Colorectal cancer is a disease developed by the accumulation of genomic alteration. Two genomic instability pathways, chromosomal instability pathway and microsatellite instability pathway, are known as the main pathways of the development of colorectal cancer. These are almost always mutually exclusive and tumors developed through each pathways show distinct clinicopathologic features. For the reason, molecular markers which represent each genomic instability pathways have been a candidate for translational research to find out prognostic or predictive factors. Loss of heterozygosity and aneuploidy are the hallmark of chromosomal instability and regarded as poor prognostic markers, whereas tumors with high frequency of microsatellite instability show better prognosis than microsatellite stable tumor. As a predictive factor of response from chemotherapy, loss of heterozygosity seems to be associated with a survival benefit from 5-FU adjuvant therapy. MSI-H has been reported as a predictive factor for poor response to 5-FU adjuvant chemotherapy. However, these molecular markers are not accepted to use in the clinic yet, since some of this kind of studies reported contradictory results. Further study will be needed to make more concrete evidences for these markers and to identify new molecular markers for routine use in the clinic.
Aneuploidy ; Chemotherapy, Adjuvant ; Chromosomal Instability ; Colorectal Neoplasms ; Fluorouracil ; Genomic Instability ; Loss of Heterozygosity ; Microsatellite Instability ; Microsatellite Repeats ; Prognosis ; Translational Medical Research

Two forms of genomic instability have been described in colorectal cancer: chromosomal (CIN) and microsatellite instability (MIN). Colorectal cancer has been considered to progress through one of these two major pathways. However, recently a CpG island methylator pathway (CIMP) has been established among sporadic MIN cancers. Aberrant methylation of a promoter CpG island is associated with inactivation of tumor suppressor genes and is one of the epigenetic alterations identified to be involved in tumorigenesis. Now, several types of epigenetic alterations appear to play roles complementary to genetic mutations in colorectal carcinogenesis and seem to contribute to the progression of cancer. Epigenetic alterations also increase the probability that genetic changes will lead to cancer initiation. So far, major epigenetic alterations have been categorized into four groups of dysregulations: 1) hypomethylation with oncogene activation and chromosomal instability, 2) hypermethylation with tumor suppressor gene silencing, 3) chromatin modifications, and 4) loss of imprinting (LOI). Especially, LOI is a common epigenetic variant and should have a field effect on the colon, making it more vulnerable to genetic insults. Genomic imprinting is parental-origin-specific allele silencing, a form of gene silencing that is epigenetic in origin and does not involving alterations in the DNA sequence but does involve methylation and other modifications that are heritable during cell division. LOI is the loss of parental-origin-specific marks, leading either to aberrant activation of a normally silent allele of a growth promoter gene or to silencing of the growth inhibitor allele. Most of the attention has been focused on LOI of the IGF2 (insulin-like growth factor II) gene in a Wilms' tumor and colorectal cancer. LOI of IGF2 involves abnormal activation of a normally silent maternally inherited allele and has been associated with personal and family history of colorectal cancer, supporting a role for LOI in carcinogenesis. LOI may be a valuable predictive marker of an individual's risk for colorectal cancer. Now, epigenetics and imprinting are emerging areas in the study of human-cancer genetics.
Alleles ; Base Sequence ; Carcinogenesis ; Cell Division ; Chromatin ; Chromosomal Instability ; Colon ; Colorectal Neoplasms* ; CpG Islands ; Epigenomics* ; Gene Silencing ; Genes, Tumor Suppressor ; Genetics ; Genomic Imprinting ; Genomic Instability ; Humans ; Methylation ; Microsatellite Instability ; Oncogenes ; Wilms Tumor

OBJECTIVE: Recent molecular genetic studies have revealed that two major types of genomic instabilities, chromosomal instability and microsatellite instability (MSI), exist in the endometrial carcinomas. Tumors with microsatellite mutator phenotype (MMP) are caused by defects in DNA mismatch repair genes. MMP tumors are believed to progress by accumulating frameshift mutations in coding microsatellite sequences of various cancer related genes including tumor suppressor genes, apoptosis related genes and DNA repair genes. Thus, the identification of the specific target genes in the MMP endometrial carcinomas is important for the elucidation of molecular pathogenesis of endometrial carcinomas. METHODS: We classified the MMP endometrial carcinomas and evaluated the frameshift mutations of the 11 genes containing coding microsatellite sequences by using 34 endometrial carcinomas and 4 MMP endometrial carcinoma cell lines. RESULTS: MSI was found in 6 of 34 endometrial carcinomas. In the endometrial carcinoma tissues, frequent mutations were found in TAF1B (68%), HT001 (50%), SLC23A1 (50%) and ACVR II (50%) in the MMP endometrial carcinoma tissues. The other 7 genes were infrequently mutated. Mutations of these target genes were more frequent in MMP endometrial carcinoma cell lines. CONCLUSION: we identified specific target genes in MMP endometrial carcinomas. These data demonstrate the mechanism of tumor progression in the MMP endometrial carcinomas.
Apoptosis ; Cell Line ; Chromosomal Instability ; Clinical Coding ; DNA Mismatch Repair ; DNA Repair ; Endometrial Neoplasms* ; Female ; Frameshift Mutation ; Genes, Tumor Suppressor ; Genomic Instability ; Microsatellite Instability ; Microsatellite Repeats* ; Molecular Biology ; Phenotype*

