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Genetic Instability (genetic + instability)
Selected AbstractsGenetic instabilities of (CCTG)·(CAGG) and (ATTCT)·(AGAAT) disease-associated repeats reveal multiple pathways for repeat deletionMOLECULAR CARCINOGENESIS, Issue 4 2009Sharon F. Edwards Abstract The DNA repeats (CTG)·(CAG), (CGG)·(CCG), (GAA)·(TTC), (ATTCT)·(AGAAT), and (CCTG)·(CAGG), undergo expansion in humans leading to neurodegenerative disease. A genetic assay for repeat instability has revealed that the activities of RecA and RecB during replication restart are involved in a high rate of deletion of (CTG)·(CAG) repeats in E. coli. This assay has been applied to (CCTG)·(CAGG) repeats associated with myotonic dystrophy type 2 (DM2) that expand to 11,000 copies and to spinocerebellar ataxia type 10 (SCA10) (ATTCT)·(AGAAT) repeats that expand to 4500 copies in affected individuals. DM2 (CCTG)·(CAGG) repeats show a moderate rate of instability, less than that observed for the myotonic dystrophy type 1 (CTG)·(CAG) repeats, while the SCA10 (ATTCT)·(AGAAT) repeats were remarkably stable in E. coli. In contrast to (CTG)·(CAG) repeats, deletions of the DM2 and SCA10 repeats were not dependent on RecA and RecB, suggesting that replication restart may not be a predominant mechanism by which these repeats undergo deletion. These results suggest that different molecular mechanisms, or pathways, are responsible for the instability of different disease-associated DNA repeats in E. coli. These pathways involve simple replication slippage and various sister strand exchange events leading to deletions or expansions, often associated with plasmid dimerization. The differences in the mechanisms of repeat deletion may result from the differential propensity of these repeats to form various DNA secondary structures and their differential proclivity for primer,template misalignment during replication. © 2009 Wiley-Liss, Inc. [source] Genomic instability in giant cell tumor of bone.GENES, CHROMOSOMES AND CANCER, Issue 6 2009A study of 52 cases using DNA ploidy, array-CGH analysis, relocalization FISH Genetic instability in relation to clinical behavior was studied in 52 cases of giant cell tumor of bone (GCTB). Ploidy was determined in the mononuclear cell population by using native cell smears and image cytometry. A relocalization technique allowed fluorescent in situ hybridization (FISH) analysis of CD68-negative neoplastic cells for numerical changes of chromosomes X, 3, 4, 6, 11, and telomeric association on 11p. Genome-wide alterations were tested using array comparative genomic hybridization (array-CGH) on magnetically separated CD68-negative tumor cells. CTNNB1, TP53, and BCL2 protein expression was also analyzed in formol-paraffin sections to see if their pathways are involved in the development of chromosomal instability. CD68-positive histiocytes showed no significant numerical chromosome and telomeric alterations. Based on ploidy values and clinical outcome, we could distinguish five groups as follows: diploid nonrecurrent (n = 20), tetraploid nonrecurrent (n = 6), diploid recurrent (n = 5), tetraploid and/or aneuploid recurrent (n = 14), and malignant cases (n = 7). Random individual-cell aneusomy was significantly (P < 0.001) more frequent in the recurrent groups (36.01 ± 11.94%) than in the benign nonrecurrent cases (10.65 ± 3.66%). The diploid recurrent group showed significantly (P < 0.001) increased balanced aneusomy compared with the diploid nonrecurrent group and the tetraploid nonrecurrent group represented eusomic polysomy. Array-CGH and FISH showed clonal aberrations almost exclusively in the malignant group. None of the protein markers tested showed significant correlation with elevated aneuploidy/polysomy (P = 0.56). Our results show that ploidy determination combined with FISH analysis may help predicting recurrence potential of GCTB and suggest that chromosomal abnormalities superimposed on telomeric associations could be responsible for an aggressive clinical course. © 2009 Wiley-Liss,Inc. [source] Optimizing flow cytometric DNA ploidy and S-phase fraction as independent prognostic markers for node-negative breast cancer specimensCYTOMETRY, Issue 3 2001C.B. Bagwell Abstract Developing a reliable and quantitative assessment of the potential virulence of a malignancy has been a long-standing goal in clinical cytometry. DNA histogram analysis provides valuable information on the cycling activity of a tumor population through S-phase estimates; it also identifies nondiploid populations, a possible indicator of genetic instability and subsequent predisposition to metastasis. Because of conflicting studies in the literature, the clinical relevance of both of these potential prognostic markers has been questioned for the management of breast cancer patients. The purposes of this study are to present a set of 10 adjustments derived from a single large study that optimizes the prognostic strength of both DNA ploidy and S-phase and to test the validity of this approach on two other large multicenter studies. Ten adjustments to both DNA ploidy and S-phase were