Homozygous deletion of the STK11/LKB1 locus and the generation of novel fusion transcripts in cervical cancer cells.
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 plays a role in 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 approximately 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 composed 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.
McCabe
Michael T
MT
Department of Radiation Oncology, Emory University School of Medicine, 1365C Clifton Road, Atlanta, GA 30322; The Winship Cancer Institute of Emory University, 1365C Clifton Road, Atlanta, GA 30322.
Powell
Doris R
DR
Zhou
Wei
W
Vertino
Paula M
PM
D000091162:AMP-Activated Protein Kinase Kinases; D020087:Alu Elements / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014158:Transcription, Genetic; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000235:genetics*
D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases