Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (10)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: PTER (cancer-related)
BACKGROUND: Long noncoding RNA HULC is highly up-regulation in human hepatocellular carcinoma (HCC). However, the functions of HULC in hepatocarcinogenesis remains unclear.
METHODS: RT-PCR, Western blotting, Chromatin immunoprecipitation (CHIP) assay, RNA Immunoprecipitation (RIP) and tumorignesis test in vitro and in vivo were performed.
RESULTS: HULC is negatively associated with expression of PTEN or miR15a in patients of human liver cancer. Moreover, HULC accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, HULC increasesthe expression of P62 via decreasing mature miR15a. On the other hand, excessive HULC increases the expression of LC3 on the level of transcription and then activates LC3 through Sirt1 (a deacetylase). Notably, HULC enhanced the interplay between LC3 and ATG3. Furthermore, HULC also increases the expression of becline-1(autophagy related gene). Therefore, HULC increases the cellular autophagy by increasing LC3II dependent on Sirt1.Noteworthy, excessive HULC reduces the expression of PTEN, β-catenin and enhances the expression of SAPK/JUNK, PKM2, CDK2, NOTCH1, C-Jun in liver cancer cells. Of significance, our observations also revealed that HULC inhibited PTEN through ubiquitin-proteasome system mediated by autophagy-P62.Ultimately,HULC activates AKT-PI3K-mTOR pathway through inhibiting PTEN in human liver cancer cells.
CONCLUSIONS: This study elucidates a novel mechanism that lncRNA HULC produces a vital function during hepatocarcinogenesis.
Qian YY, Liu ZS, Yan HJ, et al.Pterostilbene inhibits MTA1/HDAC1 complex leading to PTEN acetylation in hepatocellular carcinoma.
Biomed Pharmacother. 2018; 101:852-859 [PubMed
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PURPOSE: The aim of this study is to investigate the inhibition of cancer growth by pterostilbene through Metastasis-Associated Protein 1 (MTA1) and the histone deacetylase 1 (HDAC1) complex in hepatocellular carcinoma (HCC).
METHODS: We investigate the antitumor effects of pterostilbene (PTER) in HCC. The SMMC-7721 hepatoma cell line was cultured and treated with PTER for different time depending on the experiment. After treatment, we tested the cellular expression of proteins by Western blot and the expression of MTA1 mRNA by real-time PCR. And the immunoprecipitation was performed to confirm the acetylation in PTEN. Animal models have been established to confirm the anti-cancer effects of PTER.
RESULTS: PTER treatment could downregulate the expression of MTA1, and HDAC1 and elevates the Ac-PTEN ratio in tumors. The results suggest that PTER can decrease the expression of MTA1 and destabilize the MTA1/HDAC1 complex allowing acetylation/activation of PTEN on Lys
CONCLUSION: We demonstrated that PTER suppressed the growth, and invasion of HCC and was effective in regulating the levels of the MTA1/HDAC1/NuRD complex, promoting PTEN acetylation and apoptosis in HCC. Our findings suggest that the novel epigenetic nature of PTER anticancer activity opens up new avenues for primary chemoprevention, as well as anticancer and antimetastatic treatment.
Pterostilbene (Pter) is reported to exhibit an anticancer effect in hepatocellular carcinoma (HCC). In order to explore the anticancer mechanism in HCC cells, the present study aimed to investigate whether pterostilbene (Pter) may increase phosphatase and tensin homolog (PTEN) expression through targeted downregulation of microRNA (miRNA/miR)-19a in hepatocellular carcinoma (HCC). The proliferation, apoptosis and cell cycle was analyzed in the SMMC‑7721 HCC cell line by MTT assays and flow cytometry methods. Cells were divided into five treatment groups: Pter treatment, miR‑19a inhibitor transfection, Pter + miR‑19a inhibitor, negative control transfection and blank control. The expression of miR‑19a and PTEN was detected by reverse transcription‑quantitative polymerase chain reaction and western blot analysis following treatment. Furthermore, a luciferase reporter gene assay was performed to determine whether the PTEN gene was a direct target of miR‑19a. The results demonstrated that Pter treatment or miR‑19a inhibitor transfection downregulated miR‑19a and induced PTEN/Akt pathway regulation, which led to proliferation inhibition, cell cycle arrest in the S phase, increased apoptosis and reduced cell invasion. These results indicated that Pter may increase PTEN expression through the direct downregulation of miR‑19a in HCC. Therefore, miR‑19a may have potential as a novel molecular marker for HCC and Pter may be a promising clinical target with the potential to be developed as a HCC therapy.
Han Z, Zhou X, Li S, et al.Inhibition of miR-23a increases the sensitivity of lung cancer stem cells to erlotinib through PTEN/PI3K/Akt pathway.
Oncol Rep. 2017; 38(5):3064-3070 [PubMed
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Epidermal growth factor receptor-targeted tyrosine kinase inhibitors (EGFR-TKIs) have become first-line drugs used for non-small cell lung cancer (NSCLC) treatment. However, drug resistance to EGFR-TKIs will be developed inevitably due to the repeated use of these drugs. In the present study, we isolated cancer stem cells (CSCs) from the PC9 NSCLC cell line. We then observed that the PC9 CSCs showed significant resistance to erlotinib compared with the PC9 non-CSCs. Erlotinib failed to suppress the phosphorylation of PI3K and AKT in PC9 CSCs, although the EGFR was inhibited sufficiently. Mechanically, we observed aberrant upregulation of microRNA-23a (miR-23a) and downregulation of PTEN in PC9 CSCs compared to PC9 non-CSCs. Luciferase reporter assays proved that PTEN was the target of miR-23a in PC9 CSCs. Furthermore, knockdown of miR-23a enhanced the antitumor effect of erlotinib by increasing the expression of PTEN. In addition, transfection with miR-23a inhibitors promoted the erlotinib-dependent inhibition of PI3K/AKT pathway, thus, suppressing the proliferation and inducing apoptosis in PC9 CSCs. These results propose that upregulation of miR-23a is a potential mechanism associated with resistance to EGFR-TKIs in lung cancer stem cells. Inhibition of miR-23a serves as a novel therapeutic strategy to eliminate the EGFR-TKIs resistance of lung cancer stem cells.