developed from a single node-negative breast cancer database from Baylor College (n = 961 cases). Seven of the adjustments were used to reclassify histograms into low-risk and high-risk ploidy patterns based on aneuploid fraction and DNA index optimum thresholds resulting in prognostic P values changing from little (P < 0.02) or no significance to P < 0.000005. Other databases from Sweden (n = 210 cases) and France (n = 220 cases) demonstrated similar improvement of DNA ploidy prognostic significance, P < 0.02 to P < 0.0009 and P < 0.12 to P < 0.002, respectively. Three other adjustments were applied to diploid and aneuploid S-phases. These adjustments eliminated a spurious correlation between DNA ploidy and S-phase and enabled them to combine independently into a powerful prognostic model capable of stratifying patients into low, intermediate, and high-risk groups (P < 0.000005). When the Baylor prognostic model was applied to the Sweden and French databases, similar significant patient stratifications were observed (P < 0.0003 and P < 0.00001, respectively). The successful transference of the Baylor prognostic model to other studies suggests that the proposed adjustments may play an important role in standardizing this test and provide valuable prognostic information to those involved in the management of breast cancer patients. Cytometry (Comm. Clin. Cytometry) 46:121,135, 2001. © 2001 Wiley-Liss, Inc. [source] Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesisENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2-3 2002Daniel Medina Abstract Mouse mammary tumorigenesis is greatly influenced by a variety of exogenous agents, such as MMTV, chemical carcinogens (i.e., polycyclic aromatic hydrocarbons), and radiation, as well as by endogenous/physiological factors, such as steroid hormones, tumor-suppressor genes (i.e., Brca1/2,p53), and gene products of modifier genes. In the mouse model, the most frequently used chemical carcinogen has been 7,12-dimethylbenz[a]anthracene (DMBA), which activates the Ha- ras gene but does not alter the p53 tumor-suppressor gene. However, on an existing background of p53 gene alteration, low doses of DMBA are strongly cocarcinogenic. Using a transgenic model system, in which the p53 gene was deleted in the mammary gland, we examined the carcinogenic effects of a variety of external agents and internal factors given at either low doses or physiological doses. These agents/factors included DMBA, ,-radiation, Brca2 heterozygosity, and steroid hormones. All agents/factors increased the tumorigenic response of the p53 null mammary cells, even under conditions where no tumorigenic response was observed in the p53 wildtype mammary cell. The strongest cocarcinogenic effect was observed with the steroid hormone progesterone. The majority of tumors were highly aneuploid and composed of nuclear igh-grade cells. The mechanism for the aneuploidy and secondary events associated with high tumorigenicity were examined using array technology. These results demonstrate that, on a background of underlying genetic instability, very low doses of environmental mutagens and mitogens can produce strong cocarcinogenic effects. Environ. Mol. Mutagen. 39:178,183, 2002. © 2002 Wiley-Liss, Inc. [source] Multiple forms of genetic instability within a 2-Mb chromosomal segment of 3q26.3,q27 are associated with development of esophageal adenocarcinomaGENES, CHROMOSOMES AND CANCER, Issue 4 2006Lin Lin Gene amplification is one of the mechanisms to activate oncogenes in many cancers, including esophageal adenocarcinoma (EA). In the present study, we used two-dimensional restriction landmark genome scanning to clone a NotI/DpnII fragment that showed increased genomic dosage in 1 of 44 EAs analyzed. This fragment maps to 3q26.3,q27, and subsequent experiments identified two intrachromosomal amplicons within a 10-Mb DNA segment in 7 of 75 (9%) EAs. The distal amplified-core region maps centromeric to the PIK3CA locus, and a microsatellite (D3S1754) within this region exhibited significant instability (MSI), in stark contrast to the genomewide microsatellite stability found in EA. D3S1754-MSI arises in premalignant Barrett's dysplastic cells and preceded amplification of the nascent MSI allele in the corresponding EA. Seven ESTs within the amplified-core were overexpressed in amplicon-containing EAs. One of these, EST AW513672, represents a chimeric transcript that initiated from an antisense promoter sequence in the 5,UTR of a full-length LINE-1 element (L1-5,ASP). Similar chimeric transcripts encoding portions of the MET oncogene and the BCAS3 gene also were overexpressed in EAs, suggesting that L1-5,ASP activation may occur at a broad level in primary EAs. Thus, the fine dissection of a 2-Mb amplified DNA segment in 3q26.3,q27 in EA revealed multiple genetic alterations that had occurred sequentially and/or concurrently during EA development. This article has supplementary material, available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. © 2005 Wiley-Liss, Inc. [source] Intrinsic genetic instability of normal human lymphocytes and its implication for loss of