Lymphoma is one of the most common malignant tumor of the hematologic system. The genome instability is not only an important molecular basis for the development of lymphoma, but also has important value in the diagnosis and prognosis of lymphoma. There are 2 types of genome instability: Microsatellite instability (MSI/MIN) at gene level and chromosomal instability at chromosome level. Through the study on genes associated with lymphoma, the unstable genes associated with lymphoma could be found, meanwhile the mechanism of its occurrence and development of lymphoma could be explored, and the important basis of molecular biology could also be provided in the field of current hot lymphoma precision medical research.
Genomic Instability ; Humans ; Lymphoma/genetics* ; Microsatellite Instability ; Microsatellite Repeats ; Neoplasms

Colorectal cancers results from the progressive accumulation of genetic and epigenetic alterations that lead to cellular transformation and tumor progression. Genomic instability, including chromosomal translocations and microsatellite instability, plays a role in acquisition of enough mutations for malignant transformation. In addition, epigenetic silencing is an important mechanism in the evolution of a subgroup of colorectal cancers. These genetic and epigenetic changes causes activation of oncogene pathway (APC, KRAS) and inactivation of tumor-suppressor pathway (p53, TGF-beta). Recent advance in colorectal carcinogenensis leads to development of molecular markers for early detection and predictive and prognostic markers.
Colorectal Neoplasms ; Epigenomics ; Genetic Markers ; Genomic Instability ; Microsatellite Instability ; Oncogenes ; Translocation, Genetic

Pulmonary carcinoids are infrequent neoplasms of the lung that normally display a less aggressive biological behavior compared to small cell and non-small cell lung cancers. Approximately 15-25% of carcinoids, in particular atypical carcinoids, show lymph node metastasis and have a worse prognosis than their non-metastasized counterparts. To date, there is no morphological or molecular marker that may help to differentiate between carcinoids that metastasize and carcinoids of identical differentiation that show only local tumor growth. In this study, we analyzed 7 metastasized and 10 non-metastasized pulmonary carcinoids for chromosomal and microsatellite instability in order to determine whether microsatellite instability or chromosomal imbalances are associated with metastasis. Due to the rare occurrence of metastasized carcinoids we compared our results of chromosomal instability with the hitherto published comparative genomic hybridization (CGH) profiles of pulmonary carcinoids, for which information about the absence or presence of metastasis was available. While microsatellite instability was not detected we found chromosomal instability as a common event in pulmonary carcinoids with an increase of frequency and extent of chromosomal alterations in atypical and metastasized carcinoids. These findings are in accordance with the collected and herein compiled data of previous studies and indicate increasing numbers of chromosomal imbalances to play a role in the sequential process of tumor development and metastasis.
Carcinoid Tumor/*genetics/pathology/*secondary ; Chromosomal Instability/*genetics ; Comparative Genomic Hybridization ; Humans ; Lung Neoplasms/*genetics/pathology ; Lymphatic Metastasis ; Prognosis

Pulmonary carcinoids are infrequent neoplasms of the lung that normally display a less aggressive biological behavior compared to small cell and non-small cell lung cancers. Approximately 15-25% of carcinoids, in particular atypical carcinoids, show lymph node metastasis and have a worse prognosis than their non-metastasized counterparts. To date, there is no morphological or molecular marker that may help to differentiate between carcinoids that metastasize and carcinoids of identical differentiation that show only local tumor growth. In this study, we analyzed 7 metastasized and 10 non-metastasized pulmonary carcinoids for chromosomal and microsatellite instability in order to determine whether microsatellite instability or chromosomal imbalances are associated with metastasis. Due to the rare occurrence of metastasized carcinoids we compared our results of chromosomal instability with the hitherto published comparative genomic hybridization (CGH) profiles of pulmonary carcinoids, for which information about the absence or presence of metastasis was available. While microsatellite instability was not detected we found chromosomal instability as a common event in pulmonary carcinoids with an increase of frequency and extent of chromosomal alterations in atypical and metastasized carcinoids. These findings are in accordance with the collected and herein compiled data of previous studies and indicate increasing numbers of chromosomal imbalances to play a role in the sequential process of tumor development and metastasis.
Carcinoid Tumor/*genetics/pathology/*secondary ; Chromosomal Instability/*genetics ; Comparative Genomic Hybridization ; Humans ; Lung Neoplasms/*genetics/pathology ; Lymphatic Metastasis ; Prognosis

