title: Chimeric negative regulation of p14ARF and TBX1 by a t(9;22) translocation associated with melanoma, deafness, and DNA repair deficiency.
abstract: Melanoma is the most deadly form of skin cancer and DiGeorge syndrome (DGS) is the most frequent interstitial deletion syndrome. We characterized a novel balanced t(9;22)(p21;q11.2) translocation in a patient with melanoma, DNA repair deficiency, and features of DGS including deafness and malformed inner ears. Using chromosome sorting, we located the 9p21 breakpoint in CDKN2A intron 1. This resulted in underexpression of the tumor suppressor p14 alternate reading frame (p14ARF); the reduced DNA repair was corrected by transfection with p14ARF. Ultraviolet radiation-type p14ARF mutations in his melanoma implicated p14ARF in its pathogenesis. The 22q11.2 breakpoint was located in a palindromic AT-rich repeat (PATRR22). We identified a new gene, FAM230A, that contains PATRR22 within an intron. The 22q11.2 breakpoint was located 800 kb centromeric to TBX1, which is required for inner ear development. TBX1 expression was greatly reduced. The translocation resulted in a chimeric transcript encoding portions of p14ARF and FAM230A. Inhibition of chimeric p14ARF-FAM230A expression increased p14ARF and TBX1 expression and improved DNA repair. Expression of the chimera in normal cells produced dominant negative inhibition of p14ARF. Similar chimeric mRNAs may mediate haploinsufficiency in DGS or dominant negative inhibition of other genes such as those involved in melanoma.
authors: DNA Repair Section, Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4258, USA.
authors: Xiaohui
authors: X
authors: Tan
authors: Sarah L
authors: SL
authors: Anzick
authors: Sikandar G
authors: SG
authors: Khan
authors: Takahiro
authors: T
authors: Ueda
authors: Gary
authors: G
authors: Stone
authors: John J
authors: JJ
authors: Digiovanna
authors: Deborah
authors: D
authors: Tamura
authors: Daniel
authors: D
authors: Wattendorf
authors: David
authors: D
authors: Busch
authors: Carmen C
authors: CC
authors: Brewer
authors: Christopher
authors: C
authors: Zalewski
authors: John A
authors: JA
authors: Butman
authors: Andrew J
authors: AJ
authors: Griffith
authors: Paul S
authors: PS
authors: Meltzer
authors: Kenneth H
authors: KH
authors: Kraemer
mesh_terms: D001483:Base Sequence; D002352:Carrier Proteins; D002892:Chromosomes, Human, Pair 22; D002899:Chromosomes, Human, Pair 9; D049914:DNA Repair-Deficiency Disorders / Q000235:genetics* / Q000378:metabolism; D003638:Deafness / Q000235:genetics* / Q000378:metabolism; D050939:Gene Fusion; D019942:Genes, p16; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D062085:RNA, Long Noncoding; D017422:Sequence Analysis, DNA; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C586651:FAM230A lncRNA, human; D062085:RNA, Long Noncoding; D020825:T-Box Domain Proteins; C108625:TBX1 protein, human; D025803:Tumor Suppressor Protein p14ARF
keywords: DiGeorge syndrome; PATRR22; TBX1; deafness; melanoma; p14ARF
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