微卫星不稳定性与结直肠癌

微卫星是基因组中广泛存在的重复碱基对组成的短DNA片段,容易发生插入或缺失突变。基因组中也存在DNA错配修复系统,其主要功能便是维持微卫星的稳定。当DNA错配修复系统缺陷时微卫星序列的长度会发生改变,称为微卫星不稳定性。Ⅱ期微卫星不稳定性肠癌患者预后较好,但不推荐含氟尿嘧啶的辅助化疗方案。免疫治疗能延长微卫星不稳定性转移性肠癌患者的生存期。但免疫治疗缺少有效的疗效预测指标     

人实体瘤中的微卫星不稳定性

基因组的不稳定性研究是癌变发生机理理论的一个新的内容,是目前研究的热点。本文全面阐述微卫星不稳性的概念,发生机理,在实体瘤中发生情况,微卫星不稳定性检测的临床意义和有待深入研究的问题。     

微卫星不稳定性和误配修复与结直肠癌

微卫星ＤＮＡ广泛分布于基因组中。微卫星不稳定性、误配修复与结直肠癌发生的关系的研究已取得进展，结直肠癌的肿瘤细胞具有遗传不稳定性，表现为微卫星不稳定性，揭示了一个肿瘤发生的新机制。目前检测微卫星不稳定性的方法已较成熟，可用于临床及实验室研究     

喉癌p16区域的杂合性丢失和微卫星序列不稳定性分析

目的 缩小喉癌抑癌基因的寻找范围,探讨Ｐ１６基因在喉癌发生中的作用。方法 选择Ｐ１６基因附近５个微卫星多态标记对６０例喉癌进行杂合性丢失和微卫星序列不稳定性分析。结果 ５个标记在喉癌中杂合性丢失频率均不高,最高仅达２３．１％,但２个标记的微卫星序列不稳定性的频率较高,其中示记微卫星序列恶性循环频率高达４６．１％。结论 提示Ｐ１６基因在喉癌的发生中不以缺失为主,在Ｄ９Ｓ１７５２附近可能存在参与喉癌演     

人实体瘤中的微卫星不稳定性

基因组的不稳定性研究是癌变发生机理理论的一个新的内容，是目前研究的热点。本全面阐述卫星不稳性的概念，发生机理，在实体瘤中发生情况，微卫星不稳定性检测的临床意义和有待深入研究的问题。     

微卫星不稳定性与胃癌发生

胃癌是我国最常见的恶性肿瘤之一，其发病机制相当复杂，涉及一系列遗传学改变，包括癌基因激活及抑癌基因失活等。最近在遗传性非息肉病性结直肠癌(HNPCC)中发现的微卫星不稳定性(microsatellite instability，MSI)现象，亦是导致胃癌发生、发展的分子机制之一，MSI检测可能成为胃癌诊治的新方向。现就近年国内外关于MSI在胃癌发生发展的研究进展作一概述。     

微卫星DNA不稳定性及其在星形细胞肿瘤中的意义

星形细胞肿瘤中微卫星DNA不稳定性的出现及其频率取决于肿瘤的恶性程度.恶性程度高的星形细胞肿瘤常可检出MSI,且伴有错配修复基因的突变率也较高.某些MSI位点可作为间变性星形细胞瘤预后的一个指征.由于某些错配修复基因的缺陷导致微卫星DNA不稳定性,基因组不稳定性的影响在星形细胞肿瘤的发生、发展过程中具有重要意义.     

典型遗传性非息肉病性结直肠癌家系临床病理及分子遗传学分析

目的 了解国人遗传性非息肉病性结直肠癌（HNPCC）的临床病理及分子遗传学特征。方法 用微解剖、微卫星不稳定性分析、免疫组织化学及直接DNA测序方法,检测4例HNPCC患者的肿瘤组织微卫星不稳定性状态、错配修复基因hMSH2及hMLH1蛋白水平的表达变化以及生殖细胞突变。结果 4例先证者5个肿瘤组织均表现为高度微卫星不稳定性,3例表现为hMSH2蛋白表达异常,1例表现为hMLH1蛋白表达异常。检测出3个生殖细胞病理性突变。结论 中国人典型HNPCC病例中错配修复基因突变率较高。高度微卫星不稳定性、错配修复基因hMSH2及hMLH1蛋白表达异常与错配修复基因生殖细胞突变密切相关。微卫星不稳定性和错配修复基因蛋白分析可作为DNA测序前的筛选手段。     

