title: Homozygous deletions at 3p22, 5p14, 6q15, and 9p21 result in aberrant expression of tumor suppressor genes in gastric cancer.
abstract: Homozygous deletion is a frequent mutational mechanism of silencing tumor suppressor genes in cancer. Therefore, homozygous deletions have been analyzed for identification of tumor suppressor genes that can be utilized as biomarkers or therapeutic targets for cancer treatment. In this study, to elucidate potential tumor suppressor genes involved in gastric cancer (GC), we analyzed the entire set of large homozygous deletions in six human GC cell lines through genome- and transcriptome-wide approaches. We identified 51 genes in homozygous deletion regions of chromosomes and confirmed the deletion frequency in tumor tissues of 219 GC patients from The Cancer Genome Atlas database. We evaluated the effect of homozygous deletions on the mRNA level and found significantly affected genes in chromosome bands 9p21, 3p22, 5p14, and 6q15. Among the genes in 9p21, we investigated the potential tumor suppressive effect of KLHL9. We demonstrated that ectopic expression of KLHL9 inhibited cell proliferation and tumor formation in KLHL9-deficient SNU-16 cell line. In addition, we observed that homozygous focal deletions generated truncated transcripts of TGFBR2, CTNNA1, and STXBP5. Ectopic expression of two kinds of TGFBR2-reverse GADL1 fusion genes suppressed TGF-β signaling, which may lead to the loss of sensitivity to TGF-β tumor suppressive activity. In conclusion, our findings suggest that novel tumor suppressor genes that are aberrantly expressed through homozygous deletions may play important roles in gastric tumorigenesis.
authors.affiliation: CHA Cancer Institute, CHA University, Seongnam-si, 463-400, Republic of Korea; College of Pharmacy, Sookmyung Women's University, Seoul, 140-742, Republic of Korea.
authors.forename: Bona
authors.initials: B
authors.lastname: Lee
authors.forename: Kwiyeom
authors.initials: K
authors.lastname: Yoon
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Lee
authors.forename: Jin Muk
authors.initials: JM
authors.lastname: Kang
authors.forename: Junil
authors.initials: J
authors.lastname: Kim
authors.forename: Sung Han
authors.initials: SH
authors.lastname: Shim
authors.forename: Hak-Min
authors.initials: HM
authors.lastname: Kim
authors.forename: Sanghoon
authors.initials: S
authors.lastname: Song
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Naka
authors.forename: An Keun
authors.initials: AK
authors.lastname: Kim
authors.forename: Han-Kwang
authors.initials: HK
authors.lastname: Yang
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3; D002895:Chromosomes, Human, Pair 5; D002896:Chromosomes, Human, Pair 6; D002899:Chromosomes, Human, Pair 9; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II