Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability
Bernhard MlecnikGabriela BindeaHelen K. AngellPauline MabyMihaela AngelovaDavid TougeronSarah E. ChurchLucie LafontaineM. FischerTessa FredriksenMaristella SassoAmélie M. BilocqAmos KirilovskyAnna C. ObenaufMohamad HamiehAnne BergerPatrick BrunevalJean‐Jacques TuechJean‐Christophe SabourinFlorence Le PessotJacques MauillonArash RafiiPierre Laurent‐PuigMichael R. SpeicherZlatko TrajanoskiMichel PierreRichard SesboüéThierry FrébourgFranck PagèsViia Valge-ArcherJean‐Baptiste LatoucheJérôme Galon
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Microsatellite Instability
In many countries, colorectal cancer is one of the common cancers. It has been confirmed that microsatellite instability (MSI) is one of the most important molecular changes in colorectal cancer. As the recognized precursor lesions of colorectal cancer, adenomas and some polyps also have MSI phenomenon. This article analyzes the MSI of colorectal cancer and its closely related adenomas and polyps in domestic and foreign literature, and further discusses how to identify colorectal cancer at an early stage and the impact of MSI on the prognosis and treatment of colorectal cancer.
Microsatellite Instability
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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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Objective: To determine the role of microsatellite alterations in carcinogenesis of colorectal carcinoma (CRC). Methods: Alterations of 10 microsatellite loci from 5 different chromosomes were detected in 92 colorectal cancers and their paired normal mucosa by PCR, denatured polyacrylamide gel electrophoresis and silver staining. Associations of microsatellite alterations with clinopathologic parameters were statistically clarifield. Results: Alterations of microsatellite were classified into microsatellite instability type I, type II and loss of heterozygosity (LOH). The carcinoma with ≧30% loci microsatellite alterations was defined as replication error(RER) positive tumors. Of 92 cases, 14 were RER+. Microsatellite alterations of P53(1) and D18S363 loci (64.29%) was most commonly identified in the RER+ tumors. RER+ were more commonly seen in poorly differentiated carcinomas and tended to occur in mucoid carcinomas. The type of microsatellite alterations varied in different histological types of CRC. Conclusions: Microsatellite alteration is a common molecular event in CRC. Different microsatellite loci showed various biologic significance. P53(1) and D18S363 should be essentially detected loci that can show the RER status of tumors.
Microsatellite Instability
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Microsatellite Instability
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Widespread microsatellite instability (MSI) due to the defective DNA mismatch repair underlies the pathogenesis of the majority of hereditary non-polyposis colorectal cancer and a subset of various sporadic malignant tumors. Using 5 microsatellite markers and the criteria of MSI proposed by the National Cancer Institute (NCI) workshop, we analyzed 205 gastric adenocarcinomas for MSI. Based on the number of markers showing instability per tumor, the tumors were divided into three groups; those with two or more of the five markers displaying instability (high MSI, MSI-H), those with one of five markers displaying instability (low MSI, MSI-L), and those with no instability (microsatellite stable, MSS). Among 205 tumors, 30 (15%) were MSI-H. 15 (7%) were MSI-L, and 160 (78%) were MSS. All of the 30 MSI-H tumors demonstrated instability at BAT26, a sensitive marker for the widespread MSI, while none of the 15 MSI-L tumors did. MSI-H tumors were significantly associated with distal location and well or moderate differentiation, but MSI-H tumors were indistinguishable from MSS tumors. Bax frameshift mutations were detected in 60% of the 30 MSI-H tumors, while not in any of the 15 MSI-L tumors. These results suggest that microsatellite analysis using the criteria proposed by the NCI workshop may appropriate for gastric cancers because it unveils real differences in genotype and phenotype.
Microsatellite Instability
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Microsatellite Instability
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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.
Microsatellite Instability
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Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101).
Microsatellite Instability
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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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Summary Microsatellite markers have been established for a large number of species, but up till now very few polymorphic microsatellite markers have been reported in poultry. We have isolated 34 polymorphic chicken microsatellite markers of the poly (TG) type. The number of repeats varied from 9 up to 33. Often, other repeats such as poly (T) or poly (GAA) were present adjacent to the poly (TG) repeat. Polymerase chain reaction amplification of the microsatellites resulted in detection of three or more alleles in a test panel of five different animals for 75% of the microsatellites. Segregation of five microsatellite markers has been tested in a small family.
Dinucleotide Repeat
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