p53突变、微卫星不稳定性与多药耐药

化疗在肿瘤病人中起重要作用,但多药耐药的出现令人沮丧。ｐ５３基因目前被认为是一抑癌基因,作为转录因子的功能已被广泛接受,可能参与ｍｄｒ１基因转录的调节。微卫星不稳定性反映细胞基因组的不稳定性,而后者被认为与肿瘤的发生相关。化疗中的多药耐药现象与ｍｄｒ１基因的表达有关,而后者与ｐ５３蛋白的关系尚无明确结论。ｐ５３基因突变的肿瘤常有化疗抵抗,微卫星不稳定性与化疗效果的关系是一新兴的研究领域。     

胃癌细胞微卫生DNA不稳定性的研究进展

由错配修复基因缺陷引起的微卫星DNA不稳定性是继发现癌基因激活、抑癌基因失活之后的又一癌变机制,微卫星不稳定性胃癌具有不同的临床病理生物学行为.胃癌组织微卫星不稳定性的深入研究将对揭示胃癌的发病机制、胃癌的诊断治疗和预后将产生积极的作用.     

Testing tumors for microsatellite instability.

The methods for determining microsatellite instability in tumors are highly heterogeneous. Recently a 5-marker panel of microsatellites was suggested for this purpose. In this review attention is drawn to the fact that microsatellite instability can be assessed by analyzing tumor DNA with a single marker, BAT-26, and that normal tissue DNA from the same individual needs to be analyzed only when an aberrant allele is seen in the tumor. Whilst this simple procedure does not distinguish between different types and degrees of instability, it should be sufficient for many purposes, such as screening colorectal cancers for mismatch repair deficiency.     

Genomic instability in sporadic colorectal cancer quantitated by inter-simple sequence repeat PCR analysis

Genomic instability plays a major role in cancer by facilitating tumor progression and tumor heterogeneity. Inter-simple sequence repeat (inter-SSR) PCR has been developed to provide a rapid and reproducible technique for quantitation of the major type of genomic instability observed in sporadic tumors, namely, that manifesting itself as amplifications, deletions, translocations, and insertions. Evaluation of 59 sporadic colorectal cancers by inter-SSR PCR has demonstrated a wide range of instability, independent of tumor stage at diagnosis. Comparison of these data and the results of microsatellite PCR analysis reveals an association of high genomic instability with loss of heterozygosity but no association with the replication error phenomenon arising from defects in mismatch repair. Genes Chromosom. Cancer 18:19–29, 1997. © 1997 Wiley-Liss, Inc.     

Alternative lengthening of telomeres--an enhanced chromosomal instability in aggressive non-MYCN amplified and telomere elongated neuroblastomas

Telomere length alterations are known to cause genomic instability and influence clinical course in several tumor types, but have been little investigated in neuroblastoma (NB), one of the most common childhood tumors. In the present study, telomere-dependent chromosomal instability and telomere length were determined in six NB cell lines and fifty tumor biopsies. The alternative lengthening of telomeres (ALT) pathway was assayed by scoring ALT-associated promyelocytic leukemia (PML) bodies (APBs). We found a reduced probability of overall survival for tumors with increased telomere length compared to cases with reduced or unchanged telomere length. In non-MYCN amplified tumors, a reduced or unchanged telomere length was associated with 100% overall survival. Tumor cells with increased telomere length had an elevated frequency of APBs, consistent with activation of the ALT pathway. The vast majority of tumor biopsies and cell lines exhibited an elevated rate of anaphase bridges, suggesting telomere-dependent chromosomal instability. This was more pronounced in tumors with increased telomere length. In cell lines, there was a close correlation between lack of telomere-protective TTAGGG-repeats, anaphase bridging, and remodeling of oncogene sequences. Thus, telomere-dependent chromosomal instability is highly prevalent in NB, and may contribute to the complexity of genomic alterations as well as therapy resistance in the absence of MYCN amplification and in this tumor type.     