Multiple genetic alterations are common prerequisite for carcinogenesis including colorectal cancers (CRCs). Recently, mutations within microsatellites have been described as a result of defective DNA mismatch repair (MMR) mechanisms, resulting in the phenomenon of microsatellite instability (MSI). This has been implicated in the etiology of hereditary non-polyposis colorectal cancer (HNPCC) and significant portions of sporadic colorectal cancers. However, the mechanisms underlying the MSI are different from hereditary CRCs and sporadic CRCs. While the germline mutation of MMR genes is responsible for HNPCC, the hypermethylation of MLH1 gene promoter regions, an epigenetic, not inherited alteration is responsible for most sporadic CRCs showing MSI. MSI tumors exhibit characteristic clinco- pathologic features, i.e, tumors are preferentially located to proximal to splenic flexure, poorly differentiated, mucinous cell type, frequently showing peritumoral lymphocytic infiltration, and, of importance, showing better survival in stage- matched cases. In this article, the results of recent investigations about MSI and its clinical applications are comprehensively reviewed. Knowledge of these biochemical mechanisms are likely to lead to more effective diagnosis and therapy of CRCs in the future
Carcinogenesis ; Colon, Transverse ; Colorectal Neoplasms ; Diagnosis ; DNA Mismatch Repair ; Epigenomics ; Genomic Instability* ; Germ-Line Mutation ; Microsatellite Instability ; Microsatellite Repeats ; Mucins ; Promoter Regions, Genetic

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.
Carcinogenesis ; DNA ; Genes, Tumor Suppressor ; Genomic Instability ; Loss of Heterozygosity ; Lung Neoplasms* ; Lung* ; Microsatellite Instability* ; Microsatellite Repeats* ; Phenotype ; Prognosis ; Small Cell Lung Carcinoma

PURPOSE: Genomic instability of microsatellite in patients with defects in the mismatch repair system of DNA resulting in replication error (RER) has a high risk of accumulating mutations in oncogene and tumor suppressor gene. In this study, we evaluated the incidence of microsatellite instability (MI) in renal cell carcinoma (RCC) by comparing polymerase chain reaction (PCR)-amplified sequences from frozen samples of normal and tumor tissue from affected patients. MATERIALS AND METHODS: Analysis of MI using the PCR based assay was performed in total 25 cases of RCC, including 21 clear cell types and 4 papillary types. MI of tumor DNA was observed as the occurrence of additional or absence of constitutional autoradiographic signals, or as at least a two to threefold increase or decrease of intensity of the autographic signals in comparison to the corresponding normal tissue DNA. Total 11 microsatellite loci were studied; 4 loci at 3p (D3S1274, D3S1296, D3S1300, D3S1313), 3 loci at 9p (IFNA, D9S1747, D9S171) and 4 loci at 17p (D17S513, D17S695, TP53, D17S261). RESULTS: Twenty-one of 25 RCC (84%) displayed MI in at least one informative locus. MI was found in 15 of 25 cases (60%) at 3p region and 7 of 25 cases (28%) at 9p region. All of them were clear cell type of RCC. MI was detected in 11 cases (44%) at 17p region, 7 of them were clear cell type. In all 4 cases of papillary type, MI was observed only at 17p region. CONCLUSIONS: These results suggest that alterations of 3p region might occur in the early stage of tumorigenesis in RCC. The DNA mismatch repair system may play an important role in tumorigenesis of RCC and MI analysis could be a useful method to detect early genetic alterations in RCC. Genetic alterations in tumorigenesis of RCC may have some differences according to the histologic characteristics.
Carcinogenesis ; Carcinoma, Renal Cell* ; DNA ; DNA Mismatch Repair ; Genes, Tumor Suppressor ; Genomic Instability ; Humans ; Incidence ; Microsatellite Instability ; Microsatellite Repeats* ; Oncogenes ; Polymerase Chain Reaction