Chen CP, Wang LK, Chern SR, et al.Prenatal diagnosis of partial monosomy 5p (5p15.1→pter) and partial trisomy 7p (7p15.2→pter) associated with cystic hygroma, abnormal skull development, and ventriculomegaly.
Taiwan J Obstet Gynecol. 2016; 55(4):591-5 [PubMed
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OBJECTIVE: Prenatal diagnosis of concomitant chromosome 5p deletion syndrome and chromosome 7p duplication syndrome in a fetus with abnormal prenatal ultrasound is presented.
CASE REPORT: A 34-year-old woman was referred for amniocentesis at 22 weeks of gestation because of an irregular-shaped skull, bilateral ventriculomegaly, and nuchal cystic hygroma. Amniocentesis revealed a derivative chromosome 5 with a distal 5p deletion and an addendum of an extra unknown chromosomal segment at the breakpoint of 5p. Cytogenetic analysis of parental bloods revealed a karyotype of 46, XX, t(5;7)(p15.1;p15.2) in the mother and a karyotype of 46,XY in the father. The karyotype of the fetus was 46, XX, der(5) t(5;7)(p15.1;p15.2)mat consistent with partial monosomy 5p (5p15.1→pter) and partial trisomy 7p (7p15.2→pter). A malformed fetus was subsequently delivered with an irregular-shaped skull, a large anterior fontanelle, brachycephaly, hypertelorism, a high and prominent forehead, a large nuchal cystic hygroma, large low-set ears, a short and flattened nose, and micrognathia. Array comparative genomic hybridization analysis of the placenta revealed the result of arr 5p15.33p15.1 (22,179-18,133,327)×1.0, 7p22.3p15.2 (54,215-25,551,540)×3.0, indicating an 18.11-Mb deletion of 5p (5p15.33-p15.1) and a 22.5-Mb duplication of 7p (7p22.3-p15.2). Cord blood sampling revealed a karyotype of 46, XX, der(5)t(5;7) (p15.1;p15.2)mat.
CONCLUSION: Fetuses with 5p deletion syndrome and 7p duplication syndrome may present ventriculomegaly, abnormal skull development, and cystic hygroma on prenatal ultrasound.
Perez-Escuredo J, Lopez-Hernandez A, Costales M, et al.Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma.
Rhinology. 2016; 54(3):278-86 [PubMed
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BACKGROUND: Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC.
MATERIAL AND METHODS: Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome.
RESULTS: Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome.
CONCLUSION: ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.
OBJECTIVE: to observe relationship between chromosome imbalance and taxol resistance in nasopharyngeal carcinoma (NPC).
METHODS: three taxol-resistant sub-lines were established through repeated exposure of escalating doses of paclitaxel to NPC cell lines (CNE-1, HNE-2 and 5-8F). The change of copy number of chromosomes was investigated by the genome-wide analyses of comparative genomic hybridization (CGH). Gene profiles of both parental and resistant cell lines were determined by cDNA microarray. Cell viability was assayed by colony formation assay.
RESULTS: The taxol resistant sub-lines (CNE1/Taxol, HNE2/Taxol and 5-8F/Taxol) developed displayed an average 5~8-fold higher IC50 value than their parental cells. The common losses of chromosome 18, 10q11-qter and gains of chromosome 12, 3q21-qter, 5p13-pter and 20q11-qter were observed by CGH in all of 6 NPC cell lines. A common gain region of chromosome 8q21-qter was identified in taxol resistant sub-lines. 15 genes of 762 transcripts on this chromosome region were consistently up-regulated detected by cDNA microarray in three taxol resistant sub-lines, and functionally clustered into various groups, including genes related to vascular formation vascular formation (ANGPT1), apoptosis (MYC, TOP1MT), cell adhesion and cell cycle (PPP1R16A, SDC2, CA2, ANKRD46), gene regulation (HRSP12, ZNF696, SLC39A4, POP1), metabolism (PYCRL). Inhibition of ANGPT1 expression significantly increased the sensitivity of CNE-1/taxol to paclitaxol.
CONCLUSION: The common gain of chromosome 8q21-qter in taxol resistant sublines predicates that potential candidate genes on this region may contribute to taxol resistant phenotype. ANGPT1 may be associated with taxol resistance of NPC cells.
Benlloch M, Obrador E, Valles SL, et al.Pterostilbene Decreases the Antioxidant Defenses of Aggressive Cancer Cells In Vivo: A Physiological Glucocorticoids- and Nrf2-Dependent Mechanism.
Antioxid Redox Signal. 2016; 24(17):974-90 [PubMed
] Free Access to Full Article Related Publications
AIMS: Polyphenolic phytochemicals have anticancer properties. However, in mechanistic studies, lack of correlation with the bioavailable concentrations is a critical issue. Some reports had suggested that these molecules downregulate the stress response, which may affect growth and the antioxidant protection of malignant cells. Initially, we studied this potential underlying mechanism using different human melanomas (with genetic backgrounds correlating with most melanomas), growing in nude mice as xenografts, and pterostilbene (Pter, a natural dimethoxylated analog of resveratrol).
RESULTS: Intravenous administration of Pter decreased human melanoma growth in vivo. However, Pter, at levels measured within the tumors, did not affect melanoma growth in vitro. Pter inhibited pituitary production of the adrenocorticotropin hormone (ACTH), decreased plasma levels of corticosterone, and thereby downregulated the glucocorticoid receptor- and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent antioxidant defense system in growing melanomas. Exogenous corticosterone or genetically induced Nrf2 overexpression in melanoma cells prevented the inhibition of tumor growth and decreased antioxidant defenses in these malignant cells. These effects and mechanisms were also found in mice bearing different human pancreatic cancers. Glutathione depletion (selected as an antimelanoma strategy) facilitated the complete elimination by chemotherapy of melanoma cells isolated from mice treated with Pter.
INNOVATION: Although bioavailability-related limitations may preclude direct anticancer effects in vivo, natural polyphenols may also interfere with the growth and defense of cancer cells by downregulating the pituitary gland-dependent ACTH synthesis.
