(Cyclin D1)
Cyclin D1 (synonymes: PRAD1, parathyroid adenomatosis 1, CCND1) is a 295 amino acid protein, 36 kDa, which belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. The gene is located in chromosome 11q13. Cyclins function as regulators of cyclin dependent kinase (CDK). Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. Cyclin D1 forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. The protein has been shown to interact with tumour suppressor protein Rb and its expression is regulated positively by Rb. The expression is cell cycle dependant, maximal in G1 and minimal in S phase. Localization is mainly nuclear. In normal tissues, Cyclin D1 expression is restricted to the proliferative zone of epithelial tissues, endothelium and some fibroblasts. There is no expression in lymphoid tissue.
Mutations with amplification of the cyclin D1 gene, with overexpression of the protein, which alters cell cycle progression, are observed frequently in a variety of tumours and may contribute to tumourigenesis. Immunohistochemical analysis frequently reveals great heterogeneity in cyclin D1 expression from cell to cell and from case to case. Cyclin D1 is involved in B-lymphocytic malignancy (by a chromosomal translocation t(11;14) that also involves Ig gene regions (BCL-1 oncogene)), particularly mantle cell lymphoma, where it is detected immunohistochemically in more than 90% of the cases. Even a weak expression of cyclin D1 should be interpreted as a positive finding in mantle cell lymphoma. Cyclin D1 is also expressed in hairy cell leukaemia and in a subtype of CD20 positive multiple myeloma, where it may be prognostically favourable. Cyclin D1 has been demonstrated in in many types of carcinoma (breast, colorectum, urinary bladder, thyroid gland), in Spitz nevus and malignant melanoma. Cyclin D1 is furthermore involved in a subset of parathyroid adenomas by a chromosomal translocation t(11;11) that also involves the parathyroid hormone (PTH) enhancer (PRAD1 oncogene).
In diagnostic pathology, immunohistochemical detection of Cyclin D1 is used mainly for the diagnosis of mantle cell lymphoma. While other methods of cyclin D1 detection are being explored, immunohistochemistry is still widely used and anti-cyclin D1 antibodies remain an essential component in a small B-cell lymphoproliferative disorder panel.
Tonsil can be recommended as positive and negative tissue control for CyD1. Virtually all suprabasal squamous epithelial cells, scattered lymphocytes and endothelial cells must show a moderate to strong distinct nuclear staining reaction, whereas a weak nuclear staining reaction of germinal centre macrophages should be seen. A weak cytoplasmic staining reaction together with the specific nuclear reaction must be accepted. Mantle zone B-cells and germinal centre B-cells should be negative.
Selected references
Athanasiou E, Kaloutsi V, Kotoula V, Hytiroglou P, Kostopoulos I, Zervas C, Kalogiannidis P, Fassas A, Christakis JI, Papadimitriou CS. Cyclin D1 overexpression in multiple myeloma. A morphologic, immunohistochemical, and in situ hybridization study of 71 paraffin-embedded bone marrow biopsy specimens. Am J Clin Pathol. 2001 Oct;116(4):535-42. Donnellan R, Chetty R. Cyclin D1 and human neoplasia. Mol Pathol. 1998 Feb;51(1):1-7. Review. Jain P, Giustolisi GM, Atkinson S, Elnenaei MO, Morilla R, Owusu-Ankomah K, Rafiq-Mohammed F, Matutes E, Wotherspoon A, Catovsky D. Detection of cyclin D1 in B cell lymphoproliferative disorders by flow cytometry. J Clin Pathol. 2002 Dec;55(12):940-5. Huret JL . Mantle cell lymphoma (incomplete). Atlas Genet Cytogenet Oncol Haematol. May 1998. URL: Leoncini L, Lazzi S, Bellan C, Tosi P. Cell kinetics and cell cycle regulation in lymphomas. J Clin Pathol. 2002 Sep;55(9):648-55. Review. Miranda RN, Briggs RC, Kinney MC, Veno PA, Hammer RD, Cousar JB. Immunohistochemical detection of cyclin D1 using optimized conditions is highly specific for mantle cell lymphoma and hairy cell leukemia. Mod Pathol. 2000 Dec;13(12):1308-14. Soverini S, Cavo M, Terragna C, Zamagni E, Ruggeri D, Cellini C, Testoni N, Tosi P, De Vivo A, Amabile M, Grafone T, Ottaviani E, Giannini B, Cangini D, Bonifazi F, Neri A, Fabris S, Tura S, Baccarani M, Martinelli G. Cyclin D1 overexpression is a favorable prognostic variable for newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and single or double autologous transplantation. Blood. 2003 May 1 [Epub ahead of print] Specht K, Kremer M, Muller U, Dirnhofer S, Rosemann M, Hofler H, Quintanilla-Martinez L, Fend F. Identification of cyclin D1 mRNA overexpression in B-cell neoplasias by real-time reverse transcription-PCR of microdissected paraffin sections. Clin Cancer Res. 2002 Sep;8(9):2902-11. Torlakovic E, Nielsen S, Vyberg M. Antibody selection in immunohistochemical detection of cyclin D1 in mantle cell lymphoma. Am J Clin Pathol. 2005 Nov;124(5):782-9.
19.11.11 - ET/MV/LE