Unfavorable prognosis of CRTC1‐MAML2 positive mucoepidermoid tumors with CDKN2A deletions

The CRTC1‐MAML2 fusion oncogene underlies the etiology of mucoepidermoid salivary gland carcinoma (MEC) where it confers a favorable survival outcome as compared with fusion‐negative MEC. While these analyses suggested that detection of CRTC1‐MAML2 serves as a useful prognostic biomarker, we recently identified outlier cases of fusion‐positive MEC associated with advanced‐staged lethal disease. To identify additional genetic alterations that might cooperate with CRTC1‐MAML2 to promote disease progression, we performed a pilot high‐resolution oligonucleotide array CGH (aCGH) and PCR‐based genotyping study on 23 MEC samples including 14 fusion‐positive samples for which we had clinical outcome information. Unbiased aCGH analysis identified inactivating deletions within CDKN2A as a candidate poor prognostic marker which was confirmed by PCR‐based analysis (CDKN2A deletions in 5/5 unfavorable fusion‐positive cases and 0/9 favorable fusion‐positive cases). We did not detect either activating EGFR mutations, nor copy number gains at the EGFR or ERBB2 loci as poor prognostic features for fusion‐positive MEC in any of the tumor specimens. Prospective studies with larger case series will be needed to confirm that combined CRTC1‐MAML2 and CDKN2A genotyping will optimally stage this disease. © 2009 Wiley‐Liss, Inc.

[1]  J. Lennerz,et al.  Mucoepidermoid Carcinoma of the Cervix: Another Tumor With the t(11;19)-associated CRTC1-MAML2 Gene Fusion , 2009, The American journal of surgical pathology.

[2]  A. Nicholson,et al.  Mammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma. , 2009, Human pathology.

[3]  D. Ivan,et al.  Cutaneous Hidradenocarcinoma: A Clinicopathological, Immunohistochemical, and Molecular Biologic Study of 14 Cases, Including Her2/neu Gene Expression/Amplification, TP53 Gene Mutation Analysis, and t(11;19) Translocation , 2009, The American Journal of dermatopathology.

[4]  G. Rossi,et al.  Mucoepidermoid carcinoma of the lung, response to EGFR inhibitors, EGFR and K-RAS mutations, and differential diagnosis. , 2009, Lung cancer.

[5]  S. Thibodeau,et al.  Salivary gland-type lung carcinomas: an EGFR immunohistochemical, molecular genetic, and mutational analysis study , 2008, Modern Pathology.

[6]  Y. Bang,et al.  Mucoepidermoid carcinoma of lung: potential target of EGFR-directed treatment. , 2008, Lung cancer.

[7]  H. Kosmehl,et al.  Detection of drug-sensitizing EGFR exon 19 deletion mutations in salivary gland carcinoma , 2008, British Journal of Cancer.

[8]  Steven Piantadosi,et al.  DNA methylation markers and early recurrence in stage I lung cancer. , 2008, The New England journal of medicine.

[9]  Jörn Bullerdiek,et al.  A new type of MAML2 fusion in mucoepidermoid carcinoma , 2008, Genes, chromosomes & cancer.

[10]  S. Kannan,et al.  Differential Roles of p16INK4A and p14ARF Genes in Prognosis of Oral Carcinoma , 2008, Cancer Epidemiology Biomarkers & Prevention.

[11]  T. Löning,et al.  A closer look at Warthin tumors and the t(11;19). , 2008, Cancer genetics and cytogenetics.

[12]  T. Vaněček,et al.  Skin-type hidradenoma of the breast parenchyma with t(11;19) translocation: hidradenoma of the breast. , 2007, The American Journal of dermatopathology.

[13]  F. Kaye,et al.  CRTC1/MAML2 fusion transcript in high grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin's tumors: Implications for histogenesis and biologic behavior , 2007, Genes, chromosomes & cancer.

[14]  G. Petruzzelli,et al.  Contemporary management of tumors of the salivary glands , 2007, Current oncology reports.

[15]  F. Wei,et al.  Alterations of p16INK4a tumour suppressor gene in mucoepidermoid carcinoma of the salivary glands. , 2007, International journal of oral and maxillofacial surgery.