CONCLUSIONS: Pter downregulates glucocorticoid production, thus decreasing the glucocorticoid receptor and Nrf2-dependent signaling/transcription and the antioxidant protection of melanoma and pancreatic cancer cells. Antioxid. Redox Signal. 24, 974-990.
Weber S, Haferlach C, Jeromin S, et al.Gain of chromosome 21 or amplification of chromosome arm 21q is one mechanism for increased ERG expression in acute myeloid leukemia.
Genes Chromosomes Cancer. 2016; 55(2):148-57 [PubMed
] Related Publications
In acute myeloid leukemia (AML), acquired genomic gains and losses are common and lead to altered expression of genes located within or nearby the affected regions. Increased expression of the ETS-related transcription factor gene ERG has been described in myeloid malignancies with chromosomal rearrangements involving chromosome band 21q22, but also in cytogenetically normal AML, where it is associated with adverse prognosis. In this study, fluorescence in situ hybridization on interphase nuclei disclosed an amplification of the ERG gene (more than six copies) in 33 AML patients with structural rearrangements of 21q22. Array comparative genomic hybridization of these cases disclosed a minimal amplified region at the position 39.6-40.0 Mbp from pter that harbors ERG as the only gene. Analysis by quantitative real-time reverse transcription polymerase chain reaction revealed significantly higher ERG mRNA expression in these patients and in a group of 95 AML patients with complete or partial gain of chromosome 21 (three to six copies) compared with 351 AML patients without gain of chromosome 21. Quantification of ERG DNA copy numbers revealed a strong correlation with ERG mRNA expression. Furthermore, in patients with gain of chromosome 21, higher ERG expression was found to be associated with RUNX1 mutations. Our results suggest that acquired gain of chromosome 21 or amplification of chromosome arm 21q is one mechanism contributing to increased ERG expression in AML.
Gotoh M, Ichikawa H, Arai E, et al.Comprehensive exploration of novel chimeric transcripts in clear cell renal cell carcinomas using whole transcriptome analysis.
Genes Chromosomes Cancer. 2014; 53(12):1018-32 [PubMed
] Free Access to Full Article Related Publications
The aim of this study was to clarify the participation of expression of chimeric transcripts in renal carcinogenesis. Whole transcriptome analysis (RNA sequencing) and exploration of candidate chimeric transcripts using the deFuse program were performed on 68 specimens of cancerous tissue (T) and 11 specimens of non-cancerous renal cortex tissue (N) obtained from 68 patients with clear cell renal cell carcinomas (RCCs) in an initial cohort. As positive controls, two RCCs associated with Xp11.2 translocation were analyzed. After verification by reverse transcription (RT)-PCR and Sanger sequencing, 26 novel chimeric transcripts were identified in 17 (25%) of the 68 clear cell RCCs. Genomic breakpoints were determined in five of the chimeric transcripts. Quantitative RT-PCR analysis revealed that the mRNA expression levels for the MMACHC, PTER, EPC2, ATXN7, FHIT, KIFAP3, CPEB1, MINPP1, TEX264, FAM107A, UPF3A, CDC16, MCCC1, CPSF3, and ASAP2 genes, being partner genes involved in the chimeric transcripts in the initial cohort, were significantly reduced in 26 T samples relative to the corresponding 26 N samples in the second cohort. Moreover, the mRNA expression levels for the above partner genes in T samples were significantly correlated with tumor aggressiveness and poorer patient outcome, indicating that reduced expression of these genes may participate in malignant progression of RCCs. As is the case when their levels of expression are reduced, these partner genes also may not fully function when involved in chimeric transcripts. These data suggest that generation of chimeric transcripts may participate in renal carcinogenesis by inducing dysfunction of tumor-related genes.
Trans-3,5-dimethoxy-4'-hydroxystilbene (PTER), a natural dimethylated analog of resveratrol, preferentially induces certain cancer cells to undergo apoptosis and could thus have a role in cancer chemoprevention. Peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is a ligand-dependent transcription factor whose activation results in growth arrest and/or apoptosis in a variety of cancer cells. Here we investigated the potential of PTER-isothiocyanate (ITC) conjugate, a novel class of hybrid compound (PTER-ITC) synthesized by appending an ITC moiety to the PTER backbone, to induce apoptotic cell death in hormone-dependent (MCF-7) and -independent (MDA-MB-231) breast cancer cell lines and to elucidate PPARγ involvement in PTER-ITC action. Our results showed that when pre-treated with PPARγ antagonists or PPARγ siRNA, both breast cancer cell lines suppressed PTER-ITC-induced apoptosis, as determined by annexin V/propidium iodide staining and cleaved caspase-9 expression. Furthermore, PTER-ITC significantly increased PPARγ mRNA and protein levels in a dose-dependent manner and modulated expression of PPARγ-related genes in both breast cancer cell lines. This increase in PPARγ activity was prevented by a PPARγ-specific inhibitor, in support of our hypothesis that PTER-ITC can act as a PPARγ activator. PTER-ITC-mediated upregulation of PPARγ was counteracted by co-incubation with p38 MAPK or JNK inhibitors, suggesting involvement of these pathways in PTER-ITC action. Molecular docking analysis further suggested that PTER-ITC interacted with 5 polar and 8 non-polar residues within the PPARγ ligand-binding pocket, which are reported to be critical for its activity. Collectively, our observations suggest potential applications for PTER-ITC in breast cancer prevention and treatment through modulation of the PPARγ activation pathway.
