Mutational analysis of mononucleotide repeats in dual specificity tyrosine phosphatase genes in gastric and colon carcinomas with microsatellite instability

SONG, SANG YONG,KANG, MI RAN,YOO, NAM JIN,LEE, SUG HYUNG Blackwell Publishing Ltd 2010 APMIS Vol.118 No.5

<P>Song SY, Kang MR, Yoo NJ, Lee SH. Mutational analysis of mononucleotide repeats in dual specificity tyrosine phosphatase genes in gastric and colon carcinomas with microsatellite instability. APMIS 2010; 118: 389–93.</P><P>Coordinated protein phosphorylation and dephosphorylation are crucial in the regulation of cell signaling, and disruption of the coordination is known to play important roles in cancer development. Recent reports revealed that classical protein tyrosine phosphatase (PTP)-encoded genes are somatically mutated in human colorectal cancer. However, data on dual specificity phosphatase (DPTP) gene mutations in human cancers are lacking. By analyzing a public genomic database, we found that five DPTP genes, <I>CDC14A</I>, <I>MTM1</I>, <I>MTMR3</I>, <I>SSH1</I>, and <I>SSH2</I>, have mononucleotide repeats in their coding DNA sequences. To see whether these genes are mutated in cancers with microsatellite instability (MSI), we analyzed the mononucleotide repeats in 26 gastric cancers (GC) with MSI (MSI-H), 12 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 33 colorectal cancers (CRC) with MSI-H, 14 CRC with MSI-L, and 45 CRC with MSS by single-strand conformation polymorphism (SSCP). We found <I>CDC14A</I> and <I>MTMR3</I> mutations in five and one cancer (s), respectively. These mutations were detected in MSI-H cancers, but not in MSI-L or MSS cancers. The GC and CRC with MSI-H harbored the mutations in 15% and 6%, respectively. The <I>CDC14A</I> and <I>MTMR3</I> mutations detected in the GC and CRC were deletion or duplication mutations of one base in the nucleotide repeats that would result in premature stops of the amino acid syntheses. Our data show that frameshift mutations of DPTP genes in MSI-H cancers occur at moderate frequencies. The data suggested that alterations in the <I>CDC14A</I> and <I>MTMR3</I> genes may play a role in the development of GC and CRC with MSI-H by deregulating phosphatase functions possibly together with mutations of classical PTP genes.</P>

산발성 장형 위선암 환자의 Microsatellite Instability와 병리학적 양상

조창희,홍유찬,안지현,최경현,이상호,신영명,윤기영,정민정,장희경 고신대학교의과대학 2007 고신대학교 의과대학 학술지 Vol.22 No.2

Background : Through many researches, microsatellite is expected to be a good diagnositic and prognostic factor in colorectal cancer, endometrial cancer, gastric cancer, and the others. The prevalence of microsatellite instability (MSI) in gastric carcinoma has reported variously, 13~44%. Purpose : We aimed to determine the prevalence of MSI-high and the relationship between MSI and pathological characteristics of sporadic intestinal type adenocarcinoma of stomach. Material and Methods : We analyzed 106 sporadic intestinal type adenocarcinoma specimens excised from patients who were over thirty-five years old to determine the statue of microsatellite by DNA sequencing. The tissues were formalin-fixed and paraffin embedded. DNA were extracted and amplified by polymerase chain reaction (PCR). MSI was determined using five markers recommended by National Cancer Institute (NCI). Specimens were also studied with five patholical factors-differenciation of tumor cells, depth of invasion, lymph node metastasis, vessel invasion, and perineural invasion- to determine pathological state. Result : The microsatellite statue was determined as MSI-High in 5 cases (4.7%), no MSI-low, and MSS (microsatellite stable) in 101 cases (95.3%). Within the frequency, there was no large gap in the distinction of gender in MSI cases, but in MSS cases, there was three-times more cases in male. MSI cases had moderate-to-poor differenciation and trend to invade toward serosa. All MSI cases showed no perineural invasion. But we could not find any statistical significance between MSI and pathological characteristics of sporadic intestinal type adenocarcinoma. Conclusion : Results suggest that MSI can not make any certain pathological significance in sporadic intestinal type adenocarcinoma. Even though less than 5% of sporadic intestinal type adenocarcinoma patients showed MSI, it can be used as a influential prediagnostic factor of gastric cancer. Further study with large scale of cases will be followed to verify these results.

