Loss of Heterozygosity and Internal Tandem Duplication Mutations of the CBP Gene Are Frequent Events in Human Esophageal Squamous Cell Carcinoma

So, Chi Kwong; Nie, Yan; Song, Ying; Yang, Guang; Chen, Suzie; Wei, Caroline S.-J.; Wang, Li Dong; Doggett, Norman A.; Yang, Chung S.

doi:10.1158/1078-0432.ccr-03-0160

Cited by 25 publications

(10 citation statements)

References 46 publications

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“…The recent description of internal CBP tandem duplications in human oesophageal cancer 19 suggests that other mutations, either in the form of large genomic rearrangements or mutations in regulatory regions of the gene, undetected by the dHPLC approach described here, may be present in CBP in ovarian and/or breast tumours, and that the actual frequency of CBP mutations in ovarian cancer is higher.…”

Section: Discussionmentioning

confidence: 79%

CBP truncating mutations in ovarian cancer

Ward

2005

Journal of Medical Genetics

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T he CBP gene (OMIM #600140) encodes the 2441 amino acid cyclic AMP response element binding protein (CREB) binding protein (Mr 265 000) that functions as an essential co-activator for a number of transcription factors. 1 In particular, CBP, like its homologue EP300, enhances gene transcription by linking sequence specific transcription factors to transcription factor IIB and the RNA polymerase II holoenzyme.2 CBP can also promote gene transcription by acetylation of histones through its histone acetyltransferase activity (HAT) 3 and by acetylation of specific transcription factors such as p53. [4][5][6] Several lines of evidence suggest the involvement of CBP in tumour formation. CBP interacts with the human T cell leukaemia virus (HTLV) Tax protein and v-myb to induce viral and cellular genes that promote cell transformation, while adenovirus E1A, simian virus SV40 Tag, and human papillomavirus (HPV) E6 bind to CBP and inhibit its co-activator function. CBP is also known to modulate the actions of the hMDM2 and AML1 cellular proto-oncogenes and the BRCA1 and p53 tumour suppressors.7 More direct evidence comes from genetic studies of translocation events involving CBP in leukaemia. In particular, the t(8;16)(p11;p13) translocation in AML involves a fusion of the CBP and MOZ genes, 8 a novel t(10;16)(q22;p13) translocation in a childhood acute myelogenous leukaemia (AML-M5a) generates a MORF-CBP chimera, 9 and the t(11;16)(q23;p13.3) translocation in topoisomerase II treated acute leukaemia or myelodysplasia results in a MLL-CBP fusion. 10 In addition, haploinsufficiency of CBP in humans due to chromosomal rearrangements, microdeletions, and point mutations results in RubensteinTaybi Syndrome (RTS), and is associated with an increased risk for a variety of tumours. 11As a result of these observations, a number of studies have evaluated whether CBP is a direct mutational target in cancer and has tumour suppressor activity. One recent mutation screening study of CBP in breast, ovarian, and colorectal tumours and cell lines identified two CBP truncating mutations in ovarian cancer cell lines, but failed to detect mutations in the tumours. 12 Haematological malignances displaying loss of heterozygosity (LOH) at the CBP locus have been detected in aged CBP heterozygous mice, 13 and in chimeric mice derived from CBP -/-embryonic stem cells. 14 In addition, recent studies using an MMTV driven conditional knockout mouse model demonstrated that truncation of the CBP protein in the thymus results in development of T cell lymphomas, 15 suggesting that targeted mutations in CBP can predispose to cancer. To determine whether CBP is a mutational target in human epithelial cancers, and specifically to evaluate the presence of CBP mutations in breast and ovarian tumours, we conducted a mutational analysis of the CBP gene. MATERIALS AND METHODS Sample selectionA total of 75 unselected surgically resected fresh frozen ovarian tumour specimens and 61 unselected fresh frozen breast tumour specimens were obtained from the ovarian an...

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Section: Discussionmentioning

confidence: 79%

CBP truncating mutations in ovarian cancer

Ward

2005

Journal of Medical Genetics

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“…The arrows indicate the peak that was lost in tumor cells. The sample was considered to have LOH when the value was >2.0 or <0.5 [75,98]. Two different sets of primers were used (set 1 sense: 5’-CCCAAAGAAGCCAACCAGAG-3’ and antisense: 5’-GGCAAATGTGGGAGGTAAGG-3’; set 2 sense: 5’-GAGTGAAAGAGAGTGAGACAG-3’ and antisense: 5’-TCTCACTGTCTCGCTCTGTG-3’) to evaluate the LOH for the 3’ region of h DMP1 to increase the chance of finding a polymorphism.…”

Section: Figurementioning

confidence: 99%

Role of DMP1 and its future in lung cancer diagnostics

Sugiyama

Frazier

Taneja

et al. 2008

Expert Review of Molecular Diagnostics

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Lung cancer is the most lethal carcinoma worldwide. Mutations of p53, inactivation of p16INK4a, and overexpression of cyclins E, A and B are independently associated with poor prognoses of patients, while the prognostic value of cyclin D1 or RB expression is inconclusive. Cyclin D binding myb-like protein 1 (Dmp1) encodes a DNA binding protein that receives signals from oncogenic Ras and functions as a tumor suppressor by activating the Arf-p53 pathway. Dmp1 has been shown to be haplo-insufficient for tumor suppression in mouse models including K-ras-mediated lung carcinogenesis. The human DMP1 gene is located on chromosome 7q21, and our recent results revealed that the hDMP1 gene is deleted, but not mutated or silenced, in approximately 40 % of human non-small-cell lung carcinomas. These cases typically retained wild-type ARF and p53 and expressed very low levels of the hDMP1 protein. Thus, hDMP1 loss could be a novel diagnostic marker for non-small-cell lung carcinomas.

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“…These findings imply that CBP functions as a hematologic tumor suppressor. Moreover, LOH at the CBP locus has been reported in human solid tumors and cancer cell lines including PC-3 PCa cells (13, 14). However, the relevance and the exact role of CBP in PCa pathogenesis are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

CBP Loss Cooperates with PTEN Haploinsufficiency to Drive Prostate Cancer: Implications for Epigenetic Therapy

et al. 2014

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Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−;Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones, in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1 and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic targeted therapy in prostate cancer patients.

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Loss of Heterozygosity and Internal Tandem Duplication Mutations of the CBP Gene Are Frequent Events in Human Esophageal Squamous Cell Carcinoma

Abstract: Conclusions: These studies show that LOH and ITD of the CBP gene are frequent genetic events in human ESCC. These alterations may have functional importance in the development of human ESCC.

Cited by 25 publications

References 46 publications

CBP truncating mutations in ovarian cancer

CBP truncating mutations in ovarian cancer

Role of DMP1 and its future in lung cancer diagnostics

CBP Loss Cooperates with PTEN Haploinsufficiency to Drive Prostate Cancer: Implications for Epigenetic Therapy

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