The development of natural product agents with targeted strategies holds promise for enhanced anticancer therapy with reduced drug-associated side effects. Resveratrol found in red wine, has anticancer activity in various tumor types. We reported earlier on a new molecular target of resveratrol, the metastasis-associated protein 1 (MTA1), which is a part of nucleosome remodeling and deacetylation (NuRD) co-repressor complex that mediates gene silencing. We identified resveratrol as a regulator of MTA1/NuRD complex and re-activator of p53 acetylation in prostate cancer (PCa). In the current study, we addressed whether resveratrol analogues also possess the ability to inhibit MTA1 and to reverse p53 deacetylation. We demonstrated that pterostilbene (PTER), found in blueberries, had greater increase in MTA1-mediated p53 acetylation, confirming superior potency over resveratrol as dietary epigenetic agent. In orthotopic PCa xenografts, resveratrol and PTER significantly inhibited tumor growth, progression, local invasion and spontaneous metastasis. Furthermore, MTA1-knockdown sensitized cells to these agents resulting in additional reduction of tumor progression and metastasis. The reduction was dependent on MTA1 signaling showing increased p53 acetylation, higher apoptotic index and less angiogenesis in vivo in all xenografts treated with the compounds, and particularly with PTER. Altogether, our results indicate MTA1 as a major contributor in prostate tumor malignant progression, and support the use of strategies targeting MTA1. Our strong pre-clinical data indicate PTER as a potent, selective and pharmacologically safe natural product that may be tested in advanced PCa.
AKT is a critical signaling node downstream of phosphoinositide 3-kinase (PI3K), which is often activated in cancer. We analyzed the state of activation of AKT in 80 human non-small cell lung carcinoma cell lines under serum starvation conditions. We identified 13 lines, which showed persistent AKT activation in the absence of serum. In 12 of 13 lines, AKT activation could be attributed to loss of PTEN, activating mutation in EGF receptor (EGFR) or PIK3CA, or amplification of ERBB2. HCC2429 was the only cell line that had no alterations in those genes, but had high phospho-AKT(Ser473) levels under serum starvation conditions. However, the activation of AKT in HCC2429 was PI3K- and mTOR complex 2 (mTORC2)-dependent based upon use of specific inhibitors. Kinome tyrosine phosphorylation profiling showed that both Notch and SRC were highly activated in this cell line. Despite the activation of Notch, AKT activation and cell survival were not affected by Notch inhibitors DAPT or compound E. In contrast, SRC inhibitors PP2 and dasatinib both significantly decreased pAKT(Ser473) levels and reduced cell survival by inducing apoptosis. Furthermore, a combination of SRC and mTOR inhibition synergistically blocked activation of AKT and induced apoptosis. Overexpression of SRC has been identified previously in human lung cancers, and these results suggest that a combination of SRC and mTOR inhibitors may have unique therapeutic benefit for a subset of lung cancers with these molecular features.
Lundin C, Hjorth L, Behrendtz M, et al.Submicroscopic genomic imbalances in Burkitt lymphomas/leukemias: association with age and further evidence that 8q24/MYC translocations are not sufficient for leukemogenesis.
Genes Chromosomes Cancer. 2013; 52(4):370-7 [PubMed
] Related Publications
Chromosome banding analyses reveal secondary chromosome abnormalities in addition to the MYC translocations t(8;14)(q24;q32), t(8;22)(q24;q11), and t(2;8)(p11;q24) in 60%-80% of Burkitt lymphomas/leukemias (BL). The high incidence of such aberrations indicates that additional changes are important, perhaps necessary, for malignant transformation, i.e., the 8q24/MYC rearrangements may not be sufficient. To investigate this possibility, we performed single nucleotide polymorphism (SNP) array analysis on 20 cases of 8q24/MYC-positive BL. Nineteen (95%) harbored genomic imbalances; the only case without such aberrations displayed secondary changes by chromosome banding analysis. Thus, all BL cases had abnormalities in addition to the 8q24 translocation. The adult cases harbored more changes (median 3; range 1-21) than did the childhood cases (median 1.5; range 0-5) (P = 0.034). Several recurrent aberrations were detected by SNP array analysis, in particular losses of 6q14.1-q22.33, 9p21.3, and 13q14.2-q14.3, gains of 1q23.3-q31.3, chromosome 7, 13q31.3, and partial uniparental isodisomies for 6p12.2-pter, 9p23-pter, and 17p11.2-pter. The molecular genetic consequences of these changes include deletions of the CDKN2A and TP53 genes, and gains/losses of several genes, such as MIR17HG and E2F2K, involved in the MYC pathway. Thus, deregulation of the MYC pathway, both directly through the 8q24/MYC translocation and indirectly through secondary genomic imbalances, may be essential not only for the initiation but also for the progression of BL.
Terminal or interstitial deletions of Xp (Xp22.2→Xpter) in males have been recognized as a cause of contiguous gene syndromes showing variable association of apparently unrelated clinical manifestations such as Leri-Weill dyschondrosteosis (SHOX), chondrodysplasia punctata (CDPX1), mental retardation (NLGN4), ichthyosis (STS), Kallmann syndrome (KAL1), and ocular albinism (GPR143). Here we present a case of a 13.5 yr old boy and sister with a same terminal deletion of Xp22.2 resulting in the absence of genes from the telomere of Xp to GPR143 of Xp22. The boy manifested the findings of all of the disorders mentioned above. We began a testosterone enanthate monthly replacement therapy. His sister, 11 yr old, manifested only Leri-Weill dyschondrosteosis, and had engaged in growth hormone therapy for 3 yr. To the best of our knowledge, this is the first report of a male with a 9.7 Mb terminal Xp deletion including the OA1 locus in Korea.
Xu Y, Man X, Lv Z, et al.Loss of heterozygosity at chromosomes 1p35-pter, 4q, and 18q and protein expression differences between adenocarcinomas of the distal stomach and gastric cardia.
