The role of CCND1 alterations during the progression of cutaneous malignant melanoma

It is well demonstrated that CCND1 amplification is a frequent event in the acral subtype of cutaneous malignant melanoma; however, its role in the other subtypes of the disease is still controversial. The objectives of this study were to evaluate genetic and expression alterations of CCND1 with a focus on primary cutaneous melanomas, to define BRAF and NRAS mutation status, and correlate the data with clinical–pathological parameters. CCND1 amplification was associated with ulceration and the localization of the metastasis. After correction for the mutation state of BRAF and NRAS genes, CCND1 amplification in samples without such mutations was associated with ulceration and sun exposure. The cyclin D1 (CCND1) mRNA level decreased in lesions with multiple metastases and was correlated with both the mRNA levels and mutation state of BRAF and NRAS genes. Primary melanomas with BRAFV600 or NRASQ61 mutations exhibited lower CCND1 mRNA level. CCND1 protein expression was associated with Breslow thickness, metastasis formation, and shorter survival time. These observations suggest that CCND1 alterations are linked to melanoma progression and are modified by BRAF and NRAS mutations. Our data show that CCND1 amplification could have a prognostic relevance in cutaneous melanoma and highlight that altered CCND1 gene expression may influence the metastatic progression, survival, and the localization of metastases.

[1]  R. Assoian,et al.  Transcriptional regulation of the cyclin D1 gene at a glance , 2008, Journal of Cell Science.

[2]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[3]  T. Godfrey,et al.  Gene amplifications characterize acral melanoma and permit the detection of occult tumor cells in the surrounding skin. , 2000, Cancer research.

[4]  A. Wojas-Pelc,et al.  Cyclin D1 and D3 expression in melanocytic skin lesions , 2010, Archives of Dermatological Research.

[5]  J. Guitart,et al.  Homogeneous Staining Regions for Cyclin D1, a Marker of Poor Prognosis in Malignant Melanoma , 2012, The American Journal of dermatopathology.

[6]  M. Malumbres,et al.  MicroRNAs and the cell cycle. , 2011, Biochimica et biophysica acta.

[7]  R. Ádány,et al.  Chromosomal imbalances in laryngeal and hypopharyngeal cancers detected by comparative genomic hybridization , 2005, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[8]  Richard A Scolyer,et al.  Histologically ambiguous ("borderline") primary cutaneous melanocytic tumors: approaches to patient management including the roles of molecular testing and sentinel lymph node biopsy. , 2010, Archives of pathology & laboratory medicine.

[9]  A. Lueking,et al.  Determination and validation of off-target activities of anti-CD44 variant 6 antibodies using protein biochips and tissue microarrays. , 2008, BioTechniques.

[10]  Chenguang Wang,et al.  Cyclin D1/cyclin-dependent kinase 4 interacts with filamin A and affects the migration and invasion potential of breast cancer cells. , 2010, Cancer research.

[11]  R. Assoian,et al.  Integrin-dependent signal transduction regulating cyclin D1 expression and G1 phase cell cycle progression , 2005, Cancer and Metastasis Reviews.

[12]  L. Morrison,et al.  Fluorescence In Situ Hybridization (FISH) as an Ancillary Diagnostic Tool in the Diagnosis of Melanoma , 2009, The American journal of surgical pathology.

[13]  T. Golub,et al.  A Mechanism of Cyclin D1 Action Encoded in the Patterns of Gene Expression in Human Cancer , 2003, Cell.

[14]  Xiaolong Yang,et al.  MicroRNA-193b represses cell proliferation and regulates cyclin D1 in melanoma. , 2010, The American journal of pathology.

[15]  K. Nagashima,et al.  Cyclin D1, p16 and retinoblastoma gene product expression as a predictor for prognosis in non-small cell lung cancer at stages I and II. , 2001, Lung cancer.

[16]  R. Ádány,et al.  Prognostic relevance of the expressions of CAV1 and TES genes on 7q31 in melanoma. , 2012, Frontiers in bioscience.

[17]  Jeffrey E Gershenwald,et al.  Final version of 2009 AJCC melanoma staging and classification. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  G. C. Nogueira,et al.  Stages I and II , 2000 .