MSI/ MidIR/ II 식생지수를 이용한 봄 가뭄탐지 활용 가능성 분석

김성재,최경숙,장은미,홍성욱 대한공간정보학회 2011 Spatial Information Research Vol.19 No.5

In recent years, utilizations of satellite imagery have been extensively conducted in order to obtain accurate information on drought detection in spring season. This research also carried out utilization of satellite imagery through the various vegetation indices such as NDVI(Normalized Difference Vegetation Index), MSI(Moisture Stress Index), MidIR Index, II(Infrared Index) to find better methodology to detect drought phenomena, especially occurring in spring season. For this purpose, Landsat TM(Thematic Mapper) images were used and applied on the Yeong-cheon city. In this study, the characteristics of DN(Digital Number) for each vegetation index is analyzed, and the correlation analysis between indices and DN according to the number of days with no rain is performed. The results shows high correlation between NDVI and MSI and II with positive correlation on MSI, and negative correlation on II. This indicates the possibility for practical use of MSI, II indices with NDVI to obtain better credibility for detecting spring droughts. 봄 가뭄탐지를 위한 위성영상 활용을 위해 중 저해상 위성영상인 Landsat TM(Thematic Mapper) 영상을 이용하여 기존의 봄철 가뭄 해석에 많이 사용되어온 정규식생지수(NDVI: Normalized Difference Vegetation Index)이외에 MSI(Moisture Stress Index), MidIR Index, II (Infrared Index) 지수들의 가뭄분석 활용가능성을 알아보고자 하였다. 이를 위해 경상북도 영천시를 대상으로 무강수일수에 따른 영상을 선정하여 DN(Digital Number)값의 특성 및 상관성을 분석하고 이와 더불어 가뭄지수와의 비교 분석을 실시하였다. 그 결과 NDVI와 MSI 및 II 지수는 높은 상관관계를 보였으나, MidIR은 낮은 상관관계를 보였으며, 가뭄지수와의 분석에서도 MSI 및 II 지수는 강한 상관관계를 보여주었다. 따라서 MSI와 II 지수를 이용한 가뭄연구를 통해 정보의 다양성 및 정확도를 높일 수 있을 것으로 판단된다.

Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability

Kang, Mi Ran,Kim, Min Sung,Oh, Ji Eun,Kim, Yoo Ri,Song, Sang Yong,Kim, Sung Soo,Ahn, Chang Hyeok,Yoo, Nam Jin,Lee, Sug Hyung John Wiley Sons, Ltd. 2009 The Journal of pathology Vol.217 No.5

<P>Mounting evidence indicates that alterations of autophagy processes are directly involved in the development of many human diseases, including cancers. Autophagy-related gene (ATG) products are main players in the autophagy process. In humans there are 16 known ATG genes, of which four (ATG2B, ATG5, ATG9B and ATG12) have mononucleotide repeats with seven or more nucleotides. Frameshift mutations of genes with mononucleotide repeats are features of cancers with microsatellite instability (MSI). It is not known whether ATG genes with mononucleotide repeats are altered by frameshift mutations in gastric and colorectal carcinomas with MSI. For this, we analysed the mononecleotide repeats in ATG2B, ATG5, ATG9B and ATG12 in 32 gastric carcinomas with high MSI (MSI-H), 13 gastric carcinomas with low MSI (MSI-L), 43 colorectal carcinomas with MSI-H and 15 colorectal carcinomas with MSI-L by a single-strand conformation polymorphism (SSCP) analysis. We found ATG2B, ATG5, ATG9B and ATG12 mutations in 10, 2, 13 and 0 cancers, respectively. The mutations were detected in MSI-H cancers but not in MSI-L cancers. Gastric and colorectal cancers with MSI-H harboured one or more ATG mutations in 28.1% and 27.9%, respectively. Our data indicate that frameshift mutations in ATG genes with mononucleotide repeats are common in gastric and colorectal carcinomas with MSI-H, and suggest that these mutations may contribute to cancer development by deregulating the autophagy process. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</P>

