Mutation of K-ras Oncogene in Thyroid Tumor Tissue

Lee, Jai Hak,Lee, Jong Seo,Kim, Seung Nam,Chang, Suk Kyun,Yoo, Seung Jin,Song, Young Tack,Cho, Won Il,Choo, Sang Yong CATHOLIC MEDICAL CENTER 1993 Bulletin of the Clinical Research Institute Vol.21 No.1

Point mutation of oncogene, one of the genetic alteration in cancer development, has been found in many malignant tumor tissues, Among those malignant tumors, the incidence of point mutation of K-ras oncogene was reported over 90% in pancreatic cancers, 40-50% in colotectal cancer, 25-30% in lung cancers and less than 10% in urogenital, breast or cervical cancers. Several investigators have reported the incidence of point mutation of ras oncogene was 30-50% in benign thyroid tumors and 50-80% in malignant thyroid tumors with some difference by tumor cell differentiation. Also some reports suggested ras mutation may constitute early steps in thyroid tumorigenesis. But there if few report about relation between point mutation and characteristics of mutation. In order to find out the incidence of k-ras oncogene point mutation and relation with characteristics of mutation in thyroid tumors, authors isolated DNA from each 10 normal tissue and benign and malignant tumor tissues. And then, point mutations of K-ras oncogene (four characteristics of codon 12 and one characteristic of codon 13) were detected by paired PCR with mutation-specific primer and agarose gel electrophoresis methods. The resets are as follows; 1. Any mutation was not detected in normal thyroid tissues. While point mutations were detected 7/10 cases (70%) of benign thyroid tumor tissues and in 9/10 cases (90%) of malignant tumor tissues. 2. The incidence of GGT-AGT mutation was highest in benign thyroid tumors (60%) and lowest in malignant thyroid tumors (30%). The incidences of GGT-GAT, TGT-GTT and GGC-GAC mutations were high in malignant tumors (60%). 3. There were 8/9 cases (89%) in malignant tumors and 5/7 cases (71%) in benign tumors of positive mutations over two Hinds of mutation. And also 5/9 cases (56%) of malignant tumors and 4/7 case (51%) of benign tumors expressed positive mutations over 3 kinds. Moreover two cases of each benign and malignant turners expressed all of five mutations. With above result, authors proposed that high incidence of point mutation of k-ras oncogene was detected in benign (70%) and malignant (90%) thyroid turners, and especially high incidence of GGT-AGT mutation (60%,) in benign tumors while high incidence of GGT-GAT, TGT, GTT and GGC-GAC mutations(60%) in malignant turners were noted. Also authors suggested that the point mutation may constitute early steps of thyroid tumorigenesis.

비소세포폐암에서 p53 종양억제 유전자와 K - ras 유전자의 돌연변이가 임상상에 미치는 영향

이홍렬(Hong Lyeol Lee),류정선(Jeong Seon Ryu),김주항(Joo Hang Kim),김성규(Sung Kyu Kim),이원영(Won Young Lee),이이형(Yi Hyung Lee) 대한내과학회 1998 대한내과학회지 Vol.55 No.5

