Year: 2011
Type: dissertation
Study design: Observational Study
Abstract: Cancer is a genetic disease caused by the accumulation of genetic changes such as mutations and \nchromosomal rearrangements. An increasing number of genetic studies of both hematological and solid \nneoplasms have shown that recurrent chromosome translocations often result in fusion oncogenes. These are \nconsidered as early events in tumorigenesis and are often key regulators of cellular transformation. We have \npreviously shown that the t(6;9)(q22-23;p23-24) translocation is a recurrent gentic alteration in adenoid cystic \ncarcinoma (ACC) and that the recurrent t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma \n(MEC) results in a CRTC1-MAML2 gene fusion. Here, we have used a combination of genetic and molecular \ntechniques, including FISH, RT-PCR, qPCR, transfection studies, and arrayCGH, to (i) gain further insights \ninto the molecular pathogenesis of CRTC1-MAML2 positive/negative MECs and hidradenomas and to study \nthe clinical significance of this fusion, (ii) to identify the target genes of the t(6;9) in ACC and to study the \nmolecular consequences of this rearrangement, and (III) to characterize the genetic profile of ACC using high- \nresolution arrayCGH and to identify candidate target genes located within regions of copy number alterations \n(CNA). \nDetailed analyses of 29 MECs revealed CRTC1-MAML2 fusions in 55% of the tumors. The CRTC1-MAML2 \nfusion protein was expressed in all three MEC-specific cell types and co-localized with CREB in nuclear \ngranules. Analyses of potential targets of the fusion revealed differential expression of cAMP/CREB and \nNotch targets in fusion-positive and -negative MECs, respectively. Interestingly, fusion-positive patients had a \nsignificantly lower risk of local recurrence, metastases or tumor related death compared to fusion-negative \npatients (p<0.001), and the estimated median survival for fusion-positive patients was >10 years compared to \n1.6 years for fusion-negative patients. Our findings suggest that MECs may be molecularly classified based on \nthe presence or absence of the CRTC1-MAML2 fusion and that the fusion is a useful marker in predicting the \nbiological behavior of MECs. \nAnalyses of 20 benign cutaneous hidradenomas showed that the CRTC1-MAML2 fusion is recurrent in the \nclear cell variant of this tumor. The results indicate that the fusion is etiologically linked to benign and low- \ngrade malignant tumors originating from diverse exocrine glands. \nPositional cloning of the t(6;9) translocation in ACC of the breast and head and neck revealed a new \nmechanism of activation of the MYB oncogene involving gene fusion. The fusion gene consists of MYB exons \n1-14 fused to the last coding exon(s) of the transcription factor gene NFIB. The fusion results in loss of the 3´- \nend of MYB, including several conserved binding sites for miRNAs that regulate MYB expression negatively. \nThe data indicate that deletion of these target sites may disrupt repression of MYB leading to overexpression \nof MYB-NFIB transcripts and protein and to activation of critical MYB target genes. Our findings also indicate \nthat the MYB-NFIB fusion is a hallmark of ACCs and that deregulation of MYB and its target genes are key \noncogenic events of both diagnostic and therapeutic significance in ACC. High-resolution arrayCGH analysis \nof 40 MYB-NFIB fusion-positive and -negative ACCs, revealed novel CNAs and significant refinements of \npreviously detected CNAs. The most frequent alterations were losses involving 12q, 6q, 9p, 11q, 14q, 1p, and \n5q and gains involving 1q, 9p and 22q. Using an integrated copy number and global gene expression \napproach, we identifed several candidate target genes, including NBL1, SFN, PLAGL1, and NR4A1, that were \ndown-regulated in tumors with 1p, 6q or 12q deletions compared to tumors without such CNAs. Further \ncharacterization of these regions and genes may lead to identification of new biomarkers of pathogenetic, \nprognostic, and therapeutic importance for ACC.
Author: Marta Persson
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1567132184