Deletion mapping at 12p12-13 in metastatic prostate cancer

Kibel, Adam S.; Freije, Diha; Isaacs, William B.; Bova, G. Steven

doi:10.1002/(sici)1098-2264(199907)25:3<270::aid-gcc9>3.0.co;2-z

Cited by 42 publications

(19 citation statements)

References 21 publications

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“…Within this region, homozygous deletion [58] and mutation [59] of TEL (12p13) has been demonstrated. The functional significance of TEL in prostate cancer remains to be experimentally assessed.…”

Section: Telmentioning

confidence: 99%

ETS Transcription Factor Expression and Conversion During Prostate and Breast Cancer Progression

Watson¹,

Turner²,

Scheiber³

et al. 2010

TOCJ

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ETS factors are known to act as positive or negative regulators of the expression of genes including those that control response to various signaling cascades, cellular proliferation, differentiation, hematopoiesis, apoptosis, adhesion, migration, invasion and metastasis, tissue remodeling, ECM composition and angiogenesis. During cancer progression, altered ETS gene expression disrupts the regulated control of many of these biological processes. Although it was originally observed that specific ETS factors function either as positive or negative regulators of transcription, it is now evident that the same ETS factor may function in reciprocal fashions, reflecting promoter and cell context specificities. This report will present a discussion of ETS factor expression during prostate and breast cancer progression and its functional roles in epithelial cell phenotypes.The ETS genes encode transcription factors that have independent activities but are likely to be part of an integrated network. While previous studies have focused on single ETS factors in the context of specific promoters, future studies should consider the functional impact of multiple ETS present within a specific cell type. The pattern of ETS expression within a single tissue is, not surprisingly, quite complex. Multiple ETS factors may be able to regulate the same genes, albeit at different magnitude or in different directions. Furthermore, the precise balance between cancer promotion and inhibition by ETS factors, which may differentially regulate specific target genes, can thus control its progression. These concepts form the basis of the hypothesis that "Ets conversion" plays a critical role during tumor progression. Examples supporting this hypothesis will be described.Keywords: ETS, transcription, prostate cancer, breast cancer, cancer progression, biological control. ETS GENE FAMILYThe oncogene v-ets was first characterized in 1983 as part of the transforming fusion protein of an avian retrovirus, E26 (ets, E26 transforming sequence). Subsequent identification of v-ets related genes from metazoan species established the Ets family as one of the largest families of transcriptional regulators, with diverse functions and activities (for reviews, see [1][2][3][4] and references therein). To date, 27 human ETS family members have been identified (Fig. (1) and Table 1). All Ets genes retain a conserved winged helixturn-helix DNA binding domain (the ETS domain) of ~ 85 amino acids that recognizes a core GGAA/T sequence (ETS binding site, EBS). ETS proteins, with the exception of GABPα, bind DNA as monomers. The second conserved domain found in a subset of ETS genes is the pointed (PNT) domain. This 65-85 amino acid domain is found in 11 of 27 human ETS genes and has been shown to function in protein-protein interaction and oligomerization. ETS factors have been classified into 12 subgroups based upon Ets domain sequence homology: ETS, ERG, PEA3, ETV2, TCF, GABP, ELF, SPI, TEL, ERF, PDEF and ESE [2, 5] (See Table 1 for subgroup members). ...

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Section: Telmentioning

confidence: 99%

ETS Transcription Factor Expression and Conversion During Prostate and Breast Cancer Progression

Watson¹,

Turner²,

Scheiber³

et al. 2010

TOCJ

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“…8 ± 10 The existence of a putative 12p12 tumour suppressor gene is further substantiated by the observation of hemizygous deletions in a variety of haematological malignancies, as well as in certain solid tumours including breast, lung, ovarian and prostate carcinomas. 11,12 This region was shown to contain two known genes, LRP6 and ETV6. LRP6 encodes a member of the LDL receptor family 13 that was recently shown to act as the WNT coreceptor.…”

Section: Introductionmentioning

confidence: 98%

A detailed transcriptional map of the chromosome 12p12 tumour suppressor locus

2002

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Loss of heterozygosity of the short arm of chromosome 12 is a frequent event in a wide range of haematological malignancies and solid tumours. In previous studies, the shortest commonly deleted region was delimited to a 750-kb interval, defined by the markers D12S89 and D12S358, in pre-B acute lymphoblastic leukaemia patients, suggesting the presence of a tumour suppressor locus. Here we report the construction of a transcriptional map that integrates the data obtained by genomic sequence analysis, EST database search, comparative analysis and exon amplification. We identified seven putative transcriptional units as well as six pseudogenes. Four of these candidate genes were already known: ETV6, encoding an ets-like transcription factor, LRP6, a member of the LDL receptor gene family, BCL-G, a recently identified pro-apoptotic gene and MKP-7, encoding a new member of the dual-specificity phosphatase family. The products encoded by the three new genes identified in this study, LOH1CR12, LOH2CR12 and LOH3CR12, have no clear homology to known proteins. The gene predictions were all confirmed by expression analysis using RT ± PCR and Northern blot. This transcriptional map is a crucial step toward the identification of the tumour suppressor gene at 12p12.

