Landscape of Actionable Genetic Alterations Profiled from 1,071 Tumor Samples in Korean Cancer Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: With the emergence of next-generation sequencing (NGS) technology, profiling a wide range of genomic alterations has become a possibility resulting in improved implementation of targeted cancer therapy. In Asian populations, the prevalence and spectrum of clinically actionable genetic alterations has not yet been determined because of a lack of studies examining high-throughput cancer genomic data. MATERIALS AND METHODS: To address this issue, 1,071 tumor samples were collected from five major cancer institutes in Korea and analyzed using targeted NGS at a centralized laboratory. Samples were either fresh frozen or formalin-fixed, paraffin embedded (FFPE) and the quality and yield of extracted genomic DNA was assessed. In order to estimate the effect of sample condition on the quality of sequencing results, tissue preparation method, specimen type (resected or biopsied) and tissue storage time were compared. RESULTS: We detected 7,360 non-synonymous point mutations, 1,164 small insertions and deletions, 3,173 copy number alterations, and 462 structural variants. Fifty-four percent of tumors had one or more clinically relevant genetic mutation. The distribution of actionable variants was variable among different genes. Fresh frozen tissues, surgically resected specimens, and recently obtained specimens generated superior sequencing results over FFPE tissues, biopsied specimens, and tissues with long storage duration. CONCLUSION: In order to overcome, challenges involved in bringing NGS testing into routine clinical use, a centralized laboratory model was designed that could improve the NGS workflows, provide appropriate turnaround times and control costs with goal of enabling precision medicine.

Radon Exposure-induced Genetic Variations in Lung Cancers among Never Smokers

BACKGROUND: Lung cancer in never smokers (LCINS) differs etiologically and clinically from lung cancer attributed to smoking. After smoking, radon exposure is the second leading cause and the primary risk factor of lung cancer among never smokers. Exposure to radon can lead to genetic and epigenetic alterations in tumor genomes affecting genes and pathways involved in lung cancer development. The present study sought to explore genetic alterations associated with LCINS exposed to radon gas indoors. METHODS: Genetic associations were assessed via a case-control study of LCINS (39 cases and 30 controls) using next generation sequencing. Associations between genetic mutations and high exposure to radon were investigated by OncoPrint and heatmap graphs. Bioinformatic analysis was conducted using various tools. According radon exposure levels, we divided subjects in two groups of cases and controls. RESULTS: We found that ABL2 rs117218074, SMARCA4 rs2288845, PIK3R2 rs142933317, MAPK1 rs1803545, and androgen receptor (AR) rs66766400 were associated with LCINS exposed to high radon levels. Among these, Chromodomain helicase DNA-binding protein 4 (CHD4) rs74790047, TSC2 rs2121870, and AR rs66766408 were identified as common exonic mutations in both lung cancer patients and normal individuals exposed to high levels of radon indoor. CONCLUSION: We identified that CHD4 rs74790047, TSC2 rs2121870, and AR rs66766408 are found to be common exonic mutations in both lung cancer patients and normal individuals exposed to radon indoors. Further analysis is needed to determine whether these genes are completely responsible for LCINS exposed to residential radon.

A study on the tendency of genetic alteration of STR loci in human lung cancer tissues / 中国癌症杂志

Background and purpose: Short tandem repeats (STR) multiplex PCR fluorescence detection technology is the most widely used DNA technology in individual identity and genetic identification. It's the most direct method to obtain accurate conclusions. However, some studies have indicated that the rate of STR mutations in tumor tissue is significantly higher than that in normal tissues or blood. This study aimed to investigate the tendency of genetic instability in 20 STR loci on autosomal and Amel loci in tumor tissue samples from lung cancer. Methods: This study, collected 75 cases of human lung cancer tissues and the adjacent normal tissues. DNA samples were extracted by tissue DNA extraction kit, amplified using MicroreaderTM 21 Direct ID System PCR amplification kit. Capillary electrophoresis was performed using API 3130 analyzer, and results were analyzed by genetic analysis software (Gene Mapper ID V3.2). Results: STR alterations were detected in 24 specimens from 75 lung cancer tissues (32%). Fifty-five alterations were detected in the frequently used 21 STR loci in total, including additional alleles 10 times, loss of heterozygosity 10 times, partial loss of heterozygosity 35 times. Partial loss of heterozygosity was the most common genetic alteration types accounting for 63.64% of the total alteration frequency. And multiple genetic alteration types could occur in the same lung cancer tissue. Among them, the highest alteration frequency occurred on D5S818 (7 times), secondly on D3S1358 and D12S391 (both 5 times), and no alterations on D2S441 and Penta E. Combining the experimental results and analysis on clinical data, this study found the statistical differences between the staging of lung cancer and the age of the patients with the STR loci alterations (P0.05). Conclusion: STR loci of the lung cancer tissue were not stable, and the alteration occurred in the aged or high malignant degree lung cancer tissue more frequently. Meanwhile, no alteration was detected on D2S441 and Penta E. In the future research the two STR loci should be verified to determine whether they can be used as the stable STR loci in such cases by increasing the sample size.

