• Asian Pacific Journal of Cancer Prevention
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• 제13권11호
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• pp.5599-5603
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• 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.

• Asian Pacific Journal of Cancer Prevention
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• 제14권5호
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• pp.2879-2883
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• 2013

Objective: To investigate differences in mutations of epidermal growth factor receptor (EGFR) gene and relationships with clinicopathological features in patients with non-small cell lung cancer (NSCLC) between Uygur and Han ethnic groups. Methods: The Scorpions amplification refractory mutation system (Scorpions ARMS) was used to measure mutations in exons 18, 19, 20 and 21 of the EGFR gene in paraffin-embedded tumor tissue from NSCLC cases, and statistical analysis was performed to investigate links with clinicopathological features in different histological types of NSCLC. Results: Results from ARMS testing showed EGFR mutations in tumor tissues from six (6) of 50 NSCLC patients of Uygur ethnic group, with a positive rate of 12.0%; four of them (4) had exon 19 deletion in EGFR, and two (2) had L858R point mutation in exon 21 of EGFR. Statistically significant difference was noted in EGFR genetic mutation between adenocarcinoma and non-adenocarcinoma (P < 0.05), but no differences with gender, age group, smoking status, or stage (P > 0.05). EGFR mutations were detected in tumor tissues from 27 of 49 NSCLC patients of Han ethnic group, with a positive rate of 55.1%; 19 of them had exon 19 deletions, seven (7) had L858R point mutations in exon 21 of EGFR and one (1) had mutations in both exon 18 G719X and exon 20 T790M of EGFR. Statistically significant differences were noted in EGFR genetic mutations between genders and between adenocarcinoma and non-adenocarcinoma (P<0.05), but not with age group, smoking status, or stage (P > 0.05). Conclusion: Statistically significant differences were noted in the positive rates of EGFR genetic mutations in NSCLC patients between Uygur and Han ethnic groups, with lower positive rates for the Uygur cases.

• 대한의생명과학회지
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• 제11권4호
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• pp.455-463
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• 2005

Resistance to isoniazid (INH), which is one of the most important drugs in Mycobacterium tuberculosis chemotherapy, has been associated with mutations in genes encoding the mycobacterial catalse-peroxidase (katG), the enoyl acyl carrier protein (ACP) reductase (inhA), alkyl hydroperoxide reductase (ahpC), beta-ketoacyl acyl carrier protein synthase (kasA), and NADH dehydrogenase (ndh). In this study, we examined INH-resistance related genes in 50 INH-resistant and 24 INH-susceptible isolates by PCR-sequence analysis. In brief, mutations at the katG gene were found at codon 315 alone (2/50), at codon 463 alone (19/50), and both at 315 and 463 (29/50). However, while mutations at codon 315 were only detected in INH-resistant isolates, mutations at codon 463 were also detected in INH-susceptible isolates indicating mutations at 463 alone do not seem to confer resistance to INH. Similar to the case of katG 463, some of inhA mutations were also found among INH-susceptible isolates. For example, whereas mutations at 8 upstream of the start codon (UPS) and 15 UPS of the inhA gene were detected only in INH-resistant isolates, mutations at 101, 115, and 125 UPS were detected only in INH-susceptible isolates. Many different kinds of mutations were detected in INH­resistant isolates at ahpC, oxyR gene, and intergenic region of the oxyR-ahpC genes. Howerver, the mutations were not found oxyR and the intergenic regions in INH-susceptible isolates. No mutations were found at either kasA or at ndh gene among INH-resistant isolates. In conclusion, some of mutations such as katG 315, inhA promotor region, and oxyR-ahpC seem to be strongly related to INH-resistance. Currently we are developing a molecular diagnostic method based on these results.

• Asian Pacific Journal of Cancer Prevention
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• 제15권21호
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• pp.9327-9333
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• 2014

Breast cancer is the second most common cancer and second leading cause of cancer deaths in women. Phosphatidylinositol-3-kinase (PI3K)/AKT pathway mutations are associated with cancer and phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene mutations have been observed in 25-45% of breast cancer samples. Insulin growth factor binding protein-5 (IGFBP-5) can show different effects on apoptosis, cell motility and survival in breast cancer. We here aimed to determine the association between PIK3CA gene mutations and IGFBP-5 expressions for the first time in breast cancer patients. Frozen tumor samples from 101 Turkish breast cancer patients were analyzed with high resolution melting (HRM) for PIK3CA mutations (exon 9 and exon 20) and 37 HRM positive tumor samples were analyzed by DNA sequencing, mutations being found in 31. PIK3CA exon 9 mutations (Q546R, E542Q, E545K, E542K and E545D) were found in 10 tumor samples, exon 20 mutations (H1047L, H1047R, T1025T and G1049R) in 21, where only 1 tumor sample had two exon 20 mutations (T1025T and H1047R). Moreover, we detected one sample with both exon 9 (E542Q) and exon 20 (H1047R) mutations. 35% of the tumor samples with high IGFBP-5 mRNA expression and 29.4% of the tumor samples with low IGFBP-5 mRNA expression had PIK3CA mutations (p=0.9924). This is the first study of PIK3CA mutation screening results in Turkish breast cancer population using HRM analysis. This approach appears to be a very effective and reliable screening method for the PIK3CA exon 9 and 20 mutation detection. Further analysis with a greater number of samples is needed to clarify association between PIK3CA gene mutations and IGFBP-5 mRNA expression, and also clinical outcome in breast cancer patients.