heterozygosityGENES, CHROMOSOMES AND CANCER, Issue 4 2001Arnolda G. de Nooij-van Dalen A combination of flow cytometry and microsatellite analysis was used to investigate loss of expression of HLA-A and/or HLA-B alleles and concurrent LOH at polymorphic chromosome 6 loci both in freshly isolated lymphocytes (in vivo mutations) and in lymphocytes cultured ex vivo. The fraction of in vivo mutants that showed LOH at 6p appeared to vary from 0%,49% for various donors. During culturing ex vivo, HLA-A, cells arose at a high rate and showed simultaneous loss of expression at the linked HLA-B locus. Up to 90% of the ex vivo arisen HLA-A2, cell population showed LOH of multiple 6p markers, and 50% had lost heterozygosity at 6q. This ex vivo spectrum resembles that found in HLA-A2 mutants obtained from lymphoblastoid cells. The HLA-A2 mutants present in vivo may reflect only a small fraction of the mutants that can be detected ex vivo. In normal lymphocytes, in vivo only mitotic recombination appears to be sustained, indicating the importance of this mechanism for tumor initiation in normal cells. Although mutations resulting in LOH at both chromosome 6 arms were shown to result in nonviable cells in normal lymphocytes, they have been shown to result in viable mutants in lymphoblastoid cells. We hypothesize that these types of mutations also occur in vivo but only survive in cells that already harbor a mutated genetic background. In light of the high rate at which these types of mutations occur, they may contribute to cancer progression. © 2001 Wiley-Liss, Inc. [source] Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1,HEPATOLOGY, Issue 5 2008Silvia Martin-Lluesma Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), but its role in the transformation process remains unclear. HBV encodes a small protein, known as HBx, which is required for infection and has been implicated in hepatocarcinogenesis. Here we show that HBx induces lagging chromosomes during mitosis, which in turn leads to formation of aberrant mitotic spindles and multinucleated cells. These effects require the binding of HBx to UV-damaged DNA binding protein 1 (DDB1), a protein involved in DNA repair and cell cycle regulation, and are unexpectedly attributable to HBx interfering with S-phase progression and not directly with mitotic events. HBx also affects S-phase and induces lagging chromosomes when expressed from its natural viral context and, consequently, exhibits deleterious activities in dividing, but not quiescent, hepatoma cells. Conclusion: In addition to its reported role in promoting HBV replication, the binding of HBx to DDB1 may induce genetic instability in regenerating hepatocytes and thereby contribute to HCC development, thus making this HBV,host protein interaction an attractive target for new therapeutic intervention. (HEPATOLOGY 2008.) [source] Mismatch repair expression in testicular cancer predicts recurrence and survivalINTERNATIONAL JOURNAL OF CANCER, Issue 8 2008Alfredo Velasco Abstract We investigated mismatch repair (MMR) gene expression in testicular cancer as a molecular marker for clinical outcome (recurrence, response to chemotherapy and death) using protein expression and specific genetic alterations associated with the presence or absence of MMR activity. One hundred sixty-two cases of paraffin-embedded testis cancer specimens were subjected to immunohistochemical analysis using monoclonal antibody for MLH1 and MSH2 MMR proteins and genetic analysis using specific polymorphic markers. The degree of MMR immunoreactivity and genetic instability in the form of loss of heterozygosity (LOH) and/or microsatellite instability (MSI) were determined by comparing matched normal and tumor tissue. The degree of immunohistochemical staining for MMR expression was associated with a shorter time to tumor recurrence, resistance to chemotherapy and death. Furthermore, clinical relapse and cancer specific death was also associated with tumors exhibiting a high degree of MSI, p = 0.01 and 0.04, respectively. In contrast, LOH was not associated with recurrence, resistance to chemotherapy or death. Therefore, MMR expression defines testis cancers with distinct molecular properties and clinical behavior, such that tumors with decreased MMR immunostaining and/or increased frequency of MSI have a shorter time to recurrence and death despite chemotherapy. © 2007 Wiley-Liss, Inc. [source] Embryonic reversions and lineage infidelities in tumour cells: genome-based models and role of genetic instabilityINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 2 2005Leon P. Bignold Summary Reversions to ,embryonic precursor'-type cells and infidelities of tumour cell lineage (including metaplasias) have been recognized as aspects of various tumour types since the 19th century. Since then, evidence of these phenomena has been obtained from numerous clinical, biochemical, immunological and molecular biological studies. In particular, microarray studies have suggested that ,aberrant' expressions of relevant genes are common. An unexplained aspect of the results of these studies is that, in many tumour types, the