Recurrent DNA copy number changes revealed by comparative genomic hybridization in primary Merkel cell carcinomas

Abstract

Comparative genomic hybridization (CGH) was used to search for gains, high-level amplifications and losses of DNA sequences along all chromosome arms in 19 primary Merkel cell carcinomas (MCC). Extensive genetic aberrations, with a mean value of 5.571.1 changes per tumor were detected in 13 out of the 19 samples analyzed. Our CGH results reveal several new and other previously known chromosomal regions that are involved in the pathogenesis of MCC. The majority of the alterations were gains of whole chromosomes or whole chromosome arms. Compared to losses, the frequency of DNA copy number gains was two-fold. DNA sequence copy number gains were most common in chromosomes 6 (42%), 1 (37%), and 5 (32%). The most frequent minimal common regions of gains were 6pterqter (42%), 1q11q31 (32%), and 5p (32%). No recurrent high-level amplifications were observed. High-level amplifications of small chromosomal regions were found in four samples out of the 19 tumors analyzed (21%). Amplifications affected 1q22q24 (5%), 4p (5%), and 5p (5%). Losses most frequently affected chromosomes 13 (21%) and 4 (16%). Minimal common regions with the most frequent losses were 13q13q31 (21%), 4q (16%), and 16q (11%). No significant statistical correlation between genomic aberrations and clinicopathological factors was revealed, despite the fact that there was an obvious tendency towards it. Primary MCC expressing DNA alterations were predominantly distinguished in large tumors, and risk of metastatic dissemination was three-fold compared to tumors with no DNA alterations.

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

“…40 Cytogenetic studies revealed frequent genetic abnormalities in Merkel cell carcinoma, 5 but no alterations were observed in chromosome 4q12, the area to which KIT and PDGFRA are mapped. 41 In the study of Sihto et al 38 of 334 solid tumors, strong KIT protein expression was associated with a mutated KIT gene, with a wild-type KIT gene amplification, or with chromosome 4 aneuploidy. In addition, one of three cases of Merkel cell carcinoma revealed monosomy in chromosome 4 leading to loss of one copy of the KIT gene.…”

A second field metachronous Merkel cell carcinoma of the lip and the palatine tonsil confirmed by microarray-based comparative genomic hybridisation

“…In our case, only two regions, 2p and 10p were commonly over-represented. In a very recent study, 19 primary MCCs were analysed by CGH, and, in 13 samples, extensive gains and losses were detected [17]. It was shown that a majority of the alterations were gains, while only a few common losses were detected, mainly in regions 4q, 13q and 16q.…”

B-Cell Specific Activation Protein Encoded by the PAX-5 Gene Is Commonly Expressed in Merkel Cell Carcinoma and Small Cell Carcinomas

“…2,4,5,13,27 These observations may lead to speculation that overexpression of PAX-5 in neuroendocrine neoplasms may be related to transforming events that lead to disruption of the PAX-5 locus or dysregulation the of PAX-5 gene. However, overt structural abnormalities involving the PAX-5 locus or even chromosome 9 have never been demonstrated as a frequent finding in the extensive molecular and cytogenetic studies of Merkel cell 16,17,31,[34][35][36] and small cell carcinomas. 15,19,21,38 Furthermore, some studies on forced expression of PAX-5 by retroviral transduction and transgenic studies 26 have failed to demonstrate any transforming activity in developing mouse brain using both in vitro and in vivo approaches.…”