Advanced research on characteristics of the classical subtype of human glioblastoma / 实用肿瘤学杂志

Glioblastoma(GBM)is one of the most common primary intracranial tumor that has high de-gree of malignancy ,invasive ability and a fatal prognosis .In recent years ,with the development of modern technol-ogy in biomedical sciences ,the understanding on GBM has developed gradually from pathological diagnosis to mo -lecular classifications ,which is based on the molecular characteristics of genetic signatures .Based on gene expres-sion and DNA methylation patterns , primary glioblastoma is divided into four subtypes , including the classical , neural,proneural and mesenchymal .These molecular classifications are closely relevant to the biological charac-teristics of glioblastoma .This review briefly introduces the molecular classifications of primary glioblastoma , but mainly focuses on the changes of the major genetic EGFR ,PTEN and PI3K,CDKN2A in the classical subtype of GBM,and discusses the treatment strategies for primary glioblastoma .

Cytogenetic alterations in human lymphocyte culture following exposure to radiofrequency field of mobile phone.

The present study aims to address the possible cytogenetic effect of mobile phone on human lymphocyte culture. Human peripheral blood cultured from healthy, non-smoking donors exposed to 1950 MHz and safety limit (2w/kg) of absorption rate (SAR) mobile radiofrequency radiation for 5, 10, 15, 20, 25 and 30 min, then harvested after 24 hr after subjection. The alkaline comet assay, chromosomal aberrations and the micronucleus test were used, to check for changes, stress response and alterations in lymphocytes. The result indicated the presence of timedependant cellular response to RF exposure of mobile phone kept in the standby position, through comet tail factor, DNA fragmentation, chromosomal aberrations and centromeric negative nuclei (MN) in human lymphocyte culture. This effect may be attributed to oxidative stress induced by mobile phone radiation.

Mechanisms and role of microRNA deregulation in cancer onset and progression

MicroRNAs are key regulators of various fundamental biological processes and, although representing only a small portion of the genome, they regulate a much larger population of target genes. Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. MicroRNA targeting is mostly achieved through specific base-pairing interactions between the 5' end ('seed' region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3' UTR diminish mRNA stability. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. Calin and Croce were the first to demonstrate a connection between microRNAs and increased risk of developing cancer, and meanwhile the role of microRNAs in carcinogenesis has definitively been evidenced. It needs to be considered that the complex mechanism of gene regulation by microRNAs is profoundly influenced by variation in gene sequence (polymorphisms) of the target sites. Thus, individual variability could cause patients to present differential risks regarding several diseases. Aiming to provide a critical overview of miRNA dysregulation in cancer, this article reviews the growing number of studies that have shown the importance of these small molecules and how these microRNAs can affect or be affected by genetic and epigenetic mechanisms.

Genetic Alterations in Follicular Cell-derived Thyroid Carcinomas / 대한내분비외과학회지

The molecular approaches to human diseases are receiving greater attention following the completion of the Human Genome Project. Molecular biology techniques are being widely applied to the field of tumor biology, and thyroid carcinomas are not an exception; several genetic alterations have been suggested to play roles in thyroid carcinogenesis and its progression. Malignant tumors arising from thyroid follicular cells can be classified into papillary carcinoma, follicular carcinoma, poorly differentiated carcinoma and anaplastic carcinoma. BRAF mutation, RET/PTC rearrangement and RAS mutation are the suggested molecular causes of papillary thyroid carcinoma (PTC). RAS mutation, PAX8- PPARγ rearrangement, PTEN mutation or methylation, and PIK3CA mutation are known to induce follicular thyroid carcinoma (FTC). Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are related to adding p53 or β-catenin gene alterations to those of papillary or follicular carcinomas. The more aggressive genetic alterations are added stepwise as thyroid tumors advance from differentiated PTC or FTC to less differentiated PDTC and finally to ATC. Studying the molecular mechanisms underlying thyroid carcinogenesis may help overcome the limitations of the current diagnostic methods and this may provide more accurate diagnostic and prognostic tools. Furthermore, research at the molecular level is essential for personalized therapies and creating targeted therapies for thyroid carcinomas.

Molecular mechanisms of cholangiocacinaoma / 国际外科学杂志

The incidence of cholangiocarcinoma is rising, poor prognosis due to lack of viable treatment.Recent investigations into the underlying molecular mechanisms of cholangiocarcinogenesis and tumor growth have contributed greatly to our understanding of this disease, which will lead to the identification of therapeutic targets for this devastating cancer. The purpose of the following review is to address what has been learned over the past decade concerning the molecular basis of cholangiocarcinogenesis and factors regulating cholangiocarcinoma growth. Through a better understanding of these mechanisms, more specific diagnostic, therapeutic, and preventative strategies may be developed and hopefully improve the outcome of this devastating disease.

A Synonymous Genetic Alteration of LMX1B in a Family with Nail-Patella Syndrome

The gene responsible for nail-patella syndrome, LMX1B, has recently been identified on chromosome 9q. Here we present a patient with nail-patella syndrome and an autosomal dominant pattern of inheritance. A 17-year-old girl visited our clinic for the evaluation and treatment of proteinuria. She had dystrophic nails, palpable iliac horns, and hypoplastic patellae. Electron microscopy of a renal biopsy showed irregular thickening of the glomerular basement membrane. A family history over three generations revealed five affected family members. Genetic analysis found a change of TCG to TCC, resulting in a synonymous alteration at codon 219 in exon 4 of the LMX1B gene in two affected family members. The same alteration was not detected in an unaffected family member. This is the first report of familial nail-patella syndrome associated with an LMX1B in Korea mutation, However, we can not completely rule out the possibility that the G-to-C change may be a single nucleotide polymorphism as this genetic mutation cause no alteration in amino acid sequence of LMX1B.

High Frequency of Genetic Alterations in Non-small Cell Lung Cancer Detected by Multi-target Fluorescence In Situ Hybridization

Detection of genetic alterations could provide a tool as an adjuvant for the diagnosis of non-small cell lung cancer (NSCLC) and to define patients at risk for early relapse. In this study, a multi-target fluorescence in situ hybridization (FISH) assay was conducted to investigate the correlation between the alterations of chromosomes, including 5p15.2, 6p11.1-q11, 7p12, and 8q24.12-q24.13 (LaVysion Test), and clinicopathological variables, and to clarify the potential of the multi-target FISH assay in 37 NSCLC. The most notable finding was the higher frequency of a gain in chromosome 5p15.2 in early-stage (I+IIa) lung cancers. The frequency of the gain was 81.3% (16/22) in stage I tumors. The frequencies of gains in 6p11.1-q11 and 8q24.12-q24.13 were 61.5% (8/13) and 84.6% (11/13) in stage IIIa cancers, as compared with lower frequencies in stage I tumors at 25.0% and 31.3%, respectively. There was also a significant difference in the histological type. Our results suggest that a gain in 6p11.1-q11 and 8q24.12-q24.13 plays an important role in tumor progression and is associated with histological differentiation. On the other hand, gene amplification in the 5p region was one of the most consistent alterations in early-stage lung cancer, and thus a series of genes in the critical 5p15.2 region might potentially associated with the development of lung cancer.

Genome-Wide Genetic Study on Central Neurocytoma by Comparative Genomic Hybridization / 上海第二医科大学学报

Objective To detect the genome-wide genetic alterations in central neurocytoma,and to study the pathogensis of central neurocytoma. Methods Comparative genomic hybridization(CGH) analysis was performed in 10 central neurocytomas. Results Chromosomal imbalances were demonstrated in 6 cases.Overrepresentation of genetic material was detected in 4 cases on Chromosome 2p and 10q,and 3 cases on Chromosome 18q. Conclusion(Genetic abnormalities) on Chromosome 2p,10q and 18q may be associated with the pathogenesis of central neurocytoma.

Genetic Alterations in Primary Gastric Carcinomas Correlated with Clinicopathological Variables by Array Comparative Genomic Hybridization

Genetic alterations have been recognized as an important event in the carcinogenesis of gastric cancer (GC). We conducted high resolution bacterial artificial chromosome array-comparative genomic hybridization, to elucidate in more detail the genomic alterations, and to establish a pattern of DNA copy number changes with distinct clinical variables in GC. Our results showed some correlations between novel amplified or deleted regions and clinical status. Copy-number gains were frequently detected at 1p, 5p, 7q, 8q, 11p, 16p, 20p and 20q, and losses at 1p, 2q, 4q, 5q, 7q, 9p, 14q, and 18q. Losses at 4q23, 9p23, 14q31.1, or 18q21.1 as well as a gain at 20q12 were correlated with tumor-node-metastasis tumor stage. Losses at 9p23 or 14q31.1 were associated with lymph node status. Metastasis was determined to be related to losses at 4q23 or 4q28.2, as well as losses at 4q15.2, 4q21.21, 4q 28.2, or 14q31.1, with differentiation. One of the notable aspects of this study was that the losses at 4q or 14q could be employed in the evaluation of the metastatic status of GC. Our results should provide a potential resource for the molecular cytogenetic events in GC, and should also provide clues in the hunt for genes associated with GC.

A study on the gene alterations in 9 STR loci and Amelogenin locus in cancerous tissues / 中国法医学杂志

Objective To study genetic alterations in 9 STR loci and the Amelogenin locus in various tumor tissues. Methods twenty cancer tissues taken from 20 different unrelated individuals and their blood specimens were examined with Chelex-100 extraction of DNA, Profiler Plus PCR amplification and 310 Genetic Analyzer. Results All of the 10 STR loci exist genetic alterations. The genetic alterations occurred in 6out of 20 cases. The rate of genetic alteration was 30%. Six genetic alterations were found in one tumor tissue. Conclusion The forensic community has to take be cautious not to use the tumor tissue for personnel identification.