N/A Objective: A multistep process of gene alterations is required for tumor formation, p53 gene mutation is the most frequent and K-ras gene mutation places second in the gene abnormalities of non-small cell lung cancer (NSCLC). The effect by the mutations of the p53 and ras genes on clinical manifestation is still highly controversial Little is known about the interaction between them in NSCLC. The present study was designed to investigate the effect by the mutations of the p53 tumor suppressor gene and K-ras oncogene on clinical manifestation, and the interaction between the mutations of two genes in the Korean NSCIC. Methods: Fifty-eight patients were enrolled in this study who had been diagnosed as having NSCLC from stage I to stage Ⅲ. They all had been alive for more than one month without any complication after curative resection. The paraffin-embedded lung tissues after resection were used to investigate the p53 expression by immunohistochemical staining, the mutations of the p53 and K-ras genes by polymerase chain reactionsingle strand conformation polymorphism(PCR-SSCP) and nucleotide sequencing. Results: p53 protein was overexpressed in 25.9% by immunohistochemical staining. Overexpression was significantly more frequent in epidermoid carcinoma(p=0.01634). But there was no significant difference between the overexpression group and the negative expression group according to stage and survival. By PCR-SSCP analysis, the mobility shift of the p53 gene was found in 29.1%. There was no significant difference between the groups with and without mobility shift according to cell type, stage and survival. By nucleotide sequencing, p53 gene mutation was 37.9%. The locations of mutation were dispersed among numerous codons and the modes of mutation were also diverse. There was also no significant difference between the groups with and without mutation according to cell type, stage and survival. K-ras gene mutation was 24.1% and only in codon 12 by nucleotide sequencing. Although there was no significant difference between the groups with and without mutation according to cell type or stage, K-ras gene mutation carried a significantly worse prognosis in NSCLC (overall survival p=0.0391, disease-free survival p=0.0318). When the patients were divided into 4 groups according to p53 gene mutation and K-ras gene mutation. there was also no significant difference among any group according to cell type or stage. The prognosis became worse if K-ras gene mutation accompanied(overall survival p=0.0021, disease-free survival p=0.0166). Only the stage(p=0.0313) and K-ras gene mutation(p=0.0457) were significant prognostic factors by Cox regression test. An analysis in stage III showed the significantly shorter survival period in the patients with K-ras gene mutation. K-ras gene mutation, therefore, was confirmed as the independently significant prognostic factor separately from stage. Conclusion: p53 gene mutation had no clinical or prognostic significance because of scattered locations and diverse modes of mutation in contrast to K-ras gene mutation, which had a significantly negative effect on the prognosis of NSCLC. p53 and K-ras gene mutations were apparently independent genetic alterations which played different roles in the clinical manifestation and prognosis of NSCLC.

Mini-gel을 이용한 비방사성 SSCP의 위암 p53유전자 변이 검출

유경금,도재혁,허철행,문철,김형준,이태진,유재형,장진수,이상재 大韓消化器病學會 1997 大韓消化器病學會誌 Vol.29 No.5

갑상선 유두암에서 BRAFV600E 돌연변이와 연관된 임상병리학적 인자 및 초음파 소견과의 연관성

최향숙,김광민,박준범,배금석,강성준 대한갑상선-내분비외과학회 2012 The Koreran journal of Endocrine Surgery Vol.12 No.1

Purpose: This study evaluated the association of the BRAFV600E mutation with known prognostic factors and ultrasonographic characteristics in cases of papillary thyroid carcinoma. Methods: Subjects included 169 patients who received thyroidectomy at Wonju Christian Hospital under the diagnosis of papillary thyroid cancer from February 2010 to October 2011. Results: Of the total patients who received thyroidectomy, there were 128 cases (75,7%) of BRAFV600E mutation. Neither age nor sex were associated with the BRAFV600E mutation. Tumor size, shape, margin, extrathyroidal extension, central node metastasis and lateral node metastasis were found not to be associated with the BRAFV600E mutation. Tumor calcification, echogenicity and vascularity were also not associated with the mutation. Conclusion: As debate remains about the association between the BRAFV600E mutation and clincopathologic factors and ultrasonographic characteristics in cases of papillary thyroid carcinoma, further study is needed. Purpose: This study evaluated the association of the BRAFV600E mutation with known prognostic factors and ultrasonographic characteristics in cases of papillary thyroid carcinoma. Methods: Subjects included 169 patients who received thyroidectomy at Wonju Christian Hospital under the diagnosis of papillary thyroid cancer from February 2010 to October 2011. Results: Of the total patients who received thyroidectomy, there were 128 cases (75,7%) of BRAFV600E mutation. Neither age nor sex were associated with the BRAFV600E mutation. Tumor size, shape, margin, extrathyroidal extension, central node metastasis and lateral node metastasis were found not to be associated with the BRAFV600E mutation. Tumor calcification, echogenicity and vascularity were also not associated with the mutation. Conclusion: As debate remains about the association between the BRAFV600E mutation and clincopathologic factors and ultrasonographic characteristics in cases of papillary thyroid carcinoma, further study is needed.