Hum Pathol. 2012; 43(12):2308-17 [PubMed
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Loss of heterozygosity of 1p35-pter, 4q, and 18q is frequent in gastric carcinoma, suggesting that these regions harbor tumor suppressor genes. However, the differences in these genetic alterations between adenocarcinoma of the gastric cardia and adenocarcinoma of the distal stomach remain unclear. In this study, loss of heterozygosity at chromosomes 1p35-pter, 4q, and 18q were analyzed in adenocarcinoma of the gastric cardia and adenocarcinoma of the distal stomach samples acquired by laser capture microdissection. The expression of several tumor suppressor gene proteins, runt-related transcription factor 3 (1p36), annexin A10 (4q33), SMAD family member 4 (18q21.1), and deleted in colorectal carcinoma (18q21.3), was evaluated immunohistochemically. The adenocarcinoma of the distal stomach and adenocarcinoma of the gastric cardia lesions had a similar trend in total deletion frequency for chromosomes 1p35-pter (36.5% for adenocarcinoma of the distal stomach and 32.5% for adenocarcinoma of the gastric cardia), 4q (42.3% for adenocarcinoma of the distal stomach and 47.5% for adenocarcinoma of the gastric cardia), and 18q (38.5% for adenocarcinoma of the distal stomach and 45% for adenocarcinoma of the gastric cardia). However, loss of heterozygosity patterns were clearly different in the 2 adenocarcinomas. Deletion mapping indicated that 4q32.2-4q34.3, 18q21.2-21.31, 18q22.3-23, and 1p35.2-1p36.13 were involved in adenocarcinoma of the distal stomach, whereas 4q13.3-4q22.3, 4q31.21-4q32.2, 18q21.31-18q22.1, and 1p35.2-1p36.13 were involved in adenocarcinoma of the gastric cardia. Expression of ANXA10 (P = .038), SMAD family member 4 (P = .028), and deleted in colorectal carcinoma (P = .004) was less common in adenocarcinoma of the distal stomach than in adenocarcinoma of the gastric cardia. Expression of runt-related transcription factor 3 (P = .795) showed no significant difference in the 2 tumors. The tumors differed in the profile of genetic alterations and protein expression of these well-known tumor suppressor genes. The deleted regions defined in this study may harbor tumor suppressor genes relevant to adenocarcinoma of the gastric cardia.
Gao Y, Niu Y, Wang X, et al.Chromosome aberrations associated with centrosome defects: a study of comparative genomic hybridization in breast cancer.
Hum Pathol. 2011; 42(11):1693-701 [PubMed
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Centrosome abnormalities occur frequently in various tumors and can cause chromosomal instability and eventually promote cancer development. We investigated the chromosome aberrations associated with centrosome abnormalities in 30 cases of breast cancer, combining immunohistochemical staining and comparative genomic hybridization. Except for some common chromosome alterations (including gains of 1q, 8q, 17q, 20q, and Xq and losses of 8p, 11q, 13q, 14q, 16q, 17p, 22q, and Xp) that have also been seen more frequently in other studies, we discovered some new changes that have rarely been reported, including gains at 2p, 5p, 10p, 15q, 16p, 18q, 21q, and 22q and losses at 6p, 8p23, 11p13-pter, 13q34, and 14q32-qter. We also identified some changes (such as gains of 17q, 20q, and Xq and losses of 17p, 13q, and 14q) harboring candidate genes. We also explored the expression of centrosome protein in different molecular subtypes of breast cancer. Our findings provide a new way to explore the molecular mechanisms of breast tumorigenesis and accordingly potential new targets for therapy for this disease.
Tsai MH, Fang WH, Lin SH, et al.Mapping of genetic deletions on chromosome 3 in colorectal cancer: loss of 3p25-pter is associated with distant metastasis and poor survival.
Ann Surg Oncol. 2011; 18(9):2662-70 [PubMed
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PURPOSE: There is no detailed analysis of loss of heterozygosity (LOH) on chromosome 3 in colorectal cancer (CRC). Our aim was to define frequently deleted loci on chromosome 3 and to explore novel prognostic markers and the locations of candidate tumor suppressor genes associated with CRC.
METHODS: LOH at 23 microsatellite markers spanning on chromosome 3 was determined in 112 sporadic CRC by automated fluorescence-based polymerase chain reaction. Genetic loss was assessed for the clinicopathological significance by univariate and multivariate analyses.
RESULTS: Fifty-eight (51.8%) of 112 carcinomas exhibited LOH at one or more loci tested. Among seven loci with high LOH rates, allelic losses at D3S1297 and D3S1266 occurred more frequently in younger patients. A marked gender distortion for genetic deletion was observed at six loci, where LOH was identified more frequently in male cases. For clinical outcome, LOH solely at D3S1297 (3p26.3) was significantly associated with distant metastasis (P = 0.001) and was indicative of a shorter overall survival (P = 0.014). In addition, loss of one common deletion region at 3p25-pter was significantly correlated to distant metastasis (P = 0.009) and had an adverse effect on patients' overall survival in univariate and multivariate tests (P = 0.009 and 0.001, respectively).
CONCLUSIONS: Loss of chromosome 3p25-pter could act as an independent predicator of poor prognosis in CRC, suggesting that microsatellite analysis is a useful means to stratify patients into different risk groups. In addition, inactivation of candidate tumor suppressor genes in this region might involve in CRC progression.
Pei J, Feder MM, Al-Saleem T, et al.Combined classical cytogenetics and microarray-based genomic copy number analysis reveal frequent 3;5 rearrangements in clear cell renal cell carcinoma.
Genes Chromosomes Cancer. 2010; 49(7):610-9 [PubMed
] Free Access to Full Article Related Publications
Karyotypic analysis and genomic copy number analysis with single nucleotide polymorphism (SNP)-based microarrays were compared with regard to the detection of recurrent genomic imbalances in 20 clear cell renal cell carcinomas (ccRCCs). Genomic imbalances were identified in 19 of 20 tumors by DNA copy number analysis and in 15 tumors by classical cytogenetics. A statistically significant correlation was observed between the number of genomic imbalances and tumor stage. The most common genomic imbalances were loss of 3p and gain of 5q. Other recurrent genomic imbalances seen in at least 15% of tumors included losses of 1p32.3-p33, 6q23.1-qter and 14q and gain of chromosome 7. The SNP-based arrays revealed losses of 3p in 16 of 20 tumors, with the highest frequency being at 3p21.31-p22.1 and 3p24.3-p25.3, the latter encompassing the VHL locus. One other tumor showed uniparental disomy of chromosome 3. Thus, altogether loss of 3p was identified in 17 of 20 (85%) cases. Fourteen tumors showed both overlapping losses of 3p and overlapping gains of 5q, and the karyotypic assessment performed in parallel revealed that these imbalances arose via unbalanced 3;5 translocations. Among the latter, there were common regions of loss at 3p21.3-pter and gain at 5q34-qter. These data suggest that DNA copy number analysis will supplant karyotypic analysis of tumor types such as ccRCC that are characterized by recurrent genomic imbalances, rather than balanced rearrangements. These findings also suggest that the 5q duplication/3p deficiency resulting from unbalanced 3;5 translocations conveys a proliferative advantage of particular importance in ccRCC tumorigenesis.