embryonic reversion or lineage infidelity only occurs in a proportion of cases. As a parallel development during the molecular biological investigation of tumours over the last several decades, genetic instability has been found much more marked, at least in some preparations of tumour cells, than that identified by means of previous karyotypic investigations of tumours. This study reviews examples of embryonic reversion and lineage infidelity phenomena, which have derived from the various lines of investigation of cancer over the last 150 or so years. Four categories of circumstances of the occurrence of embryonic reversions or lineage infidelities have been identified , (i) as part of the defining phenotype of the tumour, and hence being presumably integral to the tumour type, (ii) present ab initio in only some cases of the tumour type, and presumably being regularly associated with, but incidental to, the essential features of the tumour type, (iii) occurring later in the course of the disease and thus being possibly a manifestation of in vivo genetic instability and ,tumour progression' and (iv) arising probably by genetic instability, during the processes, especially cell culture, associated with ex vivo investigations. Genomic models are described which might account for the origin of these phenomena in each of these circumstances. [source] Cutaneous sebaceous neoplasms as markers of Muir-Torre syndrome: a diagnostic algorithmJOURNAL OF CUTANEOUS PATHOLOGY, Issue 6 2009Ossama Abbas Sebaceous gland neoplasms such as adenoma, epithelioma, and carcinoma are uncommon cutaneous tumors. Although sporadic, their occurrence is clinically significant because of their association with Muir-Torre syndrome (MTS). MTS is a rare autosomal dominant genodermatosis characterized by the occurrence of sebaceous gland neoplasms and/or keratoacanthomas associated with visceral malignancies that include gastrointestinal and genitourinary cancers. MTS is usually the result of germline mutation in one or more of the DNA mismatch repair (MMR) genes. MMR genes commonly implicated include MSH -2 and MLH -1 and, more recently, MSH -6. Recent evidence suggests that immunohistochemistry is very sensitive and effective in detecting these defects in cutaneous tumors in MTS. In addition, the genetic instability of cutaneous and visceral tumors in MTS caused by the defects in MMR genes can also be detected, using polymerase chain reaction (PCR)-based techniques, for microsatellite instability (MSI). Given that some sebaceous neoplasms represent cutaneous markers of MTS, what should we as dermatopathologists be advocating? Should we be looking for absence/loss of MMRs in all sebaceous neoplasms? When should we recommend assaying for MSI? This review attempts to address all of these issues with a view to streamlining the work-up of a patient presenting for the first time with a sebaceous neoplasm and no prior personal or family history of internal malignancies. [source] Evaluation of premalignant potential in oral lichen planus using interphase cytogeneticsJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 2 2001Jin Kim Abstract: This study attempted to evaluate whether oral lichen planus (OLP) has the potential to progress to oral squamous cell carcinoma (OSCC) by comparing the degree of genetic instability between clinically-curable OLP and lesions that progressed to OSCC. Fifteen cases of steroid-responsive OLP and two cases of lichenoid dysplasia (LD) that progressed to OSCC were used for this study. Chromosome in situ hybridization (CISH) was performed for chromosomes 9 and 17. The fraction of polysomic and monosomic cells for chromosome 9 increased in mucosal epithelium compared to those of lymphocytes in OLP. This difference was statistically significant (P=0.0017, 0.0054, respectively). Two LD patients showed 15.38% and 22.58% of PI for chromosome 9. In OSCC that developed from LD, the fraction of monosomic cells for chromosome 9 increased by more than 70%. We concluded that LD should be treated as a high-risk premalignant lesion and strongly suggest that the monosomy of chromosome 9 may have a critical role in progress to malignancy from LD. [source] Transcriptional processing of G4 DNAMOLECULAR CARCINOGENESIS, Issue 4 2009Silvia Tornaletti Abstract Genomic DNA sequences with the ability to assume non-B form secondary structures have been recently shown to be particularly susceptible to genetic instability, an early contributing factor in human disease and cancer development. Transcription appears to play a central role in formation of these structures and in promoting instability at these sites. The subpathway of nucleotide excision DNA repair, transcription-coupled DNA repair (TCR), removes transcription-arresting damage from the transcribed strands of expressed genes, but little is known about how non-canonical DNA structures are processed when encountered by the transcription machinery. If such structures arrest transcription, they may elicit "gratuitous" TCR in which the resulting reiterative and futile repair replication might generate a significant level of mutagenesis in a frequently