Novel amyloid precursor protein mutation, Val669Leu (“Seoul <i>APP</i>”), in a Korean patient with early-onset Alzheimer's disease

Bagyinszky, Eva,Kang, Min Ju,Van Giau, Vo,Shim, KyuHwan,Pyun, Jung-Min,Suh, Jeewon,An, Seong Soo A.,Kim, SangYun Elsevier 2019 NEUROBIOLOGY OF AGING Vol.84 No.-

<P><B>Abstract</B></P> <P>In this study, a novel mutation in <I>APP</I> gene, Val669Leu (“Seoul <I>APP</I>”), was reported in a Korean female patient with Alzheimer's disease. She developed cognitive decline at 56 years of age, and her memory declined rapidly over one-year period from her 1st visit to the hospital. Her Mini-Mental State Examination scores dropped from 25/30 to 13/30. Two years later, she developed parkinsonian features, myoclonic jerk, and generalized seizure. As the disease progressed, aggravated diffuse brain atrophy and small-vessel ischemic lesion was also observed, and she became mute and vegetative in 4 years from the symptom onset. Magnetic resonance imaging showed mild medial temporal lobe and hippocampal atrophy, and 18F-fluoro-deoxyglucose positron emission tomography showed bilateral temporoparietal hypometabolism. Plasma amyloid oligomer analysis revealed highly elevated Aβ oligomers levels in the proband patient. Family history revealed positive without biochemical confirmation because family members testified similar type of cognitive decline from the proband's mother and one of her aunt/uncle. Her half-siblings did not present any signs of memory impairment. Sanger sequencing of the proband patient revealed a novel mutation in <I>APP</I> gene, Val669Leu, but mutation was not found in her unaffected half-sisters. A designed algorithm by Guerreiro et al. on early-onset Alzheimer's disease–associated mutations suggested the mutation as possibly pathogenic mutation. On the other hand, PolyPhen2 and SIFT tools suggested as otherwise. Since the mutation was located nearby the β-secretase cleavage site of APP, right next to the Swedish APP (Lys,Met670/671Asn,Leu) mutation, it was named as “Seoul <I>APP”</I> mutation. 3D modeling revealed that this mutation could result in significant changes in loop orientation of APP and also its intramolecular interactions. Hence, a novel <I>APP</I> Val669Leu mutation could alter the binding interactions between APP and β-secretase, which may influence the Aβ40 and Aβ42 generations.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A novel variant in APP, Val669Leu, was found in a Korean patient, named Seoul APP. </LI> <LI> Proband patient developed disease phenotype in her 50s. </LI> <LI> Family history may be positive, and mutation may segregate with disease. </LI> <LI> Mutation is located nearby the beta-secretase site of APP, and potentially disturbs the enzyme mechanism. </LI> </UL> </P>

The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma

Yen-Hsiang Huang,Kuo-Hsuan Hsu,Jeng-Sen Tseng,Kun-Chieh Chen,Chia-Hung Hsu,Kang-Yi Su,Jeremy J. W. Chen,Huei-Wen Chen,Sung-Liang Yu,Tsung-Ying Yang,Gee-Chen Chang 대한암학회 2018 Cancer Research and Treatment Vol.50 No.4

Purpose The main objective of this study was to investigate the relationship among the clinical characteristics and the frequency of T790M mutation in advanced epidermal growth factor receptor (EGFR)mutant lung adenocarcinoma patients with acquired resistance after firstline EGFRtyrosine kinase inhibitor (TKI) treatment. Materials and Methods We enrolled EGFR-mutant stage IIIB-IV lung adenocarcinoma patients, who had progressed to prior EGFR-TKI therapy, and evaluated their rebiopsy EGFRmutation status. Results A total of 205 patients were enrolled for analysis. The overall T790M mutation rate of rebiopsy was 46.3%. The T790M mutation rates among patients with exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 55.0%, 37.3%, and 27.3%, respectively. Baseline exon 19 deletion was associated with a significantly higher frequency of T790M mutation (adjusted odds ratio, 2.14; 95% confidence interval [CI], 1.20 to 3.83; p=0.010). In the exon 19 deletion subgroup, there was a greater prevalence of T790M mutation than other exon 19 deletion subtypes in patients with the Del E746-A750 mutation (61.6% vs. 40.6%; odds ratio, 2.35; 95% CI, 1.01 to 5.49; p=0.049). The progression- free survival (PFS) of first-line TKI treatment > 11 months was also associated with a higher T790M mutation rate (54.1% vs. 39.3%; adjusted odds ratio, 1.82; 95% CI, 1.02 to 3.25; p=0.044). Patients who underwent rebiopsy at metastatic sites had more chance to harbor T790M mutation (52.6% vs. 33.8%; adjusted odds ratio, 1.97; 95% CI, 1.06 to 3.67; p=0.032). Conclusion PFS of first-line EGFR-TKI, rebiopsy site, EGFR exon 19 deletion and its subtype Del E746- A750 mutation are associated with the frequency of T790M mutation.