[19]  Hong Wu,et al.  Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E–mutated melanomas , 2008, Molecular Cancer Therapeutics.

[20]  R. Sutherland,et al.  Cyclin D1 and mammary carcinoma: new insights from transgenic mouse models , 2001, Breast Cancer Research.

[21]  Andrew R. Green,et al.  CCND1 amplification and cyclin D1 expression in breast cancer and their relation with proteomic subgroups and patient outcome , 2008, Breast Cancer Research and Treatment.

[22]  K. Nathanson Using genetics and genomics strategies to personalize therapy for cancer: focus on melanoma. , 2010, Biochemical pharmacology.

[23]  T. Saida,et al.  Specific dermoscopy patterns and amplifications of the cyclin D1 gene to define histopathologically unrecognizable early lesions of acral melanoma in situ. , 2005, Archives of dermatology.

[24]  Bruno Augusto Benevenuto Andrade,et al.  Immunohistochemical Expression of p16, p21, p27 and Cyclin D1 in Oral Nevi and Melanoma , 2012, Head and Neck Pathology.

[25]  R. Ádány,et al.  EGFR gene copy number alterations in primary cutaneous malignant melanomas are associated with poor prognosis , 2007, International journal of cancer.

[26]  S Detre,et al.  A "quickscore" method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. , 1995, Journal of clinical pathology.

[27]  A. Cochran,et al.  Molecular classification of melanomas and nevi using gene expression microarray signatures and formalin-fixed and paraffin-embedded tissue , 2009, Modern Pathology.

[28]  B. Thiers Distribution and Significance of Occult Intraepidermal Tumor Cells Surrounding Primary Melanoma , 2009 .

[29]  Y. Moroi,et al.  Expression of c-Kit, p-ERK and cyclin D1 in malignant melanoma: an immunohistochemical study and analysis of prognostic value. , 2011, Journal of dermatological science.

[30]  R. Ádány,et al.  Marked genetic differences between BRAF and NRAS mutated primary melanomas as revealed by array comparative genomic hybridization , 2012, Melanoma research.

[31]  M. Imoto,et al.  Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression , 2007, Cancer science.

[32]  J. Diehl,et al.  Nuclear cyclin D1: An oncogenic driver in human cancer , 2009, Journal of cellular physiology.

[33]  S. Steinberg,et al.  Expression levels of eIF4E, VEGF, and cyclin D1, and correlation of eIF4E with VEGF and cyclin D1 in multi-tumor tissue microarray. , 2007, Oncology reports.

[34]  D. Pinkel,et al.  Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization. , 1998, Cancer research.

[35]  R. Ádány,et al.  Characterization of candidate gene copy number alterations in the 11q13 region along with BRAF and NRAS mutations in human melanoma , 2009, Modern Pathology.

[36]  Yi Tie,et al.  MicroRNA-193b regulates proliferation, migration and invasion in human hepatocellular carcinoma cells. , 2010, European journal of cancer.

[37]  Chenguang Wang,et al.  Minireview: Cyclin D1: normal and abnormal functions. , 2004, Endocrinology.

[38]  E. Schuuring,et al.  Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification. , 1996, Oncogene.

[39]  G. Nai,et al.  Role of ROC1 protein in the control of cyclin D1 protein expression in skin melanomas. , 2011, Pathology, research and practice.

[40]  A. Rademaker,et al.  Copy number gains in 11q13 and 8q24 [corrected] are highly linked to prognosis in cutaneous malignant melanoma. , 2011, The Journal of molecular diagnostics : JMD.

[41]  D. Pinkel,et al.  Cyclin D1 is a candidate oncogene in cutaneous melanoma. , 2002, Cancer research.

[42]  M. Strauss,et al.  Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer. , 1995, Cancer research.

[43]  D. Schadendorf,et al.  Somatic alterations in the melanoma genome: A high‐resolution array‐based comparative genomic hybridization study , 2010, Genes, chromosomes & cancer.

[44]  J. Stockman,et al.  Distinct Sets of Genetic Alterations in Melanoma , 2007 .

[45]  Chen Kai-hu Application of fluorescence in situ hybridization , 2012 .