• Molecules and Cells
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• 제42권1호
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• pp.8-16
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• 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.

• Journal of Genetic Medicine
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• 제7권1호
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• pp.1-8
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• 2010

Hemophilia A is a sex-linked recessive coagulation disorder associated with diverse mutations of the factor VIII gene and a variety of phenotypes. The type of mutation involved dictates the activity of factor VIII, and in turn the severity of bleeding episodes and development of alloantibodies against factor VIII (inhibitors). Missense mutations are the most common genetic risk factors for hemophilia A, especially mild to moderate cases, but carry the lowest risk for inhibitor development. On the other hand, intron 22 inversion is the most common mutation associated with severe hemophilia A and is associated with high risk of inhibitor formation. Large deletions and nonsense mutations are also associated with high risk of inhibitor development. Additional mutations associated with hemophilia A include frameshift and splice site mutations. It is therefore valuable to assess the mutational backgrounds of hemophilia A patients in order to to interpret their symptoms and manage their health problems.

• Annals of Clinical Neurophysiology
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• 제11권2호
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• pp.59-63
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• 2009

Miyoshi myopathy (MM) is caused by the mutations of dysferlin gene (DYSF), which impairs the function of dysferlin protein causing muscle membrane dysfunction. We report a patient showing the MM phenotype who has a sister with LGMD 2B phenotype, along with the results of the immunohistochemical and molecular analyses of the DYSF gene. Immunohistochemical analysis noted negative immunoreactivity against dysferlin. Direct DNA sequencing of whole exons of DYSF gene revealed heterozygous nonsense mutations (c.610C>T + c.2494C>T). To our knowledge, this is the first reported MM case with this very combination of heterozygous mutations.

• Clinical and Experimental Pediatrics
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• 제54권6호
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• pp.272-275
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• 2011

A recently recognized connective tissue disorder, Loeys-Dietz syndrome (LDS) is a genetic aortic aneurysm syndrome caused by mutations in the transforming growth factor-receptor type I or II gene (TGFBR1 or TGFBR2). They have distinctive phenotypic abnormalities including widely spaced eyes (hypertelorism), bifid uvula or cleft palate, and arterial tortuosity with aortic aneurysm or dissection throughout the arterial tree. LDS is characterized by aggressive and rapid progression of aortic aneurysm. Therefore, the patients with distinct phenotype, marked aortic dilatation and aneurysm at early age should be suspected to be affected by LDS and rapid TGFBR gene analysis should be done. We report one child diagnosed as LDS due to typical phenotypes and two novel missense mutations of the TGFBR2 gene (c.1526G>T and c.1528A>T).

• Clinical and Experimental Pediatrics
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• 제60권3호
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• pp.94-97
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• 2017

Trimethylaminuria (TMAuria), known as "fish odor syndrome," is a congenital metabolic disorder characterized by an odor resembling that of rotting fish. This odor is caused by the secretion of trimethylamine (TMA) in the breath, sweat, and body secretions and the excretion of TMA along with urine. TMAuria is an autosomal recessive disorder caused by mutations in flavin-containing monooxygenase 3 (FMO3). Most TMAuria cases are caused by missense mutations, but nonsense mutations have also been reported in these cases. Here, we describe the identification of a novel FMO3 gene mutation in a patient with TMAuria and her family. A 3-year-old girl presented with a strong corporal odor after ingesting fish. Genomic DNA sequence analysis revealed that she had compound heterozygous FMO3 mutations; One mutation was the missense mutation p.Val158Ile in exon 3, and the other was a novel nonsense mutation, p.Ser364X, in exon 7 of the FMO3 gene. Familial genetic analyses showed that the p.Val158Ile mutation was derived from the same allele in the father, and the p.Ser364X mutation was derived from the mother. This is the first description of the p.Ser364X mutation, and the first report of a Korean patient with TMAuria caused by novel compound heterozygous mutations.

• 대한유전성대사질환학회지
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• 제5권1호
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• pp.48-56
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• 2005

Purpose: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder affecting 1 per 10,000~15,000 female births worldwide. The disease-causing gene has been identified as MECP2 (methyl-CpG-binding protein). In this study, we carried out diagnostic mutational analysis of MECP2 gene in RTT patients. Methods: We analyzed four exons and putative promoter of MECP2 gene from the peripheral blood of 43 Korean patients with RTT by PCR-RFLP and direct sequencing. Results: Mutations were detected in MECP2 gene about 60.5% of patients. The mutations consisted of 14 different types including 9 missense mutations, 4 nonsense mutations and 1 frameshift mutation. Of these, three mutations (G161E, T311M, P385fsX409) were newly identified and these were determined as disease-causing mutations by PCR-RFLP and direct sequencing analysis. Most of the mutations were located within MBD (42.3%) and TRD (50%). T158M, R270X, and R306C mutations were identified with high frequency. An intronic SNP (IVS3+23C>G) was newly identified in only three of the patients. It may be a disease-related and Korea-specific SNP with RTT. The L100V and A201V have been reported to be unclassified variant and SNP. However, these mutations were not found in more than 100 normal Korean control samples. These base substitutions seem to be the disease-causing mutations in Korean RTT contrary to previous studies. Conclusion: Disease-causing mutations and polymorphisms would be very important for diagnosing of RTT in Korean. The experimental procedure used in this study might be considered for molecular biologic diagnosis used in clinical field.