A Study of Microsatellite Instability in Primary Small Cell Lung Cancers by Microsatellite Analysis
Eun Song ChoJoon ChangJae Min ParkDong-Whan ShinSe Hoon KimYoung Sam KimYoon Soo ChangChul Ho ChoSeung Min KwakJun Gu LeeKyung Young ChungSung Kyu KimWon‐Young LeeSe Kyu Kim
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BACKGROUND: Genomic instability, which is manifested by the replication error (RER) phenotype, has been proposed for the promotion of genetic alterations necessary for carcinogenesis. Merlo et al. reported frequent microsatellite instability in primary small cell lung cancers. However, Kim et al. found that instability occurred in only 1% of the loci tested and did not resemble the replication error-positive phenotype. The significance of microsatellite instability in the tumorigenesis of small cell lung cancer ( as well as the relationship between microsatellite instability and its clinical prognosis was investigated in our study. METHODS: Fifteen primary small cell lung cancers were chosen for this study. The DNAs extracted from paraffin-embedded tissue blocks with both primary tumor and corresponding control tissue were investigated. This phrase is unclear. Does this mean the blocks contained both primary tumor and control tissue samples? Forty microsatellite markers on chromosome 1p, 2p, 3p, 5q, 6p, 6q, 9p, 9q, 13q, and 17p were used in the microsatellite analysis. RESULTS: 1) Thirteen (86.7%) of 15 tumors exhibited LOH in at least one of the tested microsatellite markers. 2) Three of 13 tumors exhibiting LOH lost a larger area in chromosome 9p. 3) LOH was shown in 72.7% on chromosome 2p, 40% on 3p, 50% on 5q, 46.7% on 9p, 69.2% on 13q, and 66.7% on 17p(Table 1). 4) Nine (60%) of 15 tumors exhibited shifted bands in at least one of the tested microsatellite markers. 5) Nine cases exhibiting shifted bands showed altered loci ranging 2.5~52.5% (mean 9.4% +/-16.19)(Table 2). 6) Shifted bands occurred in 5.7% (34 of 600) of the loci tested Table 2. 7) Nine cases with shifted bands exhibited LOH ranging between 0~83.3%(,) and the median survival duration of those cases was 35 weeks. Six cases without shifted bands exhibited LOH ranging between 0~83.3%(,) and the median survival duration of those cases was 73 weeks. There was no significant difference between median survival durations of the two groups(p=0.4712). CONCLUSION: Microsatellite instability as well as the inactivation of several tumor suppressor genes may play important roles in the development and progression process of tumors. However, the relationship between microsatellite instability and its clinical prognosis in primary small cell lung cancer could not be established.Keywords:
Microsatellite Instability
Microsatellite instability implying multiple replication errors (RER) characterizes a proportion of familial and sporadic carcinomas. The purpose of this report is to analyze whether microsatellite instability occurred during the development of human gliomas.We checked prospectively 16 central nervous system tumors, including 10 glioblastomas and 6 astrocytomas of different malignancy grades, for genetic microsatellite instability. Fifteen different microsatellites, located on 6 different chromosomes, were investigated. All microsatellites are dinucleotide CA, repeats except for D11S956,P23 (CTAT) and CYP 19, which are tetranucleotide repeats and P23 (GTTTT) which is a pentanucleotide repeat. The repeats were analysed by PCR amplification, followed by electrophoresis on denaturing 6% polyacrylamide gels.We looked for all kinds of microsatellite alterations. Only microsatellite shifts were considered to represent microsatellite instability.Three out of 10 glioblastomas showed mobility shifts on gel electrophoresis in tumor, compared to corresponding normal DNA samples. In contrast, no microsatellite instability was found in any of the astrocytomas. Besides the presence of larger or smaller alleles, an imbalance in the ratio between alleles was noticed in one astrocytoma and in one glioblastoma multiforme. In addition, loss of heterozygosity (LOH) is observed without a fixed pattern in 3 glioblastomas.We conclude that genetic instability of microsatellites may be demonstrated in high grade gliomas rather than in their low grade precursors and should be regarded as an evolution in tumor progression rather than as a new mechanism for tumor initiation in gliomas.
Microsatellite Instability
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Microsatellite Instability
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Objective To study the loss of heterozygosity(LOH) and the microsatellite instability (MSI) involved in the development of human testicular tumor. Methods 22 primary testicular tumor DNA samples were examined for loss of heterozygosity(LOH) on chromosomes 3, 5, 9, 17, 18 and X and alteration of microsatellite repeats marker by means of polymerase chain reaction, 8 microsatellite repeats markers being used for the analysis of MSI. Results LOH on chromosome 9q33 34, 5q and 18q21 were observed in 45%, 43% and 25%, respectively. Difference between unrelated microsatellites for tumor and control DNA was detected in 8 of 22(36%) . LOH and/or MSI were observed in 17 of 22(77%) cases. Two cases showed alterations on 5 microsatellite loci, three cases showed alterations on 2 microsatellite loci and three cases on 1 microsatellite locus. 5 of 22(23%) patients showed replication error(RER). Conclusions Tumor suppressor genes on chromosome 9q and 5q, and microsatellite instability might play an important role in the development of human testicular tumor.
