Homozygous Deletion of the STK11/LKB1 Locus and the Generation of Novel Fusion Transcripts in Cervical Cancer Cells

• Type of Material: Article
• Authors: Michael T. McCabe, Emory University; Doris R. Powell, Emory University; Wei Zhou, Emory University; Paula M Vertino, Emory University
• Language: English
• Date: 2010-03
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.crossref.org/10.1016%2Fj.cancergencyto.2009.11.017
• Title of Journal or Parent Work: Cancer Genetics and Cytogenetics
• ISSN: 0165-4608
• Volume: 197
• Issue: 2
• Start Page: 130
• End Page: 141
• Grant/Funding Information: PMV and WZ are Georgia Cancer Coalition Distinguished Cancer Scholars.; This work was supported by National Cancer Institute grants RO1 CA077337 to PMV and P01-CA116676 to PMV and WZ, and an American Cancer Society grant PF-07-130-01-MGO and Frederick Gardner Cottrell Postdoctoral Fellowship to MTM.
• Keywords: Alu recombination-mediated deletion; cervical cancer; ARMD; homozygous deletion; SBNO2; LKB1; fusion transcript; c19orf26; STK11
• Research Categories: Biology, Genetics; Health Sciences, Oncology

Abstract

The STK11/LKB1 gene encodes a ubiquitously expressed serine/threonine kinase that is mutated in multiple sporadic cancers including non-small cell lung carcinomas, pancreatic cancers, and melanomas. LKB1 affects multiple cellular functions including cell growth, cell cycle progression, metabolism, cell polarity and migration. To date, only a limited number of studies have assessed the status of LKB1 in cervical cancers. Herein, we investigate DNA methylation, DNA mutation, and transcription at the LKB1 locus in cervical cancer cell lines. We identified homozygous deletions of 25–85kb in the HeLa and SiHa cell lines. Deletion breakpoint analysis in HeLa cells revealed that the deletion resulted from an Alu-recombination mediated deletion (ARMD) and generated a novel LKB1 fusion transcript driven by an uncharacterized CpG island promoter located ~11kb upstream of LKB1. Although the homozygous deletion in SiHa cells removes the entire LKB1 gene and portions of the neighboring genes SBNO2 and c19orf26, this deletion also generates a fusion transcript driven by the c19orf26 promoter and comprised of both c19orf26 and SBNO2 sequences. Further analyses of public gene expression and mutation databases suggest that LKB1 and its neighboring genes are frequently dysregulated in primary cervical cancers. Thus, homozygous deletions affecting LKB1 in cervical cancers may generate multiple fusion transcripts involving LKB1, SBNO2, and c19orf26.