• Journal of Genetic Medicine
• /
• v.6 no.2
• /
• pp.179-182
• /
• 2009

Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer. Among BRCA1- and BRCA2- mutation carriers, the average cumulative risks for ovarian cancer by age 70 years were 39% and 11%, respectively. There are other hereditary cancer syndromes such as Hereditary nonpolyposis colorectal cancer also confer a higher risk for developing ovarian cancer, but over 90% of all hereditary ovarian cancers are thought to be associated with BRCA1 or BRCA2 mutations. This report concerns a Korean woman diagnosed with ovarian cancer present with a family history of ovarian and various other cancers, in whom a germline BRCA1 mutation was identified and the same mutation was found in one of two daughters of her's. Since there could be more hereditary ovarian cancer patients in Korean than clinicians thought, both primary and secondary prevention of ovarian cancer based on family history and genetic information is important to reduce cancer incidence and mortality.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.4
• /
• pp.2521-2523
• /
• 2013

Background: Papillary thyroid cancer or papillary thyroid carcinoma (PTC) is the most common thyroid cancer. The fact that it occasionally occurs in women aged 30-40 years old suggests that genetic alterations are involved its genesis. Recently, activator mutations in BRAF gene have been relatively frequently discovered. Materials and Methods: In this study, we tested 63 DNA samples from PTC patients to identify the V600E mutation frequency in the Ahvaz population. DNA was isolated from formalin fixed paraffin-embedded (FFPE) PTC tumor tissues. Genotyping was performed by PCR-RFLP and confirmed by direct DNA sequencing of a subset of PCR products. PCR-RFLP data were reported as genotype frequencies and percentages. Results: Forty nine out of 63 patients (77.8%) had a mutated heterozygote form while 14 (22.2%) showed normal genotype but none demonstrated a mutant homozygote genotype. The frequency of V600E mutation was significantly high in PTC patients. Conclusions: These findings support involvement of V600E mutations in PTC occurrence in Iran. Assessment of correlations between BRAF V600E mutations and papillary thyroid cancer progression needs to be performed.

• BMB Reports
• /
• v.50 no.1
• /
• pp.37-42
• /
• 2017

The tubby protein (Tub), a putative transcription factor, plays important roles in the maintenance and function of neuronal cells. A splicing defect-causing mutation in the 3'-end of the tubby gene, which is predicted to disrupt the carboxy-terminal region of the Tub protein, causes maturity-onset obesity, blindness, and deafness in mice. Although this pathological Tub mutation leads to a loss of function, the precise mechanism has not yet been investigated. Here, we found that the mutant Tub proteins were mostly localized to puncta found in the perinuclear region and that the C-terminus was important for its solubility. Immunocytochemical analysis revealed that puncta of mutant Tub co-localized with the aggresome. Moreover, whereas wild-type Tub was translocated to the nucleus by extracellular signaling, the mutant forms failed to undergo such translocation. Taken together, our results suggest that the malfunctions of the Tub mutant are caused by its misfolding and subsequent localization to aggresomes.

• Genomics & Informatics
• /
• v.12 no.2
• /
• pp.50-57
• /
• 2014

We present a new next-generation sequencing-based method to identify somatic mutations of lung cancer. It is a comprehensive mutation profiling protocol to detect somatic mutations in 30 genes found frequently in lung adenocarcinoma. The total length of the target regions is 107 kb, and a capture assay was designed to cover 99% of it. This method exhibited about 97% mean coverage at $30{\times}$ sequencing depth and 42% average specificity when sequencing of more than 3.25 Gb was carried out for the normal sample. We discovered 513 variations from targeted exome sequencing of lung cancer cells, which is 3.9-fold higher than in the normal sample. The variations in cancer cells included previously reported somatic mutations in the COSMIC database, such as variations in TP53, KRAS, and STK11 of sample H-23 and in EGFR of sample H-1650, especially with more than $1,000{\times}$ coverage. Among the somatic mutations, up to 91% of single nucleotide polymorphisms from the two cancer samples were validated by DNA microarray-based genotyping. Our results demonstrated the feasibility of high-throughput mutation profiling with lung adenocarcinoma samples, and the profiling method can be used as a robust and effective protocol for somatic variant screening.

• BMB Reports
• /
• v.51 no.1
• /
• pp.27-32
• /
• 2018

Non-small-cell lung cancer (NSCLC) is commonly caused by a mutation in the epidermal growth factor receptor (EGFR) and subsequent aberrant EGFR signaling with uncontrolled kinase activity. A deletion mutation in EGFR exon 19 is frequently observed in EGFR gene mutations. We designed a DNAzyme to suppress the expression of mutant EGFR by cleaving the mutant EGFR mRNA. The DNAzyme (named Ex19del Dz) specifically cleaved target RNA and decreased cancer cell viability when transfected into gefitinib-resistant lung cancer cells harboring EGFR exon 19 deletions. The DNAzyme decreased EGFR expression and inhibited its downstream signaling pathway. In addition to EGFR downregulation, Ex19del Dz containing CpG sites activated Toll-like receptor 9 (TLR9) and its downstream signaling pathway via p38 kinase, causing an immunostimulatory effect on EGFR-mutated NSCLC cells. Thus, dual effects of this DNAzyme harboring the CpG site, such as TLR9 activation and EGFR downregulation, leads to apoptosis of EGFR-mutated NSCLC cells.