[16]  M. Luna Salivary Mucoepidermoid Carcinoma: Revisited , 2006, Advances in anatomic pathology.

[17]  F. Kaye,et al.  Sustained expression of Mect1-Maml2 is essential for tumor cell growth in salivary gland cancers carrying the t(11;19) translocation , 2006, Oncogene.

[18]  Shigeo Nakamura,et al.  MECT1-MAML2 Fusion Transcript Defines a Favorable Subset of Mucoepidermoid Carcinoma , 2006, Clinical Cancer Research.

[19]  A. Russo,et al.  TP53 and p16INK4A, but not H‐KI‐Ras, are involved in tumorigenesis and progression of pleomorphic adenomas , 2006, Journal of cellular physiology.

[20]  L. Szekely,et al.  Molecular classification of mucoepidermoid carcinomas—Prognostic significance of the MECT1–MAML2 fusion oncogene , 2006, Genes, chromosomes & cancer.

[21]  A. El-Naggar Clear Cell Hidradenoma of the Skin—A Third Tumor Type With a t(11;19)-Associated TORC1-MAML2 Gene Fusion: Genes Chromosomes Cancer. 2005;43:202–205 , 2006, Advances in anatomic pathology.

[22]  S. Baylin,et al.  Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? , 2006, Nature Reviews Cancer.

[23]  L. Mao,et al.  Promoter methylation of p16INK4a, RASSF1A, and DAPK is frequent in salivary adenoid cystic carcinoma , 2005, Cancer.

[24]  F. Kaye,et al.  Mect1-Maml2 fusion oncogene linked to the aberrant activation of cyclic AMP/CREB regulated genes. , 2005, Cancer research.

[25]  L. Myeroff,et al.  Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. , 2005, Journal of the National Cancer Institute.

[26]  J. J. van den Oord,et al.  Clear cell hidradenoma of the skin—a third tumor type with a t(11;19)‐associated TORC1–MAML2 gene fusion , 2005, Genes, chromosomes & cancer.

[27]  G. Tonon,et al.  A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin's tumor of salivary glands. , 2004, The Journal of molecular diagnostics : JMD.

[28]  U. Lendahl,et al.  Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors. , 2004, Experimental cell research.

[29]  G. Tonon,et al.  t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway , 2003, Nature Genetics.

[30]  G. Tonon,et al.  t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway , 2003, Nature Genetics.

[31]  F. Kaye,et al.  RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer , 2002, Oncogene.

[32]  M. Urken,et al.  Mucoepidermoid Carcinoma: A Clinicopathologic Study of 80 Patients With Special Reference to Histological Grading , 2001, The American journal of surgical pathology.

[33]  D. Sidransky,et al.  p16(MTS-1/CDKN2/INK4a) in cancer progression. , 2001, Experimental cell research.

[34]  P. Auclair,et al.  Mucoepidermoid carcinoma of the major salivary glands: clinical and histopathologic analysis of 234 cases with evaluation of grading criteria , 2000 .

[35]  C. Moskaluk,et al.  Analysis of chromosome 9p21 deletion and p16 gene mutation in salivary gland carcinomas. , 1999, Human pathology.

[36]  Y. Fujioka,et al.  Deletion of the p16 Gene and Microsatellite Instability in Carcinoma Arising in Pleomorphic Adenoma of the Parotid Gland , 1998, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[37]  G. Ellis,et al.  Mucoepidermoid carcinoma of the major salivary glands , 1998, Cancer.

[38]  J. Herman,et al.  Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. , 1995, Cancer research.

[39]  F. Kaye,et al.  CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16INK4 protein induction by 5-aza 2'deoxycytidine. , 1995, Oncogene.

[40]  J. Batsakis,et al.  Histocytologic grading of mucoepidermoid carcinoma of major salivary glands in prognosis and survival: A clinicopathologic and flow cytometric investigation , 1995, Head & neck.

[41]  I. Fonseca,et al.  Mucoepidermoid carcinoma of the salivary glands: A reappraisal of the influence of tumor differentiation on prognosis , 1991, Journal of surgical oncology.

[42]  J. Zeitlhofer,et al.  Mucoepidermoid Carcinoma of the Cervix , 1982 .