한국인 임신부에서 Factor V 유전자 돌연변이와 중증 전자간증의 관계

이주롱 ( Joo Long Lee ),이순곤 ( Soon Gone Lee ),이정재 ( Jeong Jae Lee ),이해혁 ( Hae Hyeog Lee ),정집광 ( Jib Kwang Chung ),최규연 ( Kyu Yeon Choi ),이임순 ( Im Soon Lee ),이권해 ( Kwon Hae Lee ) 대한주산의학회 2002 大韓周産醫學會雜誌 Vol.13 No.4

연구목적:단백 C는 활성화 단백 C(Activated protein C, APC)로 활성화되어 응고인자중 factor Va와 factor Ⅷa를 불활성화시키는 항응고 물질이다. 활성화 단백 C 내성이 유전성 혈전증의 중요한 원인이라는 사실이 밝혀졌으며, 이 대부분이 factor V 유전자의 돌연변이(factor V Leiden mutation)에 의한 것임이 알려졌다. 본 연구에서는 factor V 유전자 돌연변이로 야기되는 활성화 단백 C에 대한 내성이 중증 임신 전자간증의 임신부에서 관찰된 보고가 있고 병태 생리에 역할을 한다는 가설을 접하고 중증 전자간증 임신부에서의 factor V Leiden mutation의 빈도를 조사해 정상 임신부와 비교해 보고자 하였다. 방법:정상 혈압을 가진 403명의 임신부와 중증 전자간증으로 진단된 158명의 임신부의 혈청을 대상으로 factor V 유전자의 506번 아르기닌(arginin) 구간에 대한 중합 효소 연쇄 반응을 시행한 후 Mnl 1 제한 효소로 절단하여 절단 여부를 관찰하여 factor V Leiden mutation여부를 관찰하였다. 결과:정상 임신부 403명과 중증 전자간증 임신부 158명중 factor V Leiden mutation은 한 예에서도 관찰되지 않았다. 결론:본 연구결과 백인에서와는 달리 한국인에서는 활성화 단백 C 내성 및 factor V Leiden mutation이 발견되지 않았으며, 한국인에서의 중증 전자간증에 대한 위험요소중 유전자에 대한 다른 연구가 필요할 것으로 생각된다. Objective: A study showed that resistance to activated protein C may develope some cases of severe preeclampsia. A common missense mutation in the factor V gene, the Leiden mutation, is the most frequent genetic cause of resistance to activated protein C. Our objective was to determine whether this mutation is more prevalent in patients with severe preeclampsia than in normotensive controls. Method: Deoxyribonucleic acid was extracted from whole blood of 158 gravid women of severe preeclampsia and 403 normotensive gravid women. The polymerase chain reaction was used to amplify exon 10 of the factor V gene, followed by allele-specific restriction with Mnl 1 for mutation detection. Results: No patients were homozygous for the Leiden mutation. We could not find any positive case with FV: Q506 in the normal or patient group. Conclusion: We could not find that carriers of the factor V Leiden mutation are increased risk for severe preeclampsia. In contrast to the reports in Caucasian, the prevalence of APC resistance and FV: Q506 might be very low or absent in the Korean population. But, carriers of this common thrombophilic mutation may be identified so that other causes and risk factors for inherited thrombophilia should be investigated in the Korean population.