transcribed gene because of faulty processing in the area of transcription arrest. Here we will describe our current understanding of how TCR may be elicited at non-B DNA structures and summarize recent literature describing the behavior of RNA polymerases when encountering non-canonical DNA structures, with particular emphasis on quadruplex DNA. © 2009 Wiley-Liss, Inc. [source] A possible link between the pubertal growth of girls and breast cancer in their daughtersAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 2 2008David J.P. Barker One hypothesis for the origins of breast cancer is that it is initiated by exposure of developing breast tissue in utero to maternal sex hormones. The sex hormone profile is established at puberty, when it regulates growth of the pelvic bones. The pubertal growth of girls is characterized by broadening and rounding of the pelvis. The maximal width between their iliac crests, the intercristal width, increases more rapidly than in boys. We hypothesized that higher sex hormone concentrations at puberty produce larger intercristal widths, and these are markers of increased breast cancer risk in the next generation. We followed up 6,370 women who were born in Helsinki during 1934,1944, and whose mothers' pelvic bones were measured during routine antenatal care. Women whose mothers had large intercristal widths had higher rates of breast cancer. In those born at or after 40 weeks gestation, the hazard ratio for breast cancer was 3.7 (95% CI: 2.1,6.6) if their mother's intercristal width was greater than 30 cm. Among women born to multiparous mothers this hazard ratio rose to 7.2 (3.4,15.4). Hazard ratios for breast cancer were also higher in the daughters of mothers with round iliac crests. Pelvic bone measurements which increase similarly in girls and boys at puberty did not predict breast cancer. We conclude that the intercristal width, and the roundness of the iliac crests, are markers of mothers' sex hormones, and postulate that high concentrations cause genetic instability in differentiating breast cells in their daughters in utero. Am. J. Hum. Biol., 2008. © 2007 Wiley-Liss, Inc. [source] JNK is constitutively active in mantle cell lymphoma: cell cycle deregulation and polyploidy by JNK inhibitor SP600125,THE JOURNAL OF PATHOLOGY, Issue 1 2009Miao Wang Abstract Mantle cell lymphoma (MCL) is characterized by genetic instability and a poor prognosis. Many blastoid variants are (hypo)tetraploid and have an even worse prognosis. We investigated the role of signalling by mitogen-activated protein kinases (MAPKs) in MCL. As compared to normal tonsil B cells, MCL cells showed higher activation of the JNK MAPK in both an MAPK array and a sandwich ELISA assay. Immunohistochemistry showed overexpression of phospho (p)-JNK (Thr183/Tyr185) in 30 of 37 MCL cases. Inhibition of p-JNK with SP600125 resulted in growth arrest in all four MCL cell lines (Jeko-1, HBL-2, UPN-1, Granta-519), which could be partly reversed by the addition of CD40L and IL-4. Furthermore, SP600125 led to G2/M phase arrest on day 1 and a striking increase in endoreduplication on day 2 and day 3, which was confirmed by karyotype analysis. G2/M arrest was associated with down-regulation of EGR1 and p21 protein expression. SP600125-induced polyploidy could be blocked by the BCL-2 inhibitor YC137. These data suggest that constitutive JNK activity is necessary to promote proliferation and maintain diploidy in MCL. JNK inhibition leads to cell cycle deregulation and endoreduplication, mimicking the tetraploid state seen in a subset of MCL cases. Thus, our data also provide an experimental model to study polyploid MCL cells. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Grading gastrointestinal dysplasia and what to call it when you don't know what it is,THE JOURNAL OF PATHOLOGY, Issue 2 2007GJ Offerhaus Abstract Dysplasia in the gastrointestinal tract is defined as intraepithelial neoplasia (IEN) according to the WHO nomenclature. Neoplastic growth in the gastrointestinal tract evolves through stepwise tumour progression in which consecutive morphological stages are characterized by increasing genetic instability accompanied by specific genetic alterations. Invasive cancer is preceded by non-invasive precursor stages and the clonal epithelial cell proliferation in these pre-invasive stages is diagnosed as dysplasia or IEN. Dysplasia is therefore a marker for cancer risk and guides surveillance. Dysplasia is conventionally graded using a two-tier system and low- and high-grade dysplasia convey different connotations regarding cancer risk. This perspective argues that the critical differential diagnosis is the one between neoplastic and non-neoplastic epithelial cell proliferations and the relevance of grading dysplasia is questionable. It is furthermore expected that a molecular signature will predict the propensity to invasive carcinoma more accurately than routine histopathology in the near future. Research in this field needs to focus on a combination of biomarkers representing genetic instability, clonal mutations, and genetic clonal divergence. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Aurora-A over-expression in high-grade PIN lesions and prostate cancer,THE PROSTATE, Issue 4 2005Holly McKlveen Buschhorn Abstract BACKGROUND Over-expression of Aurora-A (Aurora 2 kinase, STK-15), a protein found in centrosomes thought to be associated with genetic instability, has been previously documented in prostate cancer [Pihan et al.: Cancer Res 61(5):2212,2219, 2001]. It is unknown if this protein is also over-expressed in high-grade prostatic intraepithelial neoplasia (PIN) lesions. METHODS PIN lesions were examined for increased Aurora-A using immunohistochemical staining on archival paraffin embedded prostatectomy tissue. Aurora-A expression was scored using size, number, and staining intensity. Protein expression was examined and compared between stromal cells, normal glands, high-grade PIN lesions, and invasive cancer. RESULTS Immunohistochemistry shows an increased expression of Aurora-A in 96% of high-grade PIN cases, and 98% in cancer lesions. Twenty-nine percent of cases of normal glands from cancerous prostates also showed increased Aurora-A expression. CONCLUSIONS Over-expression of Aurora-A is present in some normal and the majority of high-grade PIN lesions indicating that this may be an early event that leads to the genetic instability seen in prostate carcinogenesis. © 2005 Wiley-Liss, Inc. [source] Preliminary evidence that the allogeneic response might trigger antitumour immunity in patients with advanced prostate cancerBJU INTERNATIONAL, Issue 5 2006Gordon Muir OBJECTIVE To explore the possibility that allogeneic responses might, by chance, encompass cross-reactive T cell clones specific for neo-antigenic tumour determinants, and thereby activate antitumour immunity; such cross-reactions are well documented for antiviral immunity, and genetic instability in developing cancers generates many neo-antigenic determinants as potential targets for immune responses, but the biology inevitably favours tumour progression. PATIENTS AND METHODS Fourteen patients with hormone-refractory prostate cancer received full-thickness skin allografts from different, unrelated donors (fellow patients) until each had received six grafts. Serum prostate-specific antigen (PSA) level was used as a surrogate for tumour mass. RESULTS One patient had a remarkable decline in PSA level, with levels at 1 year lower than before grafting. A second patient had stable PSA levels for almost 2 years. A third patient had stable PSA levels for 10,12 months before they resumed an exponential rise. Of four patients with PSA levels of >10 ng/mL, three required surgery or radiotherapy for obstructive symptoms during or shortly after grafting. CONCLUSION Transplant rejection involves mechanistically atypical T cell recognition of allogeneic major histocompatibility complex antigens, with massive polyclonal T cell activation. This unique aspect of T cell biology might represent a novel approach for initiating cross-reactive antitumour responses. [source] Low frequency of microsatellite instability in hereditary prostate cancerBJU INTERNATIONAL, Issue 4 2001A.-K. Åhman Objective To investigate whether there is widespread microsatellite instability (MSI) in families with hereditary prostate cancer (HPC). Patients and methods Eighty-four prostate tumours from 80 Swedish men in 35 families with HPC were screened for genetic instability at microsatellite marker loci BAT-25, BAT-26, BAT-34C4, D2S123 and D17S250. Results MSI was detected in only five individuals from different families. Three tumours (4%) were unstable at more than two MSI loci and hence classified as high-frequency MSI (MSI-H) according to a previous definition. Interestingly, two of the MSI-H tumours were from patients in families with both HPC and familial colon cancer. Conclusions Widespread MSI is a rare event in hereditary prostate cancer, indicating that defective DNA mismatch repair is not an important element in the genesis of HPC. [source] Multiple myeloma patients with CKS1B gene amplification have a shorter progression-free survival post-autologous stem cell transplantationBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2006Hong Chang Summary The prevalence and prognostic relevance of recurrent gains of CKS1B (cyclin kinase subunit 1B) gene at chromosome 1q21 region was investigated by interphase fluorescence in situ hybridisation in a cohort of 99 multiple myeloma (MM) patients treated with intensive chemotherapy followed by autologous stem cell transplantation. CKS1B amplification (3,8 CKS1B signals) was detected in 31of 99 (31%) patients and was associated with deletions of p53 (P = 0·003) and 13q (P = 0·039) but not with translocation t(11;14) or t(4;14). CKS1B amplification was associated with bone marrow plasmacytosis (P = 0·02), but there was no correlation with patient age, gender, disease stage, lytic bone lesions, albumin, creatinine, C-reactive protein or beta-2 microglobulin levels. Patients with CKS1B amplification had a significantly shorter progression-free survival than those without such amplification (18·5 vs. 25·7 months, P = 0·035). Likewise, a shorter overall survival (44·8 months vs. not reached) was observed; however, the difference did not reach statistical significance (P = 0·20). Seven patients had paired bone marrows obtained at diagnosis and at relapse, the percentage of cells with CKS1B amplification and the level of amplification were significantly increased in the relapse marrows. In this cohort of patients, CKS1B was frequently amplified in MM and may represent genetic instability associated with disease progression. [source] Polymorphisms in ERCC2, MSH2, and OGG1 DNA repair genes and gallbladder cancer risk in a population of Northern IndiaCANCER, Issue 13 2010Kshitij Srivastava MSc Abstract BACKGROUND: Genetic variants of DNA repair enzymes may lead to genetic instability and contribute to gallbladder (GB) carcinogenesis. METHODS: A case-control study (230 GB carcinogenesis patients and 230 controls) was undertaken to evaluate whether genetic variations in 3 DNA repair genes ERCC2 (Asp312Asn [rs1799793] and Lys751Gln [rs13181]), MSH2 (,118T>C [rs2303425] and IVS1 + 9G>C [rs2303426]), and OGG1 (Ser326Cys [rs1052133] and 748-15C>G [rs2072668]) are associated with GB carcinogenesis risk in a North Indian population. RESULTS: The authors found that the ERCC2 Asp312Asn AA, MSH2 IVS1 + 9G>C CC, OGG1 Ser326Cys GG and CG + GG, and OGG1 748-15C>G GG and CG + GG genotypes were significantly associated with an increased risk of GB carcinogenesis (odds ratio [OR], 2.1, 1.8, 2.5, 1.8, 2.0, and 1.6, respectively). In contrast, ERCC2 Lys751Gln, and MSH2 ,118T>C markers showed no significant associations with GB carcinogenesis risk, although because of the small sample size their effects cannot be ruled out. Female GB carcinogenesis patients with the OGG1 748-15C>G GG, OGG1 Ser326Cys GG, and ERCC2 Asp312Asn genotypes had a greater risk for developing the disease (OR, 3.6, 7.7, and 2.7, respectively). There was a significant interaction between MSH2 IVS1 + 9G>C and OGG1 748-15C>G polymorphisms (P = .001). Furthermore, individuals with >6 variant alleles of the studied polymorphisms were at 4-fold increased risk for developing GB carcinogenesis. Classification and Regression Tree analysis revealed potential higher-order gene-gene interactions and categorized a few higher-risk subgroups for GB carcinogenesis. CONCLUSIONS: These results suggest that genetic variants in the DNA repair pathways may be involved in GB carcinogenesis etiology. Cancer 2010. © 2010 American Cancer Society. [source] Histopathologic characterization of radioactive iodine-refractory fluorodeoxyglucose-positron emission tomography-positive thyroid carcinomaCANCER, Issue 1 2008Michael Rivera MD Abstract BACKGROUND. Radioactive iodine-refractory (RAIR) 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) positive thyroid carcinomas represent the major cause of deaths from thyroid carcinomas (TC) and are therefore the main focus of novel target therapies. However, to the authors' knowledge, the histology of FDG-PET-positive RAIR metastatic thyroid carcinoma has not been described to date. METHODS. Metastatic tissue from RAIR PET-positive patients identified between 1996 and 2003 at the study institution were selected for histologic examination. The biopsied metastatic site corresponded to a FDG-PET positive lesion sampled within 2 years (87% of which were sampled within 1 year) of the PET scan. Detailed microscopic examination was performed on the metastatic deposit and the available primary tumors. Poorly differentiated thyroid carcinomas (PDTC) were defined on the basis of high mitotic activity (,5 mitoses/10 high-power fields) and/or tumor necrosis. Other types of carcinomas were defined by conventional criteria. The histology of the metastases and primary were analyzed, with disease-specific survival (DSS) as the endpoint. RESULTS. A total of 70 patients satisfied the selection criteria, 43 of whom had primary tumors available for review. Histologic characterization of the metastasis/recurrence in 70 patients revealed that 47.1% (n = 33 patients) had PDTC, 20% (n = 14 patients) had the tall cell variant (TCV) of papillary thyroid carcinoma, 22.9% (n = 16 patients) had well-differentiated papillary thyroid carcinoma (WDPTC), 8.6% (n = 6 patients) had Hurthle cell carcinoma (HCC), and 1.4% (n = 1 patient) had anaplastic carcinomas. The histopathologic distribution of the tumor in the primaries was: PDTC, 51%; TCV, 19%; WDPTC, 23%; and widely invasive HCC, 7%. A differing histology between the primary tumor and metastasis was observed in 37% of cases (n = 16 patients). In the majority of instances (63%; 10 of 16 patients) this was noted as transformation to a higher grade. Of the primary tumors classified as PTC, 70% progressed to more aggressive histotypes in the metastasis. Tumor necrosis and extensive extrathyroid extension in the primary tumor were found to be independent predictors of poorer DSS in this group of patients (P = .015). Approximately 68% of the PDTC primary tumors were initially classified by the primary pathologist as better-differentiated tumors on the basis of the presence of papillary and/or follicular architecture or the presence of typical PTC