglioma progression remain elusive. We report a case of a 38-year-old woman with metastatic CPGL manifesting as a recurrent tumor with lymph node metastasis. The tumor was fast-growing and had a high Ki-67 proliferation index. Immunohistochemical (IHC) examination and whole-exome sequencing were performed for both recurrent tumor and metastasis. A germline pathogenic splice acceptor variant in the SDHB gene was found in the patient. Immunoreactivity of the SDHB subunit was weak diffuse in both samples, indicating deficiency of the succinate dehydrogenase. Moreover, the recurrent tumor exhibited loss of heterozygosity (LOH) at the SDHB locus, that is according to Knudson’s "two-hit" hypothesis of cancer causation. We also identified a rare somatic promotor mutation in the TERT gene associated with the tumor progression. Obtained results confirmed the indicative role of the germline SDHB mutation for metastatic CPGLs, as well as the potential prognostic value of the TERT promoter mutation. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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