CCND1

The proto-oncogene cyclin D1 has been implicated in the genesis of a large proportion of human tumors from diverse histological origins.

Function

 activator of cdk4 and cdk6 in progression through the G1 phase of the cell cycle

Pathology

 cyclin D1 overexpression in mantle cell lymphoma

• The cytogenetic and diagnostic hallmark of mantle cell lymphoma (MCL) is translocation t(11;14)(q13;q32), resulting in overexpression of cyclin D1.
• There are rare cyclin D1-negative cases of MCL overexpressing cyclin D2 (CCND2).

 germline mutations in familial cylindromatosis
 somatic mutations in

• sporadic spiradenocylindroma (11756779)

 Chromosomal translocations involving the CCND1 locus at 11q13 and overexpression of cyclin D1 occur in a subset of renal oncocytomas.

• Renal oncocytomas lacking cyclin D1 overexpression may be associated with the development of multiple renal oncocytomas and these patients are more likely to develop subsequent renal oncocytomas.
• The data also show that cyclin D1 overexpression and CCND1 rearrangements by fluorescence in situ hybridization are absent in chromophobe renal cell carcinoma, suggesting that these are useful when differentiating between renal oncocytoma and chromophobe renal cell carcinoma.

 Cyclin-D1 in melanocytic tumors

All melanocytic tumors with increased copy number overexpress cyclin D1 protein. However, about 25% of melanomas also overexpress cyclin D1 but do have normal copy number of the cyclin D1 gene. (Bastian BC, 2003; 12789284)

Antisense-mediated inhibition of cyclin D1 expression led to massive apoptosis in melanoma cell lines with cyclin D1 amplification, but not in normal melanocytes.

The amplifications target oncogenes and that gene amplifications could be an essential mechanism of oncogene activation in acral melanomas. It appears possible that a distinct defect, for example, in the repair of double-stranded DNA breaks is responsible for the permissiveness for gene amplification in this melanoma type. (Bastian BC, 2003; 12789284)

 Improved diagnostic segregation of mantle cell lymphoma can be determined by cyclin D1/D3 expression ratio in formalin-fixed tissue. (19704260)

Diagnostic use

 overexpression in mantle zone lymphoma (MZL)

 Cyclin D1 can be expressed in CLL proliferation centers

• https://twitter.com/Gleason4plus5/status/740977055395893250

References

 Improved diagnostic segregation of mantle cell lymphoma by determination of cyclin D1/D3 expression ratio in formalin-fixed tissue. Mangseth K, Helgeland L, Klos J, Molven A, Vintermyr OK. Diagn Mol Pathol. 2009 Sep;18(3):150-5. PMID: 19704260

 Complex analysis of cyclin D1 expression in mantle cell lymphoma: two cyclin D1-negative cases detected. Stefancikova L, Moulis M, Fabian P, Falkova I, Vasova I, Kren L, Macak J, Smardova J. J Clin Pathol. 2009 Oct;62(10):948-50. PMID: 19783727

 CCND1 rearrangements and cyclin D1 overexpression in renal oncocytomas: frequency, clinicopathologic features, and utility in differentiation from chromophobe renal cell carcinoma. Sukov WR, Ketterling RP, Lager DJ, Carlson AW, Sinnwell JP, Chow GK, Jenkins RB, Cheville JC. Hum Pathol. 2009 Apr 20. PMID: 19386349

 Strobel P, Zettl A, Ren Z, Starostik P, Riedmiller H, Storkel S, Muller-Hermelink HK, Marx A. Spiradenocylindroma of the kidney: clinical and genetic findings suggesting a role of somatic mutation of the CYLD1 gene in the oncogenesis of an unusual renal neoplasm. Am J Surg Pathol. 2002 Jan;26(1):119-24. PMID: 11756779

 Chung DC. Cyclin D1 in human neuroendocrine tumorigenesis.
Ann N Y Acad Sci. 2004 Apr;1014:209-17. PMID: 15153436

 Ewen ME, Lamb J. The activities of cyclin D1 that drive tumorigenesis. Trends Mol Med. 2004 Apr;10(4):158-62. PMID: 15059606