Caramazza D, Hussein K, Siragusa S, et al.Chromosome 1 abnormalities in myeloid malignancies: a literature survey and karyotype-phenotype associations.
Eur J Haematol. 2010; 84(3):191-200 [PubMed
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Chromosome 1 is the largest human chromosome and contains over 1600 known genes and 1000 novel coding sequences or transcripts. It is, therefore, not surprising that recurrent chromosome 1 abnormalities are regularly encountered in both neoplastic and non-neoplastic medical conditions. The current review is focused on myeloid malignancies where we summarize the relevant published literature and discuss specific karyotype-phenotype associations. We show that chromosome 1 abnormalities are most frequent in BCR-ABL-negative classic myeloproliferative neoplasms (MPN): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Specific abnormalities include duplications (e.g. 1q12-->1q32 in PV, 1q21-32-->1q32-44 in post-PV MF or PMF), deletions (e.g. 1p13-36-->pter in PV or PMF, 1q21 in PMF) and unbalanced translocations involving chromosome 6, such as der(6)t(1;6)(q21-25;p21.3-23), and other partner chromosomes involving 1q10/1p11 and 1q21-25 breakpoints. Although occasionally seen in chronic phase MPN, unbalanced 1;7 translocations, e.g. der(1;7)(q10;p10), are usually seen in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and post-MPN AML/MDS. These observations suggest that certain chromosome 1 regions, especially 1q21-1q32 and 1p11-13, might harbor oncogenes or tumor suppressor genes that are pathogenetically relevant to both chronic and advanced phases of MPN.
A clonal cytogenetic abnormality was observed in Philadelphia chromosome-negative bone marrow cells of 6/27 chronic myeloid leukemia patients (+8 in 4, -7 in 1, and 20q- in 1) with dasatinib-induced remissions. The X-linked human androgen receptor gene assay demonstrated clonality in one additional patient. Single nucleotide polymorphism array analysis revealed somatic uniparental disomy involving chromosome 17(p12-pter) in another patient. The TP53 gene had a 5' splice site deletion of exon 6 that caused alternative splicing, frame shifting and introduction of a premature stop codon. After three years, no patient developed myelodysplastic syndrome or acute myeloid leukemia.
Mohammed AM, Kamel AK, Hammad SA, et al.Constitutional retinoblastoma gene deletion in Egyptian patients.
World J Pediatr. 2009; 5(3):222-5 [PubMed
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BACKGROUND: Retinoblastoma is a neuroblastic tumor of childhood with an incidence of 1: 20 000. Retinoblastoma gene (Rb1) is a tumor suppressor gene that is located on the long arm of chromosome 13 at region 14. This study was to evaluate the constitutional monoallelic Rb1 deletion among retinoblastoma families.
METHODS: Nine families with an affected Rb proband were evaluated. Clinical examination, pedigree analysis, and complete eye examination were given to patients, their sibs and parents. Standard cytogenetic and fluorescence in situ hybridization (FISH) analyses were carried out for all of them. Also, two sib fetuses were tested for Rb1 deletion.
RESULTS: No dysmorphic features were detected in any patient. Developmental milestones were within normal limit except in one proband who had a mild delay. The age of onset ranged from one month to 4 years. Positive family history was found in two families. In one, the father and 3 sibs had retinoblastoma, and in the other, 2 sibs were affected, but the parents were free. Chromosomal study revealed no abnormalities in all parents and sibs. Two patients had mosaic chromosome 13 abnormalities, 46,XY/46,XY,del(13)(pter-->q14:) and 46,XX/46,inv(13)(q14q22). FISH analysis detected mosaic Rb1 deletion in two patients and excluded Rb1 deletion in two fetuses.
CONCLUSIONS: The detection of genetic alterations affecting the Rb1 locus is important for the establishment of carriers, and prenatal and presymptomatic diagnosis. The search for deleted Rb1 mosaic cell lines is important for genetic counseling. Germline mutation may be considered as genetic transmission method of the Rb1 gene.
The identification of genetic aberrations may help understand the mechanisms of tumorigenesis and has important implications in diagnosis, prognosis and treatment. We applied Illumina's 317K high-density single nucleotide polymorphism (SNP) arrays to profile chromosomal aberrations in clear cell renal cell carcinoma (ccRCC) from 80 patients and analyzed the association of LOH/amplification events with clinicopathological characteristics and telomere length. The most common loss of heterozygosity (LOH) were 3p (69 cases) including 38 whole 3p arm losses, 30 large fragment LOH (spanning 3p21-36), and 1 interstitial LOH (spanning 3p12-14, 3p21-22, 3p24.1-24.2 and 3p24.3), followed by chromosome losses at 8p12-pter, 6q23.3-27, 14q24.1-qter, 9q32-qter, 10q22.3-qter, 9p13.3-pter, 4q28.3-qter and 13q12.1-21.1. We also found several smallest overlapping regions of LOH that contained tumor suppressor genes. One smallest LOH in 8p12 had a size of 0.29 Mb and only contained one gene (NRG1). The most frequent chromosome gains were at 5q (32 cases), including 10 whole 5q amplification, 21 large amplifications encompassing 5q32-ter and 1 focal amplification in 5q35.3 (0.42 Mb). The other common chromosome gains were 1q25.1-qter, 7q21.13-qter, 8q24.12-qter and whole 7p arm. Significant associations of LOH at 9p, 9q, 14q and 18q were observed with higher nuclear grade. Significant associations with tumor stage were observed for LOH at 14q, 18p and 21q. Finally, we found that tumors with LOH at 2q, 6p, 6q, 9p, 9q and 17p had significantly shorter telomere length than those without LOH. This is the first study to use Illumina's SNP-CGH array that provides a close estimate of the size and frequency of chromosome LOH and amplifications of ccRCC. The identified regions and genes may become diagnostic and prognostic biomarkers as well as potential targets of therapy.