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AIM: To investigate the role of DNA microsatellite instability (MSI) in gastric carcinogenesis by studying associations between MSI status, clinicopathological features, and loss of genetic loci. METHODS: Six microsatellite loci and loss of heterozygosity at APC, DCC, and MCC were analysed by polymerase chain reaction based methods in 53 cases of advanced gastric cancer. RESULTS: MSI was observed in 32.1% of gastric carcinomas (17/53) and 20% of foci of intestinal metaplasia (3/15). Seven gastric carcinomas (13.7%) were MSI-high (MSI-H) (three loci or more) and 10 (18.9%) were MSI-low (MSI-L) (one or two loci). The frequency of MSI-H was higher in intestinal (25.0%) than in diffuse carcinomas (3.7%) (p < 0.05). None of the MSI-H tumours showed loss of heterozygosity at APC, MCC, or DCC loci. CONCLUSIONS: MSI may have an important and early role in a subset of gastric cancers, particularly the intestinal type. The MSI-H subset of gastric cancer has features in common with its colorectal counterpart, whereas MSI-L and microsatellite stable cancers appear to develop through the loss of heterozygosity pathway.
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In breast cancer, the rates of positivity for microsatellite instability (MSI), vary greatly in the literature. Using high-resolution fluorescent microsatellite analysis (HFRMA), we studied microsatellite alterations in 75 patients with sporadic breast cancer. In this system, several devices were prepared to improve reproducibility of polymerase chain reaction products, migration accuracy of electrophoresis, and characteristics of the detection system. Precise and objective analyses of microsatellite alterations are made feasible using HRFMA. Seven of the 75 cases were judged to be positive for MSI, the rate of positivity being 9.3%. This rate is relatively low compared to the data in the literature. All the microsatellite changes observed in this system can be classified into two types: type A with relatively small changes in microsatellite sequences observed in limited loci and type B with drastic and widely dispersed changes. The former was thought to be connected to abnormal activity in DNA mismatch repair (MMR). Among the 7 cases, 6 (8.0%) had type A alterations, which means that the tumors may have an abnormal MMR activity. Application of precise and objective systems for microsatellite analysis is expected to be clinically useful to detect patients at high risk for cancers.
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목적：Microsatellite는 개인의 각각의 세포에 일생동안 고정된 염기서열을 가지며 유전체에 분포하는 nucleotide의 짧은 일렬반복(tandem repeat)이다. Microsatellite instability (MSI)는 DNA 복제과정에서 일어나는 mismatch repair의 이상에 의해 초래되고 이로 인해 생긴 하나의 nucleotide의 변이가 축적되어 microsatellite 염기서열의 길이의 변화를 초래하게 된다. 이러한 MSI는 mismatch repair의 가장 중요한 지표가 되어 대장암 외 유방암, 자궁내막암, 위암 등 다른 장기의 암에서도 연구가 활발히 진행되고 있다. 연구 방법：본 연구에서는 경북대학교병원에서 수술로 절제된 난소 조직 중 양성, 경계성 및 악성종양 각 20예 등 총 60예의 상피성 난소종양을 대상으로 하였다. 종양조직과 정상조직을 종양세포와 정상세포를 보다 세밀하게 분리할 수 있는 미세절제술을 이용하여 MSI 변이의 빈도가 높다고 알려진 11종의 microsatellite marker를 이용, MSI 분석을 하여 양성, 경계성 및 악성 종양에서 유전자의 변이를 조사하고자 한다. 결과：11종의 microsatellite marker 중 D2S123과 D5S346은 양성종양에서는 MSI 변이가 발견되지 않았지만 경계성 종양에서는 각각 30% 및 25%, 악성종양에서는 각각 60% 및 55%에서 변이가 있는 것으로 각각 분석되었다. D11S860의 경우, 악성종양에서 20예 중 10예가 변이를 보였으며 양성종양과 경계성 종양의 경우 각각 20예 중 4예에서 변이가 발견되었다. 나머지 marker에서는 1예나 2예에서 변이를 보였을 뿐이며 양성종양과 경계성 종양에서도 1예 정도는 변이가 발견되었다. Microsatellite marker 분석 결과를 NCI의 정의에 따라 MSI-H, MSI-L, microsatellite stable (MSS)로 분류하면, 양성종양에서 MSI-H인 경우는 없었으며 대부분이 MSS로 분석되었다. 경계성 종양에서는 MSI-H 2예, MSI-L 8예, MSS는 10예로 나타나 양성종양보다는 변이가 일어난 예가 증가했음을 알 수 있다. 반면, 악성종양에서는 MSS 6예, MSI-L 2예, MSI-H가 12예로 나타나 양성종양(0%)이나 경계성 종양(10%)에 비해 MSI-H의 비율(60%)이 크게 증가했음을 확인하였다. 결론：연구에서 사용한 microsatellite marker 중 D2S123과 D5S346의 변이가 악성종양에서 높은 비율로 발견되었으며 D11S860은 양성종양이나 경계성 종양에서 비교적 높은 비율로 변이가 검출되는데 이러한 소견은 이 염색체에 포함된 종양억제 유전자 등이 난소암의 악성진행 또는 초기발생에 관여되었을 것이라 추정한다. 앞으로 더 많은 예의 양성, 경계성 및 악성종양을 포함한 신선한 난소종양조직으로 미세절제술 방법을 적용해 microsatellite 분석을 한다면 보다 정확한 결과를 산출해 낼 수 있을 것으로 기대한다.
Microsatellite Instability
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