nuclear features. CONCLUSIONS. Several observations can be made based on the results of the current study. The majority of metastases in patients with RAIR PET-positive metastases are of a histologically aggressive subtype. However, well,differentiated RAIR metastatic disease is observable. Poorly differentiated disease is underrecognized in many cases if defined by architectural and nuclear features alone. The presence of tumor necrosis was found to be a strong predictor of aggressive behavior, even within this group of clinically aggressive tumors. Finally, there is a significant amount of histologic plasticity between primary tumors and metastases that may reflect the genetic instability of these tumors. Cancer 2008. © 2008 American Cancer Society. [source] Search for new biomarkers of gastric cancer through serial analysis of gene expression and its clinical implicationsCANCER SCIENCE, Issue 5 2004Wataru Yasui Gastric cancer is one of the most common human cancers and is the second most frequent cause of cancer-related death in the world. Serial analysis of gene expression (SAGE) is a powerful technique to allow genome-wide analysis of gene expression in a quantitative manner without prior knowledge of the gene sequences. SAGE on 5 samples of gastric cancer with different histology and clinical stages have created large SAGE libraries of gastric cancer that enable us to identify new cancer biomarkers. Commonly up-regulated genes in gastric cancer in comparison with normal gastric epithelia included CEACAM6, APOC1 and YF13H12. By comparing gene expression profiles of gastric cancers at early and advanced stages, several genes differentially expressed by tumor stage were also identified, including FUS, CDH17, COL1A1 and COL1A2, which should be novel genetic markers for high-grade malignancy. Regenerating gene type IV (REGIV) is one of the most up-regulated genes in a SAGE library of a scirrhous-type gastric cancer. In vitro studies using RegIV-transfected cells revealed that RegIV is secreted by cancer cells and inhibits apoptosis, suggesting that RegIV may serve as a novel biomarker and therapeutic target for gastric cancer. Production of RNA aptamers could be a useful approach to establish a detection system in blood. A custom-made array, named Ex-STO-MACHIP, consisting of 395 genes, including highly differentially expressed genes identified by our SAGE and other known genes related to carcinogenesis and chemosensitivity, is useful to study the molecular pathogenesis of gastric cancer and to obtain information about biological behavior and sensitivity to therapy in the clinical setting. Combined analyses of gene expression profile, genetic polymorphism and genetic instability will aid not only cancer detection, but also characterization of individual cancers and patients, leading to personalized medicine and cancer prevention. [source] Lack of Ku80 Alteration in Multiple MyelomaCANCER SCIENCE, Issue 4 2002Miyuki Kato Chromosomal rearrangement involving the immunoglobulin gene locus, as a result of marked chromosomal instability, is the hallmark of human multiple myeloma (MM) cells. Since Ku80 plays a key role in the non-homologous end-joining (NHEJ) system, we investigated whether Ku80 alteration contributes to this genetic instability by examining its status in 16 MM cell lines. Our study demonstrated a lack of Ku80 alterations at the protein, mRNA and gene level in 15 out of the 16 cell lines. Only the U266 cell line carried a missense mutation of Ser335Leu in one allele of the cDNA. Six marrow samples derived from myeloma patients also did not show any aberrant Ku80 protein, in terms of size. Accordingly, Ku80 alteration is unlikely to be involved in MM, in disagreement with a previous study reporting frequent presence of a 69-kD Ku80 variant (Ku86v) with reduced DNA binding activity in MM cells. [source] Mutations in the hMLH1 gene in Slovenian patients with gastric carcinomaCLINICAL GENETICS, Issue 5 2004P Hudler Alterations of multiple oncogenes and tumor suppressor genes, together with genetic instability, are responsible for carcinogenesis in gastric cancer. The microsatellite mutator phenotype is the cause of many somatic frameshift and point mutations in non-coding repetitive sequences and in coding regions associated with cell proliferation and apoptosis. Genetic mutations in hMLH1 and transcriptional silencing of its promoter by hypermethylation lead to the inactivation of the mismatch repair system. In our study, we screened for mutations the hMLH1 gene in patients expressing the microsatellite instability genotype by using single-strand conformational polymorphism analysis and direct sequencing. Seven changes were identified; of these, three (A92P, E433Q, and K618A) were germline mutations and the other four (IVS5 453 + 79 A > G, I219V, 1039 , 7 del (T)n, and IVS15 1668 , 19 A > G) germline polymorphisms. A92P and E433Q are novel, previously unidentified mutations. In addition, we found a rather complex distribution of mutations and polymorphisms in individual patients and in two cases also a methylated hMLH1 promoter. [source] | |||||||||||||||||||||||||