Manderson EN, Birch AH, Shen Z, et al.Molecular genetic analysis of a cell adhesion molecule with homology to L1CAM, contactin 6, and contactin 4 candidate chromosome 3p26pter tumor suppressor genes in ovarian cancer.
Int J Gynecol Cancer. 2009; 19(4):513-25 [PubMed
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Loss of heterozygosity (LOH) analyses of epithelial ovarian cancers (EOCs) previously identified a candidate tumor suppressor gene (TSG) locus within the chromosomal region 3p25.3-pter. Loss of heterozygosity analysis was performed to define the locus and identify candidates for further study. Loss of heterozygosity analysis of 124 malignant EOC samples of different histopathologic subtypes using 12 polymorphic microsatellite repeat markers identified a 330-kilobase minimal region of overlapping deletions at 3p26.3 that contained contactin 4 (CNTN4) as the only known TSG candidate. However, evaluation of the LOH patterns in the serous EOC samples, the most common subtype, enabled the identification of a second, broader region of LOH also included the cell adhesion molecule with homology to L1CAM (CHL1) and CNTN6 as candidates. Gene expression by reverse transcription polymerase chain reaction was not detectable in primary cultures of normal ovarian surface epithelial cells for any of these candidates. CNTN6 expression was also not detectable in serous EOC samples. In contrast, gene expression of CNTN4 and CHL1, particularly overexpression of CHL1, was observed in serous EOC samples. Mutation and gene expression analyses of well-defined EOC cell lines (OV-90, TOV-112D, TOV-21G, and TOV-81D) that differ in their tumorigenic potential and chromosome 3p26-pter genomic content revealed CNTN4 expression and a novel mutation only in the tumorigenic EOC cell line TOV-21G. This mutation was neither observed in controls (n = 105) nor detected by sequencing analysis of complementary DNA. Taken together, these results do not support the candidacy of CHL1, CNTN6, and CNTN4 as TSGs in the 3p26-pter region. However, the overexpression of CHL1, a member of the L1 cell adhesion molecule (L1CAM) family, warrants further investigation.
Chinnasri P, Pairojkul C, Jearanaikoon P, et al.Preferentially different mechanisms of inactivation of 9p21 gene cluster in liver fluke-related cholangiocarcinoma.
Hum Pathol. 2009; 40(6):817-26 [PubMed
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Cholangiocarcinoma in northeast Thailand is associated with liver fluke infection. Mechanisms of inactivation of the p15(INK4b), p16(INK4a), and p14(ARF) have been reported in many human cancers but have not hitherto been studied in liver fluke-related cholangiocarcinoma, particularly genetic and epigenetic effects on protein expression. We investigated loss of heterozygosity and microsatellite instability and performed fine mapping of the chromosomal region 9p21-pter in 94 microdissected cholangiocarcinoma samples using polymerase chain reaction based-microsatellite markers. Methylation and protein expression of p14(ARF), p15(INK4b), and p16(INK4a) was determined using methylation-specific polymerase chain reaction and immunohistochemistry, respectively. Genetic and epigenetic alterations, including loss of protein expression, were correlated with clinicopathological data. Fine mapping at 9p21-pter showed a distinctive region between D9S286 and D9S1752 of common loss. Methylation frequency was 40.2% for p14(ARF), 48.9% for p15(INK4b), and 28.3% for p16(INK4a). Loss of protein expression of p14(ARF), p15(INK4b), and p16(INK4a) was 30.9%, 58%, and 81.5%, respectively. Both p14(ARF) methylation and allelic loss at 9p21 were associated with loss of p14(ARF) expression. Poor prognosis was associated with loss of p16(INK4a) expression. In conclusion, mechanisms of inactivation of p14(ARF), p15(INK4b), and p16(INK4a) in liver fluke-related cholangiocarcinoma are preferentially different, by which epigenetic event being the main mechanism of p14(ARF), whereas p16(INK4a) and p15(INK4b) inactivation occurs through genetic and both genetic and epigenetic events, respectively.
Kotliarov Y, Kotliarova S, Charong N, et al.Correlation analysis between single-nucleotide polymorphism and expression arrays in gliomas identifies potentially relevant target genes.
Cancer Res. 2009; 69(4):1596-603 [PubMed
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Primary brain tumors are a major cause of cancer mortality in the United States. Therapy for gliomas, the most common type of primary brain tumors, remains suboptimal. The development of improved therapeutics will require greater knowledge of the biology of gliomas at both the genomic and transcriptional levels. We have previously reported whole genome profiling of chromosome copy number alterations (CNA) in gliomas, and now present our findings on how those changes may affect transcription of genes that may be involved in tumor induction and progression. By calculating correlation values of mRNA expression versus DNA copy number average in a moving window around a given RNA probe set, biologically relevant information can be gained that is obscured by the analysis of a single data type. Correlation coefficients ranged from -0.6 to 0.7, highly significant when compared with previous studies. Most correlated genes are located on chromosomes 1, 7, 9, 10, 13, 14, 19, 20, and 22, chromosomes known to have genomic alterations in gliomas. Additionally, we were able to identify CNAs whose gene expression correlation suggests possible epigenetic regulation. This analysis revealed a number of interesting candidates such as CXCL12, PTER, and LRRN6C, among others. The results have been verified using real-time PCR and methylation sequencing assays. These data will further help differentiate genes involved in the induction and/or maintenance of the tumorigenic process from those that are mere passenger mutations, thereby enriching for a population of potentially new therapeutic molecular targets.
Hermsen MA, Llorente JL, Pérez-Escuredo J, et al.Genome-wide analysis of genetic changes in intestinal-type sinonasal adenocarcinoma.
Head Neck. 2009; 31(3):290-7 [PubMed
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BACKGROUND: Intestinal-type sinonasal adenocarcinomas are rare tumors related to professional exposure to wood dust. Little is known about the genetic changes in these tumors.
METHODS: Twenty-two tumors were analyzed by microarray comparative genomic hybridization (CGH). In addition, DNA ploidy was measured by flow cytometry and microsatellite instability (MSI) by multiplex PCR.