Clinical Utility of a Fully Automated Microsatellite Instability Test with Minimal Hands-on Time

이미선,전성민,성창옥,김선영,김태원,장세진,김지훈 대한병리학회 2019 Journal of Pathology and Translational Medicine Vol.53 No.6

Background: Microsatellite instability (MSI) analysis is becoming increasingly important in many types of tumor including colorectal cancer (CRC). The commonly used MSI tests are either time-consuming or labor-intensive. A fully automated MSI test, the Idylla MSI assay, has recently been introduced. However, its diagnostic performance has not been extensively validated in clinical CRC samples. Methods: We evaluated 133 samples whose MSI status had been rigorously validated by standard polymerase chain reaction (PCR), clinical nextgeneration sequencing (NGS) cancer panel test, or both. We evaluated the diagnostic performance of the Idylla MSI assay in terms of sensitivity, specificity, and positive and negative predictive values, as well as various sample requirements, such as minimum tumor purity and the quality of paraffin blocks. Results: Compared with the gold standard results confirmed through both PCR MSI test and NGS, the Idylla MSI assay showed 99.05% accuracy (104/105), 100% sensitivity (11/11), 98.94% specificity (93/94), 91.67% positive predictive value (11/12), and 100% negative predictive value (93/93). In addition, the Idylla MSI assay did not require macro-dissection in most samples and reliably detected MSI-high in samples with approximately 10% tumor purity. The total turnaround time was about 150 minutes and the hands-on time was less than 2 minutes. Conclusions: The Idylla MSI assay shows good diagnostic performance that is sufficient for its implementation in the clinic to determine the MSI status of at least the CRC samples. In addition, the fully automated procedure requires only a few slices of formalin-fixed paraffin-embedded tissue and might greatly save time and labor.

유방의 침윤성 관암에서의 현미부수체 불안정성

박찬흔 한국유방암학회 2007 Journal of breast cancer Vol.10 No.1

Purpose: Breast cancer shows various molecular and genetic alterations in its development and progression. Microsatellite alterations, and especially microsatellite instability (MSI) and loss of heterozygosity (LOH), have recently been postulated as a novel mechanism of carcinogenesis and as a useful prognostic factor for several gastrointestinal malignancies. LOH is related to the allelic loss of various tumor suppressor genes; however, MSI has been found to be the result of an erroneous DNA mismatch repair system and this has been known to be involved in the carcinogenesis of the hereditary non-polyposis colon cancers and some portion of the sporadic colorectal or gastric cancers. Yet MSI has rarely been studied in invasive ductal carcinoma. Our objectives were to evaluate the MSI and p53 protein expression in invasive ductal carcinomas and to correlate this with various clinicopathological factors. Methods: The MSI analysis was performed by using polymerase chain reaction with five polymorphic microsatellite markers (the BAT25, BAT26, D2S123, D5S346 and D17S250 loci as recommended by the 1998 NCI International Workshop on Microsatellite Instabilitis and RER phenotypes) in 50 surgically resected tumors and each of their non-tumorous counterpart. The p53 protein expression was studied using unohistochemistry. Results: MSI and a p53 protein expression were detected in 22% and 54% of the tumors and non-tumorous tissues, respectively. MSI was more frequently detected in tumor grade I, T-stage I, non-metastatic tumor and tumor stage I. Also there were rare cases showing a high grade and stage with metastasis in the MSI-high group, in which more than 3 microsatellite loci had MSI. The p53 expression results correlated well with a higher tumor grade. Correlation between MSI and the p53 expression was not found. Conclusion: These results may suggest that MSI may be involved in some portions in mammary carcinogenesis and tumor invasion. Also the clinical use of the MSI status may help to determine a better prognosis among invasive ductal cancer patients.