• Archives of Pharmacal Research
• /
• v.22 no.1
• /
• pp.1-8
• /
• 1999

Transforming growth factor-$\beta$ (TGF-$\beta$) is the prototypical multifunctional cytokine, participating in the regulation of vital cellular activities such as proliferation and differentiations as well as a number of basic physiological functions. The effects of TGF-$\beta$ are critically dependent on the expression and distribution of a family of TGF-$\beta$ receptors, the TGF-$\beta$ types I, II, and III. It is now known that a wide variety of human pathology can be caused by aberrant expression and function of these receptors. the coding sequence of the type II receptor (RII) appears to render it uniquely susceptible to DNA replication errors in the course of normal cell division. By virtue of its key role in the regulation of cell proliferation, TGF-$\beta$ RII should be considered as a tumor suppressor gene. High levels of mutation in the TGF-$\beta$ RII gene have been observed in a wide range of primarily epithelial malignancies, including colon and gastric cancer. It appears likely that mutation of the TGF-$\beta$ RII gene may be a very critical step in the pathway of carcinogenesis.

• Molecules and Cells
• /
• v.42 no.1
• /
• pp.8-16
• /
• 2019

Mutations in the ${\beta}-catenin$ gene (CTNNB1) have been implicated in the pathogenesis of some cancers. The recent development of cancer genome databases has facilitated comprehensive and focused analyses on the mutation status of cancer-related genes. We have used these databases to analyze the CTNNB1 mutations assembled from different tumor types. High incidences of CTNNB1 mutations were detected in endometrial, liver, and colorectal cancers. This finding agrees with the oncogenic role of aberrantly activated ${\beta}-catenin$ in epithelial cells. Elevated frequencies of missense mutations were found in the exon 3 of CTNNB1, which is responsible for encoding the regulatory amino acids at the N-terminal region of the protein. In the case of metastatic colorectal cancers, in-frame deletions were revealed in the region spanning exon 3. Thus, exon 3 of CTNNB1 can be considered to be a mutation hotspot in these cancers. Since the N-terminal region of the ${\beta}-catenin$ protein forms a flexible structure, many questions arise regarding the structural and functional impacts of hotspot mutations. Clinical identification of hotspot mutations could provide the mechanistic basis for an oncogenic role of mutant ${\beta}-catenin$ proteins in cancer cells. Furthermore, a systematic understanding of tumor-driving hotspot mutations could open new avenues for precision oncology.

• BMB Reports
• /
• v.36 no.4
• /
• pp.399-402
• /
• 2003

Early detection of bladder cancer is particularly important since it dramatically affects the survival rates. However, neither urinary cytology nor tumor markers that are currently used are sensitive enough for the early detection of bladder cancer or recurrent disease. The ras genes are frequently mutated in cancer. In this study, we investigated the diagnostic potential of ras mutation analysis in urinary sediments of patients with bladder cancer using a single-strand conformation polymorphism analysis and polymerase chain reaction. Mutation in codon 12 of the H-ras gene was observed in 39% of the patients. Our results indicate that this approach may significantly improve diagnostic sensitivity in detecting bladder tumors.

• Tuberculosis and Respiratory Diseases
• /
• v.46 no.4
• /
• pp.533-541
• /
• 1999

Background: Lung cancer in younger patients seems to be a more aggressive disease and their prognosis may be worse than that of older patients. Abnormal p53 expression in primary lung cancer may be an independent prognostic factor for poor prognosis. This study was conducted to determine the difference of abnormal p53 mutation in patients with primary non-small cell lung cancer (NSCLC) under 45 years of age and 55 years old or greater. Method: The present study was performed to compare the clinical and pathological features of primary NSCLC between patients younger than 45 years old and older than 55 years old and to evaluate the difference of abnormal p53 mutation between two groups. Immunohistochemical detection of abnormal p53 mutation was assessed in all primary NSCLC specimens by pathologist. Results: Positive nuclear staining of p53 mutation was found in 76.0% of younger patients and in 76.9% of older patients with variable intensity of staining. And there was no significant correlation between abnormal p53 mutation according to the disease stage or histologic subtype. Conclusion: In this investigation, these were no difference in p53 mutation between two groups.

• Asian Pacific Journal of Cancer Prevention
• /
• v.13 no.11
• /
• pp.5599-5603
• /
• 2012

Background: The epidermal growth factor receptor (EGFR) is a potential therapeutic target for breast cancer treatment; however, its use does not lead to a marked clinical response. Studies of non-small cell lung cancer and colorectal cancer showed that mutations of genes in the PIK3CA/AKT and RAS/RAF/MEK pathways, two major signalling cascades downstream of EGFR, might predict resistance to EGFR-targeted agents. Therefore, we examined the frequencies of mutations in these key EGFR pathway genes in Chinese breast cancer patients. Methods: We used a high-throughput mass-spectrometric based cancer gene mutation profiling platform to detect 22 mutations of the PIK3CA, AKT1, BRAF, EGFR, HRAS, and KRAS genes in 120 Chinese women with breast cancer. Results: Thirteen mutations were detected in 12 (10%) of the samples, all of which were invasive ductal carcinomas (two stage I, six stage II, three stage III, and one stage IV). These included one mutation (0.83%) in the EGFR gene (rs121913445-rs121913432), three (2.50%) in the KRAS gene (rs121913530, rs112445441), and nine (7.50%) in the PIK3CA gene (rs121913273, rs104886003, and rs121913279). No mutations were found in the AKT1, BRAF, and HRAS genes. Six (27.27%) of the 22 genotyping assays called mutations in at least one sample and three (50%) of the six assays queried were found to be mutated more than once. Conclusions: Mutations in the EGFR pathway occurred in a small fraction of Chinese breast cancers. However, therapeutics targeting these potential predictive markers should be investigated in depth, especially in Oriental populations.