RESULTS: The most frequent gains were, in descending order, as follows: 5p15, 20q13, and 8q24. Losses occurred most frequently at 4q31-qter, 18q12-22, 8p12-pter, and 5q11-qter. MSI was not detected. Seven cases that harbored very few changes were mostly DNA diploid and had more favorable clinicopathological features, such as lack of intracranial invasion, less metastases, and longer overall survival.
CONCLUSION: The microarray CGH results enabled to better define hotspots of chromosomal gains and losses for further investigation of genes involved in the tumorigenesis of sinonasal adenocarcinoma. In addition, the data allowed classification of a group of patients with better clinical outcome.
Gao Y, Niu Y, Wang X, et al.Genetic changes at specific stages of breast cancer progression detected by comparative genomic hybridization.
J Mol Med (Berl). 2009; 87(2):145-52 [PubMed
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Although a simple linear progression model for breast cancer has already been proposed, its validity still remains controversial. Especially, the genetic and molecular features of breast cancer at different stages during the development and progression, as well as their relationship, have rarely been studied under the same experimental conditions simultaneously. According to these limitations in this research area, the current study applied comparative genomic hybridization technique to investigate genomic changes in 15 cases of breast atypical ductal hyperplasia (ADH), 15 cases of ductal carcinomas in situ (DCIS), and 15 cases of invasive ductal carcinomas (IDC) and the relationship among the genetic changes. Thirty commonly altered regions that were identified included known (gains of 1q,8q, 17q,20q,Xq and losses of 8p,13q,16q,17p,22q) and several uncharacterized (gains of 2q,5p, 10p,12q,16p,18q, etc. and losses of 11p13-pter,11q,14q,Xp, etc). The overall frequency of copy number losses was higher in IDC than that in DCIS (P = 0.013). ADH showed more frequent gain of 17q than that in IDC (P = 0.007), and IDC exhibited a higher frequency for the loss of 22q than that in ADH (P = 0.018). On one hand, several common genomic changes shared by ADH, DCIS, and IDC make a linear relationship for these three lesions possible. On the other hand, the heterogeneity has also showed clonal diversification and different pathways of breast cancer progression. The regions of chromosomal copy number alterations may bring new insights into the strategy for tumor progression blocking and the discovery of new potential targets for breast cancer treatment.
Priego S, Feddi F, Ferrer P, et al.Natural polyphenols facilitate elimination of HT-29 colorectal cancer xenografts by chemoradiotherapy: a Bcl-2- and superoxide dismutase 2-dependent mechanism.
Mol Cancer Ther. 2008; 7(10):3330-42 [PubMed
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Colorectal cancer is one of the most common malignancies worldwide. The treatment of advanced colorectal cancer with chemotherapy and radiation has two major problems: development of tumor resistance to therapy and nonspecific toxicity towards normal tissues. Different plant-derived polyphenols show anticancer properties and are pharmacologically safe. In vitro growth of human HT-29 colorectal cancer cells is inhibited ( approximately 56%) by bioavailable concentrations of trans-pterostilbene (trans-3,5-dimethoxy-4'-hydroxystilbene; t-PTER) and quercetin (3,3',4',5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols. I.v. administration of t-PTER and QUER (20 mg/kg x day) inhibits growth of HT-29 xenografts ( approximately 51%). Combined administration of t-PTER + QUER, FOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil; a first-line chemotherapy regimen), and radiotherapy (X-rays) eliminates HT-29 cells growing in vivo leading to long-term survival (>120 days). Gene expression analysis of a Bcl-2 family of genes and antioxidant enzymes revealed that t-PTER + QUER treatment preferentially promotes, in HT-29 cells growing in vivo, (a) superoxide dismutase 2 overexpression ( approximately 5.7-fold, via specificity protein 1-dependent transcription regulation) and (b) down-regulation of bcl-2 expression ( approximately 3.3-fold, via inhibition of nuclear factor-kappaB activation). Antisense oligodeoxynucleotides to human superoxide dismutase 2 and/or ectopic bcl-2 overexpression avoided polyphenols and chemoradiotherapy-induced colorectal cancer elimination and showed that the mangano-type superoxide dismutase and Bcl-2 are key targets in the molecular mechanism activated by the combined application of t-PTER and QUER.
Prasad M, Bernardini M, Tsalenko A, et al.High definition cytogenetics and oligonucleotide aCGH analyses of cisplatin-resistant ovarian cancer cells.
Genes Chromosomes Cancer. 2008; 47(5):427-36 [PubMed
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Array comparative genomic hybridization (aCGH) is a key platform to assess cancer genomic profiles. Many structural genomic aberrations cannot be detected by aCGH alone. We have applied molecular cytogenetic analyses including spectral karyotyping, multicolor banding, and fluorescence in situ hybridization with aCGH to comprehensively investigate the genomic aberrations associated with cisplatin resistance in A2780 ovarian cancer cells. A2780 is a well-established model of chemotherapeutic resistance with distinct karyotypic abnormalities in the parental and cisplatin-resistant cells. Cytogenetic analysis revealed that two unbalanced translocations, der(8)t(1;8) and der(X)t(X;1), and loss of chromosome 13 were present only in the resistant line. Our aCGH analyses detected imbalances affecting an additional 10.59% of the genome in the cisplatin-resistant cells compared with the parental. DNA copy number changes included deletions at 1p10-p22.1, 8p23.3, and Xq13.1-pter, and a duplication of 8q11.22-q23. Cryptic genomic aberrations associated with concurrent localized changes of specific gene expression included a homozygous deletion of 0.38 Mb at 1p21.3 adjacent to SNX7, and an insertional transposition of 0.85 Mb from 13q12.12 into chromosome 22. This latter rearrangement led to an overexpression of four contiguous genes that flanked one of the breakpoint regions in chromosome 13. Furthermore, 17 genes showed differential expression correlating with genomic gain or loss between the resistant and parent lines, validated by a second expression array platform. These results highlight the integration of comprehensive profiling to determine relationships of genomic aberrations and genes associated with an in vitro drug resistance model in ovarian cancer. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.