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“…13 Many reports of hemizygous deletions in various human malignancies, such as lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, ovarian cancer, and prostate cancer, implicate CDKN1B haploinsufficiency. [14][15][16][17] Underexpression of p27 KIP1 has also been identified as a poor prognostic factor in epithelial cancers. 18 Furthermore, animal models provide direct evidence for the role of haploinsufficiency in cancer by showing that Cdkn1b hemizygote mice are more sensitive than wild-type animals to mutagenesis, and that tumors arising in this context maintained a Cdkn1b haploinsufficient status.…”

Section: Introductionmentioning

confidence: 99%

Haploinsufficiency of CDKN1B contributes to leukemogenesis in T-cell prolymphocytic leukemia

Toriellec

Despouy

Pierron

et al. 2008

Blood

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T-cell prolymphocytic leukemia (T-PLL) isconsistently associated with inactivation of the ATM gene and chromosomal rearrangements leading to an overexpression of MTCP1/TCL1 oncoproteins. These alterations are present at the earliest stage of malignant transformation, suggesting that additional events are required for overt malignancy. In this study, we pursued the investigation of the 12p13 deletion, previously shown to occur in approximately half of T-PLLs. We refined the minimal region of deletion by single nucleotide and microsatellite polymorphism allelotyping. We defined a 216-kb region containing the CDKN1B gene that encodes the cyclin-dependent kinase inhibitory protein p27 KIP1 . Sequencing this gene in 47 T-PLL patient samples revealed a nonsense mutation in one case without 12p13 deletion. The absence of biallelic inactivation of CDKN1B for most patients suggested a haploinsufficiency mechanism for tumor suppression, which was investigated in an animal model of the disease. In a Cdkn1b ϩ/Ϫ background, MTCP1 transgenics had consistent and multiple emergences of preleukemic clones not observed in control cohorts. The second Cdkn1b allele was maintained and expressed in these preleukemic clones. Altogether, these data strongly implicate CDKN1B haploinsufficiency in the pathogenesis of T-PLL. IntroductionT-cell prolymphocytic leukemia (T-PLL) is a rare hematologic disease of elderly people characterized by a mature T-cell phenotype, a large tumoral mass, and an aggressive clinical course. Two genetic alterations are known to play a major role in this disease. First, ATM is somatically deleted or mutated in almost 95% of T-PLL patients (for review, see Stankovic et al 1 ), and germinal mutations of ATM responsible for the ataxia telangiectasia (AT) predispose to T-PLL (for review, see Taylor et al 2 ). Second, chromosomal translocations and inversions involving TCR genes and MTCP1/TCL1 gene family members are consistently and specifically associated with T-PLL, leading to overexpression of these oncogenes. 3,4 The oncogenic role of the MTCP1/TCL1 genes was demonstrated using transgenic mouse models. 5,6 Recently, we showed that MTCP1/TCL1 oncogene expression modified T-cell homeostasis, 7 which may be related to the impairment of activationinduced cell death (AICD) by these oncoproteins. 8 ATM inactivation and MTCP1/TCL1 overexpression are present at the earliest stage of the malignant transformation in clonal T-cell populations frequently found in AT patients. However, the indolent course of these populations suggests that these events are insufficient to induce a leukemic phenotype. 9 In the search for additional events crucial for full-blown transformation, we undertook a comparative genomic hybridization analysis in a series of T-PLL cases that revealed numerous recurrent copy number alterations. 10 One of these alterations was the deletion of the 12p13 region, which was further characterized by allelotyping. This deletion was shown to occur in almost half of T-PLL cases and the minimal region of delet...

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Deletion mapping at 12p12-13 in metastatic prostate cancer

Cited by 42 publications

References 21 publications

ETS Transcription Factor Expression and Conversion During Prostate and Breast Cancer Progression

ETS Transcription Factor Expression and Conversion During Prostate and Breast Cancer Progression

A detailed transcriptional map of the chromosome 12p12 tumour suppressor locus

Haploinsufficiency of CDKN1B contributes to leukemogenesis in T-cell prolymphocytic leukemia

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