| Entity | B-cell acute lymphoblastic leukaemia (B-ALL) with t(6;14)(p22;q32) --> ID4- IGH |
| Note | ID4 was juxtaposed to the IGH enhancer, leading to ID4 overexpression. (Bellido et al 2003, Russell et al 2008). |
| Prognosis | Prognosis in this disease looks fair. |
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| Entity | Non Hodgkin lymphoma |
| Note | ID4 promoter was found hypermethylated in follicular lymphomas, diffuse large B-cell lymphomas, as well as lymphoid cell lines (Hagiwara K et al 2007). |
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| Entity | Brain tumours |
| Note | In oligodendroglial tumours and glioblastomas, ID4 is expressed in neoplastic astrocytes but not in neoplastic oligodendrocytes (Liang et al, 2005). |
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| Entity | Breast cancer |
| Note | Hypermethylation of ID4 promoter and ID4 mRNA suppression was found in breast cancer cell lines as well as in primary breast cancers. In one study, it was a significant risk factor for nodal metastasis (Umetani et al, 2006). In another study, BRCA1, ER (estrogen receptor), and ID4 were found expressed in breast cancer specimens from patients with invasive carcinomas. Most of the patients who expressed BRCA1 also expressed ER, but were negative for ID4, and vice versa. BRCA1-ER and ID4 are linked in a negative correlation (Roldan et al 2006). Id4 regulates BRCA1 expression and may be involved in hormone-dependent regulation of BRCA1 homeostasis (de Candia et al 2004). ID4 is constitutively expressed in the normal human mammary epithelium but is suppressed in ER-.
Positive breast carcinomas and preneoplastic lesions. ER-negative carcinomas are Id4 positive (de Candia et al 2006).
These results support a possible role of Id4 as a tumor suppressor factor in the human breast and suggest that the expression of Id4 in the mammary ductal epithelium may be regulated by estrogen (de Candia et al 2006). |
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| Entity | Bladder cancer |
| Note | ID4 is part of the 6p22.3 amplicon frequently observed in advanced stage bladder cancer. ID4, as well as E2F3 and DEK, was overexpressed in bladder cancer cell lines. This overexpression was correlated with the copy number. However, ID4 expression was equivalent in fresh cancer tissues and normal urothelium (Wu et al, 2005). |
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| Entity | Gastric cancer |
| Note | ID4 promoter is hypermethylated and showed a low level of expression in 30% of gastric adenocarcinomas and in most gastric cancer cell lines, while it's expression was high in normal gastric mucosa. Furthermore, there was a significant association of ID4 promoter hypermethylation / ID4 down regulation and that of hMLH1 and microsatellite instability (Chan et al 2003). |
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| Entity | Colorectal cancer |
| Note | ID4 is silenced in colorectal cancer: Hypermethylation was found in half of the primary colorectal cancer specimens tested (and in cell lines as well), in 3/4 of liver metastases of colorectal cancer specimens tested, but not in normal epitheliums nor in adenomas. Moreover, the methylation status was correlated with the histopathological grade, and hypermethylation of ID4 was identified as a significant independant risk factor of poor prognosis (Umetani et al 2005). |
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| Entity | Rett syndrome |
| Note | A significantly increased protein expression of ID genes was found in human brain tissue of Rett syndrome patients, compared to controls (Peddada et al 2006). Rett syndrome is a X-linked neurodevelopmental disorder resembling autism, and due to MECP2 (Xq28 ) mutations in most cases, more rarely due to mutations of CDKL5 (Xp22) or, much less convaincingly, NTNG1 (1p13). |
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| Injury selectively down-regulates the gene encoding for the Id4 transcription factor in primary cultures of forebrain astrocytes. |
| Andres-Barquin PJ, Hernandez MC, Israel MA. |
| Neuroreport. 1998 Dec 21;9(18):4075-80. |
| PMID 9926850 |
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| Id4 expression induces apoptosis in astrocytic cultures and is down-regulated by activation of the cAMP-dependent signal transduction pathway. |
| Andres-Barquin PJ, Hernandez MC, Israel MA. |
| Exp Cell Res. 1999 Mar 15;247(2):347-55. |
| PMID 10066362 |
| |
| Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. |
| Massari ME, Murre C. |
| Mol Cell Biol. 2000 Jan;20(2):429-40. |
| PMID 10611221 |
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| Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach. |
| Beger C, Pierce LN, Kruger M, Marcusson EG, Robbins JM, Welcsh P, Welch PJ, Welte K, King MC, Barber JR, Wong-Staal F. |
| Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):130-5. |
