Array-CGH Reveals Recurrent Genomic Changes in Merkel Cell Carcinoma Including Amplification of L-Myc

Abstract

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with poorly characterized genetics. We performed high-resolution comparative genomic hybridization on 25 MCC specimens using a high-density oligonucleotide microarray. Tumors frequently carried extra copies of chromosomes 1, 3q, 5p, and 6 and lost chromosomes 3p, 4, 5q, 7, 10 and 13. MCC tumors with less genomic aberration were associated with improved survival (p=0.04). Tumors from 13 of 22 MCC patients had detectable Merkel cell polyomavirus DNA, and these tumors had fewer genomic deletions. Three regions of genomic alteration were of particular interest: a deletion of 5q12-21 occurred in 26% of tumors, a deletion of 13q14-21 was recurrent in 26% of tumors and contains the well-characterized tumor suppressor RB1, and a novel focal amplification at 1p34 was present in 39% of tumors and centers on L-Myc (MYCL1). L-Myc is related to the c-Myc proto-oncogene, has transforming activity, and is amplified in the closely related small cell lung cancer. Normal skin showed no L-Myc expression, while 4/4 MCC specimens tested expressed L-Myc RNA in relative proportion to the DNA copy number gain. These findings suggest several genes that may contribute to MCC pathogenesis, most notably L-Myc.

Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus

“…For example, if the MKL2 tumor cell line contains 2 copies of MCPyV DNA per cell, then each tumor specimen would contain twice as many viral cop ies than we have reported here. In addition, it should be noted that normalization of each tumor specimen to its corresponding TPO DNA content may not be accurate in all cases, since some tumors may have undergone copy number alterations of this gene (28). We observed a significant correlation in the intensity of immuno histochemistry staining with Ab3 and CM2B4 relative to the copy number of MCPyV per cell.…”

“…These primer sequences were identical to most MCPyV sequences and were not crossreactive to any other DNA sequence in the NCBI database. Primers specific for the human TPO gene were used to normalize for diploid gene copy number, since this gene was reported to have infrequent copy number alterations in a study of MCC using array comparative genomic hybridization (28).…”

Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

“…3 Although multiple microarray studies have provided insights into MCC pathogenesis, molecular events essential to MCC pathogenesis are largely unknown. [4][5][6] Though the principal tenet in cancer is that tumor is initiated and driven by mutations, it is now clear that epigenetic pathways also play a significant role in oncogenesis. Moreover, diverse gene mutations generally converge functionally to deregulate similar core cellular process, which can be targeted by approaching epigenetic vulnerabilities.…”

Oncogenes and Tumor Suppressor Genes in Small Cell Lung Carcinoma

“…Amplification of the c-MYC oncogene has been observed in various human malignancies (Komiya et al, 2011). Studies in small cell lung cancer have suggested that although amplification of the MYC family genes is seen in only about 10% of patients with newly diagnosed SCLC, this proportion increases following treatment (Komiya et al, 2011;Paulson et al, 2009;Xion et al, 2011 ;Barr et al, 1998), suggesting that MYC expression increases with resistance of SCLC to therapy. Other studies have suggested that higher levels of expression of the MYC gene family may play a significant role in the carcinogenesis of SCLC (Kumimoto et al, 2002).…”

“…c-MYC, N-MYC and L-MYC are proto-oncogenes that code for proteins involved in the regulation of proliferation, differentiation, and apoptosis (Komiya et al, 2011;Paulson et al, 2009;Xion et al, 2011). Amplification of the c-MYC oncogene has been observed in various human malignancies (Komiya et al, 2011).…”