Mutations of the Epidermal Growth Factor Receptor Gene in Triple-Negative Breast Cancer

김애리,장민혜,이수정,배영경 한국유방암학회 2017 Journal of breast cancer Vol.20 No.2

Purpose: Epidermal growth factor receptor (EGFR) is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). However, the frequency of EGFR gene mutation in TNBC is low and varies with ethnicity. This study aimed to investigate the incidence of EGFR gene mutation in TNBC. Methods: EGFR protein expression was evaluated by immunohistochemistry in tissue microarrays of 493 TNBC cases using four different primary antibodies, which included mutationspecific antibodies. For cases with an immunoreactivity level ≥1+, we performed pyrosequencing analysis for EGFR gene mutation. A case was considered mutation-positive when its mutation frequency minus its limit of detection (LOD) was >10%. Cases with mutation frequency higher than LOD were assessed for EGFR gene mutation status using the Cobas assay and by peptide nucleic acid-mediated polymerase chain reaction (PNA-clamping). Results: Among 493 TNBCs, 148 (30.0%) exhibited staining ≥1+ for EGFR, including 78 with 1+, 49 with 2+, and 21 with 3+. Positive EGFR expression (≥2+) was significantly associated with lymphovascular invasion (p=0.010), but not with overall survival (p=0.444) or disease-free survival (p=0.388). None of the 493 TNBCs harbored an EGFR gene mutation. Among 148 cases with an EGFR staining result ≥1+, five (3.4%) showed mutation frequencies (4.4%–10.9%) higher than LOD (2.6%–4.3%) in exons 19 (L747_P753>Q) or 21 (L858R and L861Q) as determined by pyrosequencing. However, Cobas and PNA-clamping failed to detect the presence of EGFR gene mutation in these five cases. Conclusion: No activating mutation of EGFR gene of clinical significance was observed in 148 TNBC cases using three commercially available methods. Thus, EGFR gene mutation appears to be an extremely rare event in patients with TNBC.

결장암종 및 직장암종에서 p53 유전자 돌연변이의 염기서열

심영란,최준혁,최원희 대한병리학회 1999 Journal of Pathology and Translational Medicine Vol.33 No.6

<i>TP53</i> mutation in allogeneic hematopoietic cell transplantation for de novo myelodysplastic syndrome

Kim, Yoo-Jin,Jung, Seung-Hyun,Hur, Eun-Hye,Choi, Eun-Ji,Lee, Kyoo-Hyung,Yim, Seon-Hee,Kim, Hye-Jung,Kwon, Yong-Rim,Jeon, Young-Woo,Lee, Sug Hyung,Chung, Yeun-Jun,Lee, Je-Hwan Elsevier 2018 Leukemia research Vol.74 No.-

<P><B>Abstract</B></P> <P>We investigated the prognostic role of somatic mutations in allogeneic hematopoietic cell transplantation (HCT) for de novo myelodysplastic syndrome (MDS). We performed targeted deep sequencing analysis of 26 genes on bone marrow samples obtained within 6 weeks before HCT from 202 patients with de novo MDS. Overall, 76% of patients carried one or more somatic mutations, and <I>TP53</I> mutation was present in 23 patients (11.4%). Overall survival (OS) at 5 years was 63.6%, cumulative incidence of relapse (CIR) was 18.6%, event-free survival (EFS) was 58.5%, and non-relapse mortality (NRM) was 22.9%. <I>TP53</I> mutation was an independent risk factor for lower OS (41% vs. 67%; <I>P</I> = 0.001), higher CIR (49% vs. 15%; <I>P</I> = 0.001), and lower EFS (38% vs. 61%; <I>P</I> = 0.005), but not for NRM (13% vs. 24%). <I>N-RAS</I> mutation was an independent risk factor for higher CIR (HR, 5.91; <I>P</I> = 0.008). <I>TP53</I> mutation did not have significant interactions with conditioning intensity or the occurrence of graft-versus-host disease with regard to post-transplant outcomes. In conclusion, <I>TP53</I> mutation was significantly associated with poor outcomes after HCT for patients with de novo MDS, mainly due to a higher incidence of disease relapse.</P> <P><B>Highlights</B></P> <P> <UL> <LI> 76% of patients with de novo myelodysplastic syndrome had at least one mutation. </LI> <LI> <I>TP53</I> mutations were present in 11.4% of the patients. </LI> <LI> <I>TP53</I> mutations were associated with poor outcomes after transplantation. </LI> <LI> Only <I>TP53</I> mutations were independently associated with shorter survival. </LI> <LI> <I>TP53</I> mutations were also associated with higher relapse. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>