Measurement and analysis of the chemotherapy-induced genetic instability in pediatric cancer patients

Bleomycin sensitivity has been proven to be a useful biomarker for environmental carcinogenesis and tumor genetic instability. We have previously reported a significant increase in the chromosomal aberrations induced by chemotherapy regimens. This study aimed to test whether there is an inherent increased genetic instability in cancer patients at diagnosis, to determine the increase and time course of the chemotherapy-induced instability and to test whether bleomycin sensitivity can be used as a predictor of tumor evolution or relapse. The analysis included 99 pediatric cancer patients with four different tumor types (Ewing's sarcoma, osteosarcoma, lymphoma and CNS tumors) and 25 controls. Blood samples (n = 171) were obtained before and at the end of treatment, during clinical remission and at relapse and bleomycin tests on lymphocyte cultures were performed. We detected a significant increase (P = 0.004) in mutagen sensitivity in patients at the end of treatment compared with untreated patients, regardless of the tumor type. In both the longitudinal and cross-sectional analyses maximal and similar values of mutagen sensitivity were found in patients during treatment (1.84 +/- 0.82) and at relapse (1.78 +/- 0.52); minimum and similar values were found in controls (0.93 +/- 0.23), untreated patients (1.15 +/- 0.65) and in those who had fulfilled the chemotherapy protocols for at least 2 years before their sample was collected (1.09 +/- 0.53). From this preliminary data we can conclude that cytostatic drugs induce a transient increase in chromosomal instability in pediatric cancer patients that can be monitored by bleomycin-induced sensitivity tests and that the genetic instability indices should be further investigated as predictors of relapse.     

Grading der Tumoren des tubulären Verdauungssystems

Grading of tumors located in the tubular digestive tract is an integral component of pathology assessment reports but is subordinate to the histological typing of tumors with respect to the prognostic significance. Tumor grading has not been shown to be an independent prognostic marker for most tumor entities in the gastrointestinal tract; however, it may be relevant for further routine treatment decision making in early Union Internationale Contre le Cancer (UICC) stage cancers in which the prognosis for patients is less dominated by advanced tumor spread. Owing to the more favorable prognosis of microsatellite instability in colorectal cancer, the World Health Organization (WHO) has recommended that poorly differentiated tumors should be tested and graded as low grade (G1/G2) when microsatellite instability is detected. This recommendation has been integrated into the German S3 guidelines for colorectal cancers. Accordingly, microsatellite instability testing for grading purposes should become routine practice.     

Microsatellite instability in adenocarcinoma of the prostate.

Instability of dinucleotide tandem repeat sequences has been reported to play a major role in the carcinogenic pathway of familial colon cancer, as well as a potential role in the carcinogenesis of other sporadic neoplasms. To determine the frequency of short tandem repeat instability in adenocarcinoma of the prostate, we studied 40 tumors that were stratified according to tumor grade. The tissue samples were screened with di-, tri- and tetranucleotide markers spanning a wide range of chromosomal loci, including an androgen receptor gene trinucleotide repeat. Microsatellite instability was observed overall in only one of the 40 (2.5%) prostate adenocarcinomas studied. This replication error-positive tumor demonstrated repeat length alterations at two loci. Five other tumors showed an alteration in microsatellite size at a single locus. These tumors were not considered to have the microsatellite instability phenotype. All changes were identified either within tetranucleotide sequences or within the androgen receptor gene repeat (4 or 20 total markers analyzed). Both repeat length expansions and contractions were identified. The replication error-positive case also included separate metastatic nodal tissue. Additional microsatellite analysis of the metastatic tumor tissue revealed allelic patterns identical with the normal tissue control. Our data indicate that microsatellite instability is rare in prostate adenocarcinoma. Therefore, observation of this low replication error frequency suggests that most prostate carcinomas develop in the absence of widespread accumulation of somatic mutations in short tandem repeat sequences. Additionally, these genetic alterations appear to occur more often in tetranucleotide repeat sequences as well as in an androgen receptor gene trinucleotide repeat.     

Molecular pathology of endometrial hyperplasia and carcinoma.