Mutational and expressional analysis of RFC3, a clamp loader in DNA replication, in gastric and colorectal cancers

Kim, Yoo Ri,Song, Sang Yong,Kim, Sung Soo,An, Chang Hyeok,Lee, Sug Hyung,Yoo, Nam Jin Elsevier 2010 Human pathology Vol.41 No.10

<P><B>Summary</B></P><P>Parts of gastric (GC) and colorectal cancers (CRC) exhibit microsatellite instability (MSI) that causes frameshift mutations and contributes to cancer development. DNA replication and repair play crucial roles in maintenance of genome stability, and their alterations contribute to cancer development. In this study, we analyzed mutation of RFC1 and RFC3, clamp loaders in DNA replication, in GC and CRC with MSI. We analyzed mononucleotide repeats in <I>RFC1</I> and <I>RFC3</I> in 29 GC with high MSI (MSI-H), 20 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 35 CRC with MSI-H, 20 CRC with MSI-L, and 45 CRC with MSS by single-strand conformation polymorphism. We also analyzed RFC3 expression in the GC and CRC. We found <I>RFC3</I> frameshift mutations in 7 GC (24.1%) and 9 CRC with MSI-H (25.7%) but not in cancers with MSI-L or MSS. The mutations consisted of 14 c.244delA, one 243_244delAA, and one c.244dupA, which would result in premature stops of RFC3 amino acid synthesis. Loss of RFC3 expression was observed in 51% of the GC and 65% of the CRC, but all of the cancers with <I>RFC3</I> frameshift mutations were weak or negative. Our data indicate <I>RFC3</I> mutation and loss of RFC3 expression occur in large fractions of GC and CRC and suggest that these alterations may contribute to the cancer pathogenesis by deregulating DNA repair and replication.</P>

제약회사 영업사원의 마케팅-영업-인터페이스능력이 영업성과에 미치는 영향

김응준(Eung-Jun Kim),이상원(Sang-Won Lee) 한국콘텐츠학회 2021 한국콘텐츠학회논문지 Vol.21 No.11

마케팅-영업-인터페이스(MSI) 능력은 영업사원들이 시장에서의 지식과 경험을 보다 효과적으로 조직 내부자원들과 소통하는 능력으로서 영업성과에 긍정적인 영향을 주는 것으로 알려져 있다. 본 연구는 제약회사 영업사원의 마케팅-영업-인터페이스(MSI) 능력이 직무만족도를 통해 영업성과에 영향을 미치는 매개효과를 분석하였다. 전국 제약회사 5곳의 영업사원을 대상으로 2021년 4월 15일부터 4월 23일까지 설문조사를 실시하였으며, 총 257부를 최종 분석에 사용하였다. 분석 결과 영업사원이 지각하는 MSI능력은 직무만족도 및 영업성과에 통계적으로 유의한 정(+)의 영향을 보였다. 또한 제약회사 영업사원이 지각하는 MSI능력은 직무만족도를 매개하여 영업성과에 통계적으로 유의한 정(+)의 영향을 보였다. 분석결과는 제약회사 영업사원의 영업성과 향상을 위해 MSI능력과 직무만족도의 중요성을 시사하며, 직무만족도의 매개효과에 주목하여 영업사원 관리와 관련된 방안 마련이 필요함을 보여준다. Marketing-Sales-Interface(MSI) capabilities are known to have a positive impact on sales performance as pharmaceutical salespersonss ability to more effectively communicate their knowledge and experience in the market with internal resources in the organization. This study was conducted to analyze the mediating effect of pharmaceutical salespersons marketing-sales-interface (MSI) ability on sales performance through job satisfaction. Salespersons from five pharmaceutical companies nationwide were studied, and the survey was carried out for about a week from April 15 to April 23, 2021, and a total of 257 questionnaires were used for the final analysis. The main analysis result of this research is that, first, the MSI capabilities that pharmaceutical salespersons perceive showed a statistically significant positive (+) impact on job satisfaction and sales performance. Also, the MSI capabilities that pharmaceutical salespersons perceive had a statistically significant positive (+) impact on sales performance by mediating job satisfaction. The analysis results suggest the importance of MSI capability and job satisfaction for improving the sales performance of pharmaceutical salespersons. This study aims to come up with measures and provide baseline data related to salesperson management by paying attention to the mediating effects of job satisfaction on the impact of MSI on sales performance.

