title: High expression of CAI2, a 9p21-embedded long noncoding RNA, contributes to advanced-stage neuroblastoma.
abstract: Neuroblastoma is a pediatric cancer with significant genomic and biologic heterogeneity. p16 and ARF, two important tumor-suppressor genes on chromosome 9p21, are inactivated commonly in most cancers, but paradoxically overexpressed in neuroblastoma. Here, we report that exon γ in p16 is also part of an undescribed long noncoding RNA (lncRNA) that we have termed CAI2 (CDKN2A/ARF Intron 2 lncRNA). CAI2 is a single-exon gene with a poly A signal located in but independent of the p16/ARF exon 3. CAI2 is expressed at very low levels in normal tissue, but is highly expressed in most tumor cell lines with an intact 9p21 locus. Concordant expression of CAI2 with p16 and ARF in normal tissue along with the ability of CAI2 to induce p16 expression suggested that CAI2 may regulate p16 and/or ARF. In neuroblastoma cells transformed by serial passage in vitro, leading to more rapid proliferation, CAI2, p16, and ARF expression all increased dramatically. A similar relationship was also observed in primary neuroblastomas where CAI2 expression was significantly higher in advanced-stage neuroblastoma, independently of MYCN amplification. Consistent with its association with high-risk disease, CAI2 expression was also significantly associated with poor clinical outcomes, although this effect was reduced when adjusted for MYCN amplification. Taken together, our findings suggested that CAI2 contributes to the paradoxical overexpression of p16 in neuroblastoma, where CAI2 may offer a useful biomarker of high-risk disease.
authors.affiliation: Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego;
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Barnhill
authors.affiliation: Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego;
authors.forename: Richard T
authors.initials: RT
authors.lastname: Williams
authors.affiliation: Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego;
authors.forename: Olga
authors.initials: O
authors.lastname: Cohen
authors.affiliation: Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego;
authors.forename: Youngjin
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego;
authors.forename: Ayse
authors.initials: A
authors.lastname: Batova
authors.affiliation: Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego;
authors.forename: Jenna A
authors.initials: JA
authors.lastname: Mielke
authors.affiliation: Division of Biostatistics and Bioinformatics, Moores UCSD Cancer Center, La Jolla, California;
authors.forename: Karen
authors.initials: K
authors.lastname: Messer
authors.affiliation: Division of Biostatistics and Bioinformatics, Moores UCSD Cancer Center, La Jolla, California;
authors.forename: Minya
authors.initials: M
authors.lastname: Pu
authors.affiliation: Division of Biostatistics and Bioinformatics, Moores UCSD Cancer Center, La Jolla, California;
authors.forename: Lei
authors.initials: L
authors.lastname: Bao
authors.affiliation: Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego; Academia Sinica, Genomics Research Center, Taipei; and Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan mdiccianni@ucsd.edu aliceyu@ucsd.edu.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Yu
authors.affiliation: Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego; mdiccianni@ucsd.edu aliceyu@ucsd.edu.
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Diccianni
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002899:Chromosomes, Human, Pair 9; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005500:Follow-Up Studies; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D020727:ADP-Ribosylation Factors