Four different genetic abnormalities may occur in endometrioid adenocarcinomas of the endometrium (mircosatellite instability and mutations in the PTEN, k-RAS and beta-catenin genes), whereas nonendometrioid carcinomas of the endometrium often have p53 mutations and loss of heterozygosity on several chromosomes. Occasionally, a nonendometrioid carcinoma may develop as a result of dedifferentiation of a preexisting endometrioid carcinoma; in such a case, the tumor exhibits overlapping clinical, morphologic, immunohistochemical, and molecular features of the 2 types. The insaturation of microsatellite instability in endometrial carcinogenesis seems to occur late in the transition from complex hyperplasia to carcinoma, and it is preceded by progressive inactivation of MLH-1 by promoter hypermethylation. Moreover, the endometrioid adenocarcinomas that exhibit microsatellite instability show a stepwise progressive accumulation of secondary mutations in oncogenes and tumor suppressor genes that contain short-tandem repeats in their coding sequences. Mutations in the PTEN and k-RAS genes are also frequent in endometrioid adenocarcinomas of the endometrium, particularly in the tumors that exhibit microsatellite instability, whereas beta-catenin mutations do not seem to be associated with such a phenomenon.     

Hypoxia-induced genetic instability—a calculated mechanism underlying tumor progression

The cause of human cancers is imputed to the genetic alterations at nucleotide and chromosomal levels of ill-fated cells. It has long been recognized that genetic instability-the hallmark of human cancers-is responsible for the cellular changes that confer progressive transformation on cancerous cells. How cancer cells acquire genetic instability, however, is unclear. We propose that tumor development is a result of expansion and progression-two complementary aspects that collaborate with the tumor microenvironment-hypoxia in particular, on genetic alterations through the induction of genetic instability. In this article, we review the recent literature regarding how hypoxia functionally impairs various DNA repair pathways resulting in genetic instability and discuss the biomedical implications in cancer biology and treatment.     

Informed consent to microsatellite instability and immunohistochemistry screening for Lynch syndrome

ObjectiveRoutine microsatellite instability and immunohistochemistry screening of colorectal cancers can assist in identifying a significant proportion of cancers attributable to Lynch syndrome. This article considers whether it is necessary to obtain patient informed consent for microsatellite instability and immunohistochemistry screening.ResultsAlthough microsatellite instability screening examines genetic features of a tumor, it lacks several important characteristics that typically mandate formal informed consent to genetic testing. Microsatellite instability screening describes discrete tissue samples and does not provide information about the rest of the patient's body or germline. In contrast, immunohistochemistry screening is a proteomic test that may reveal information about the patient's germline. As such, immunohistochemistry screening can be viewed as similar to other forms of genetic testing, in which explicit patient consent is regarded as an ethical prerequisite.ConclusionThere is no ethical requirement to obtain explicit informed consent for microsatellite instability screening of colorectal tumor samples for Lynch syndrome. There is support for obtaining patient consent to immunohistochemistry testing, given its similarities with other genetic analyses for which informed consent is typically deemed necessary. Regardless of which screening test is used, it is important to prepare patients and their families for the possibility of a positive screening test. Genet Med 2011:13(4):356–360.     

Centrosomes,genomic instability,and cervical carcinogenesis

High-risk human papillomavirus (HPV)-associated carcinogenesis of the uterine cervix is a particularly useful model to study basic mechanisms of genomic instability in cancer. Cervical carcinogenesis is associated with the expression of two high-risk HPV-encoded oncoproteins, E6 and E7. Aneuploidy, the most frequent form of genomic instability in human carcinomas, develops as early as in nonmalignant cervical precursor lesions. In addition, cervical neoplasia is frequently associated with abnormal multipolar mitotic figures, suggesting disturbances of the cell-division process as a mechanism for chromosome segregation defects. Spindle poles are formed by centrosomes, and the high-risk HPV E6 and E7 oncoproteins can each induce abnormal centrosome numbers. These two HPV oncoproteins, however, induce centrosome abnormalities through fundamentally different mechanisms and, presumably, with different functional consequences. High-risk HPV E7, which targets the pRB tumor suppressor pathway, can provoke abnormal centrosome duplication in phenotypically normal cells. On the contrary, cells expressing the HPV E6 oncoprotein, which inactivates p53, accumulate abnormal numbers of centrosomes in parallel with multinucleation and nuclear atypia. These two pathways are not mutually exclusive, since co-expression of HPV E6 and E7 has synergistic effects on centrosome abnormalities and chromosomal instability. Taken together, these findings support the general model in which chromosomal instability arises as a direct consequence of oncogenic insults and can develop at early stages of tumor progression.