Evaluation of MT1XT20 Single Quasi-Monomorphic Mononucleotide Marker for Characterizing Microsatellite Instability in Persian Lynch Syndrome Patients

Farahani, Najmeh,Nikpour, Parvaneh,Emami, Mohammad Hassan,Hashemzadeh, Morteza,Zeinalian, Mehrdad,Shariatpanahi, Seyed Shervin,Salehi, Rasoul Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.9

Background: Colorectal malignancies with high microsatellite instability (MSI-H), either hereditary (Lynch syndrome) or sporadic, demonstrate better prognosis and altered response to 5FU chemotherapy. It is now recommended to perform MSI testing for all new cases of colorectal cancer regardless of being categorized as hereditary or sporadic. For MSI detection, immunohistochemistry or PCR-based protocols using a cohort of various sets of STR markers are recommended. Here we aimed to evaluate a simplified protocol using just a single STR marker, MT1XT20 mononucleotide repeat, for detection of MSI in Lynch syndrome patients. A Promega five-marker MSI testing panel and immunohistochemistry (IHC) were used as the gold standard in conjunction with MT1XT20. Materials and Methods: Colorectal patients with a positive history of familial cancers were selected by evaluating medical records. Based on Amsterdam II criteria for Lynch syndrome 20 families were short listed. DNA was extracted from formalin fixed paraffin embedded tumour and adjacent normal tissues resected from the index case in each family. Extracted DNA was subjected to MT1XT20 mononucleotide marker analysis and assessment with a commercially available five marker MSI testing kit (Promega, USA). IHC also was performed on tissue sections and the results were compared with PCR based data. Results: Eight (40%), seven (35%) and five (25%) cases were MSI positive using with the Promega kit, IHC and MT1XT20, respectively. Among the markers included in Promega kit, BAT26 marker showed instability in all 8 samples. NR24 and NR21 markers showed instability in 7 (87.5%), and BAT25 and MONO 27 in 6 (75%) and 5 (62.5%). Conclusions: Although MT1XT20 was earlier reported as a valid standalone marker for MSI testing in CRC patients, we could not verify this in our Iranian patients. Instead BAT26 among the markers included in Promega MSI testing kit showed instability in all 8 MSI-H CRC samples. Therefore, it seems BAT26 could act well as a single marker for MSI testing in Iranian CRC patients.

Somatic frameshift mutations of <i>bone morphogenic protein receptor 2</i> gene in gastric and colorectal cancers with microsatellite instability

PARK, SANG WOOK,HUR, SOO YOUNG,YOO, NAM JIN,LEE, SUG HYUNG Blackwell Publishing Ltd 2010 APMIS Vol.118 No.11

<P>Park SW, Hur SY, Yoo NJ, Lee SH. Somatic frameshift mutations of <I>bone morphogenic protein receptor 2</I> gene in gastric and colorectal cancers with microsatellite instability. APMIS 2010; 118: 824–9.</P><P>Mounting evidence exists that perturbation of bone morphogenic protein (BMP) signaling is involved in cancer development, especially in gastrointestinal cancers. However, somatic mutations of the genes encoding BMP and BMP receptors have not yet been discovered in human cancer tissues. By analyzing a public database, we found that <I>BMP receptor 2</I> (<I>BMPR2</I>) and <I>BMP1</I> genes had mononucleotide repeats in their coding sequences that could be mutation targets in cancers with microsatellite instability (MSI). In this study, we analyzed the mutation of <I>BMPR2</I> and <I>BMP1</I> genes in gastric (GC) and colorectal cancers (CRC) with MSI [31 GC with high MSI (MSI-H), 13 GC with low MSI (MSI-L), 38 CRC with MSI-H and 15 CRC with MSI-L] by single-strand conformation polymorphism analysis and DNA sequencing. Overall, we found seven frameshift mutations in the <I>BMPR2</I> gene, but not in the <I>BMP1</I> gene. The mutations were an identical deletion mutation of one base in the repeats (c.1748delA) that would result in premature stops of the amino acid synthesis (p.Asn583ThrfsX44). The <I>BMPR2</I> mutations were detected in 6.5% of GC and 13.2% of CRC with MSI-H. All the cancers with the <I>BMPR2</I> mutation showed loss of BMPR2 expression. Our data indicate that frameshift mutation of <I>BMPR2</I> gene occurs in GC and CRC with MSI-H, and suggest that the <I>BMPR2</I> mutation might contribute to cancer pathogenesis by inactivating BMPR2-mediated BMP signaling.</P>