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

53BP1 is an important genome stability regulator, which protects cells against double-strand breaks. Following DNA damage, 53BP1 is rapidly recruited to sites of DNA breakage, along with other DNA damage response proteins, including gamma-H2AX, MDC1, and BRCA1. The recruitment of 53BP1 requires a tandem Tudor fold which associates with methylated histones H3 and H4. It has already been determined that the majority of DNA damage response proteins are phosphorylated by ATM and/or ATR after DNA damage, and then recruited to the break sites. 53BP1 is also phosphorylated at several sites, like other proteins after DNA damage, but this phosphorylation is not critically relevant to recruitment or repair processes. In this study, we evaluated the functions of phosphor-53BP1 and the role of the BRCT domain of 53BP1 in DNA repair. From our data, we were able to detect differences in the phosphorylation patterns in Ser25 and Ser1778 of 53BP1 after neocarzinostatin-induced DNA damage. Furthermore, the foci formation patterns in both phosphorylation sites of 53BP1 also evidenced sizeable differences following DNA damage. From our results, we concluded that each phosphoryaltion site of 53BP1 performs different roles, and Ser1778 is more important than Ser25 in the process of DNA repair.
DNA ; DNA Damage ; DNA Repair ; Genomic Instability ; Histones ; Phosphorylation ; Proteins

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

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

BACKGROUND: Telomerase is a ribonucleoprotein complex with RNA-dependent DNA polymerase which is necessary in maintenance of the length of chromosome, and therefore, in preventing genomic instability. Its activity is regarded as an indicator of cell immortalization. So far, there is no comprehensive answer on which step the telomerase activity is required; in some studies, telomerase activity has been found in benign, premalignant, and malignant conditions equally, which means it affects early stage of carcinogenesis, but in other studies, it has been found in malignant conditions at a higher rate. OBJECTIVE: This study was performed to examine telomerase activity in normal and skin cancer tissues and to assess the role of telomerase in the development of malignant transformation of skin cancer by examining benign, premalignant, and malignant conditions together. METHODS: Telomerase activities in four benign skin tumors, five precancerous lesions, and 17 skin cancer tissues of the skin were measured by a method telomeric repeat amplification protocol(TRAP). TRAP assay was also performed on normal control tissue of the same patients and eight skin tissues of the healthy volunteers. RESULTS: Telomerase activity was detected in 50% of benign tumors, 100% of precancerous, and 82% of malignant tissues. Among them, three out of four BCC tissues were shown to contain telomerase activity, whereas normal tissue of the same patients were not. No telomerase activity was detected in all of the eight skin samples of the healthy volunteers. CONCLUSION: Telomerase activities may be required at early stage of tumorigenesis as these activities are required for further steps down of the oncogenesis.
Carcinogenesis ; Genomic Instability ; Healthy Volunteers ; Humans ; Ribonucleoproteins ; RNA-Directed DNA Polymerase ; Skin Neoplasms ; Skin* ; Telomerase*

Cellular senescence is a mechanism that induces an irreversible growth arrest in all somatic cells. Senescent cells are metabolically active but lack the capacity to replicate. Evolutionary theories suggest that cellular senescence is related to the organismal decline occurring in aging organisms. Also, such theories describe senescence as an antagonistically pleiotropic process that can have beneficial or detrimental effect on the organism. Cellular senescence is believed to be involved in the cellular changes observed as aging progresses. Accumulation of senescent cells appears to occur widely as the organism ages. Furthermore, senescence is a key element of the tumor suppressor pathways. Therefore, it is part of the natural barrier against the uncontrolled proliferation observed in cellular development of malignancies in multicellular organisms. Activation of the senescence process guarantees a limited number of cellular replications. The genetic network led by p53 is responsible for activation of senescence in response to DNA damage and genomic instability that could lead to cancer. A better comprehension of the genetic networks that control the cell cycle and induce senescence is important to analyze the association of senescence to longevity and diseases related to aging. For these reasons, experimental research both in vitro and in vivo aims to develop anticancer therapies based on senescence activation. The last decade of research on role and function of senescence in aging and cancer are discussed in this paper.
Aging ; Cell Aging ; Cell Cycle ; Comprehension ; DNA Damage ; Genomic Instability ; Longevity ; Telomere