| PMID 11136250 |
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| Hormonal regulation and differential actions of the helix-loop-helix transcriptional inhibitors of differentiation (Id1, Id2, Id3, and Id4) in Sertoli cells. |
| Chaudhary J, Johnson J, Kim G, Skinner MK. |
| Endocrinology. 2001 May;142(5):1727-36. |
| PMID 11316735 |
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| The regulation and function of the Id proteins in lymphocyte development. |
| Rivera R, Murre C. |
| Oncogene. 2001 Dec 20;20(58):8308-16. |
| PMID 11840323 |
| |
| Id4 is deregulated by a t(6;14)(p22;q32) chromosomal translocation in a B-cell lineage acute lymphoblastic leukemia. |
| Bellido M, Aventín A, Lasa A, Estivill C, Carnicer MJ, Pons C, Matías-Guiu X, Bordes R, Baiget M, Sierra J, Nomdedeu JF. |
| Haematologica. 2003 Sep;88(9):994-1001. |
| PMID 12969807 |
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| Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma. |
| Chan AS, Tsui WY, Chen X, Chu KM, Chan TL, Chan AS, Li R, So S, Yuen ST, Leung SY. |
| Oncogene. 2003 Oct 9;22(44):6946-53. |
| PMID 14534543 |
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| Id4 regulates mammary epithelial cell growth and differentiation and is overexpressed in rat mammary gland carcinomas. |
| Shan L, Yu M, Qiu C, Snyderwine EG. |
| Am J Pathol. 2003 Dec;163(6):2495-502. |
| PMID 14633621 |
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| A role for Id proteins in mammary gland physiology and tumorigenesis. |
| de Candia P, Benera R, Solit DB. |
| Adv Cancer Res. 2004;92:81-94. Review. |
| PMID 15530557 |
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| Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis. |
| Umetani N, Takeuchi H, Fujimoto A, Shinozaki M, Bilchik AJ, Hoon DS. |
| Clin Cancer Res. 2004 Nov 15;10(22):7475-83. |
| PMID 15569977 |
| |
| Id4 regulates neural progenitor proliferation and differentiation in vivo. |
| Yun K, Mantani A, Garel S, Rubenstein J, Israel MA. |
| Development. 2004 Nov;131(21):5441-8. Epub 2004 Oct 6. |
| PMID 15469968 |
| |
| Id4 is required for the correct timing of neural differentiation. |
| Bedford L, Walker R, Kondo T, van Cruchten I, King ER, Sablitzky F. |
| Dev Biol. 2005 Apr 15;280(2):386-95. |
| PMID 15882580 |
| |
| Id4 and FABP7 are preferentially expressed in cells with astrocytic features in oligodendrogliomas and oligoastrocytomas. |
| Liang Y, Bollen AW, Nicholas MK, Gupta N. |
| BMC Clin Pathol. 2005 Jul 15;5:6. |
| PMID 16018821 |
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| Aberrant hypermethylation of ID4 gene promoter region increases risk of lymph node metastasis in T1 breast cancer. |
| Umetani N, Mori T, Koyanagi K, Shinozaki M, Kim J, Giuliano AE, Hoon DS. |
| Oncogene. 2005 Jul 7;24(29):4721-7. |
| PMID 15897910 |
| |
| Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer. |
| Wu Q, Hoffmann MJ, Hartmann FH, Schulz WA. |
| Mol Cancer. 2005 May 5;4(1):16. |
| PMID 15876350 |
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| Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. |
| Yu L, Liu C, Vandeusen J, Becknell B, Dai Z, Wu YZ, Raval A, Liu TH, Ding W, Mao C, Liu S, Smith LT, Lee S, Rassenti L, Marcucci G, Byrd J, Caligiuri MA, Plass C. |
| Nat Genet. 2005 Mar;37(3):265-74. |
| PMID 15723065 |
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| Id4 messenger RNA and estrogen receptor expression: inverse correlation in human normal breast epithelium and carcinoma. |
| de Candia P, Akram M, Benezra R, Brogi E. |
| Hum Pathol. 2006 Aug;37(8):1032-41. Epub 2006 May 22. |
| PMID 16867866 |
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| Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome. |
| Peddada S, Yasui DH, LaSalle JM. |
| Hum Mol Genet. 2006 Jun 15;15(12):2003-14. Epub 2006 May 8. |
| PMID 16682435 |
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| Tumoral expression of BRCA1, estrogen receptor alpha and ID4 protein in patients with sporadic breast cancer. |
| Roldan G, Delgado L, Muse IM. |
| Cancer Biol Ther. 2006 May;5(5):505-10. Epub 2006 May 13. |
| PMID 16582598 |
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| Frequent DNA methylation but not mutation of the ID4 gene in malignant lymphoma. |
| Hagiwara K, Nagai H, Li Y, Ohashi H, Hotta T, Saito H. |
| J Clin Exp Hematop. 2007 Apr;47(1):15-8. |
| PMID 17510533 |
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| t(6;14)(p22;q32): a new recurrent IGHa translocation involving ID4 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). |
| Russell LJ, Akasaka T, Majid A, Sugimoto KJ, Loraine Karran E, Nagel I, Harder L, Claviez A, Gesk S, Moorman AV, Ross F, Mazzullo H, Strefford JC, Siebert R, Dyer MJ, Harrison CJ. |
| Blood. 2008 Jan 1;111(1):387-91. |
| PMID 17940204 |
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