Chronic myeloid leukemia (CML) is a myeloproliferative disorder, characterized by excessive proliferation of myeloid cells. CML patients in early phase [also known as chronic phase (CP)] usually respond to treatment with tyrosine kinase inhibitors (TKI), some patients respond initially to TKI, but later become resistant, then resulting in the transformation from CP to more advanced phase, which were subclassified as either accelerated phase or blastic phase. At present, the molecular mechanisms of CML have been not yet clear, and acute transformation has been not fully understood, studies have shown that genomic instability promotes the acute conversion of CML. This review discusses the molecular mechanisms leading to the transformation of CML, and some therapeutic approaches.
Blast Crisis ; Drug Resistance, Neoplasm ; Genomic Instability ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Colorectal cancer (CRC) arise from multi-step carcinogenesis due to genetic mutations and epigenetic modifications of human genome. Genetic mutations and epigenetic modifications were originally established as 2 independent mechanisms contributing to colorectal carcinogenesis. However, recent evidences demonstrate that there are interactions between these 2 mechanisms. Genetic mutations enable disruption of epigenetic controls while epigenetic modifications can initiate genomic instability and carcinogenesis. This review summarized genetic mutations and epigenetic modifications in colorectal carcinogenesis and molecular classification of CRC subtype based on genetic or epigenetic biomarkers for treatment response and prognosis. Molecular subtypes of CRC will permit the implementation of precision medicine with better outcome of management for CRC.
Biomarkers ; Carcinogenesis ; Classification ; Colorectal Neoplasms* ; Epigenesis, Genetic ; Epigenomics* ; Genome, Human ; Genomic Instability ; Humans ; Precision Medicine ; Prognosis

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

BACKGROUND/AIMS: The pattern of chromosomal gains and losses in HCC with hepatitis B in Korean patients is very complex and involves virtually every site in the genome. This study was done to know the chromosomal aberrations in hepatocellular carcinoma with HBV and relationship between these lesions and previously known oncogenes and tumor suppressor genes. METHODS: DNA changes in 23 hepatocellular carcinomas (HCC) associated with hepatitis B virus (HBV) were analyzed by CGH technique. RESULTS: Eighteen of the 23 cases showed genetic alterations. The remaining 5 cases showed no detectable aberrations. The losses of chromosome regions 17p (74%), 4q (57%), 16p (52%), 16q (48%), 8p (43%) and 13q (43%) were detected in the order of decreasing frequency. In cases of multiple losses of chromosomes, a combination of 17p, 16p, 16q, 4q, and 8p losses was found in 5 cases (30%). On the other hand, chromosomal gains occurred on 1q (65%), 8q (52%), 20p (48%) and 20q (43%) in the order of decreasing frequency. And the simultaneous genomic gains of these 4 chromosomes were found in 9 cases (40%). Moreover, the combination of 5 genomic losses (17p, 16p, 16q, 4q, & 8p) and 4 genomic gains (1q, 8q, 20p, & 20q) was observed in 4 cases (23%). CONCLUSIONS: The pattern of chromosomal gains and losses in HCC with hepatitis B in Korean patients is very complex and involves virtually every site in the genome. This indicates a high genomic instability. This could possibly be explained either as the result of random chromosomal changes during early development of tumor, or as the highly variable and random pattern of integration of HBV in the HCC. The hepatocarcinogenesis may be the result of cumulative effects rather than those orders of occurrence of those genomic changes. The sites of cellular DNA at which HBV integrates frequently undergo rearrangements, resulting in translocations, inverted duplications, deletions, and possibly recombinational events. But, CGH only detects changes of chromosomal copy number but could not identify translocations, inversions, and other aberrations of chromosome. The chromosomal analysis of HCC with HBV in Korean patients by CGH technique confirms the presence of complex and sporadic, but nonrandom genetic changes in the chromosome. In the future, more detailed oncogenic study could be carried out on the chromosomes which showed abnormal aberrations through this study.
Carcinoma, Hepatocellular* ; Chromosome Aberrations* ; Comparative Genomic Hybridization ; DNA ; Genes, Tumor Suppressor ; Genome ; Genomic Instability ; Hand ; Hepatitis B ; Hepatitis B virus ; Humans ; Oncogenes