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Chimeric Negative Regulation of p14ARF and TBX1 by a t(9;22) Translocation Associated with Melanoma, Deafness, and DNA Repair Deficiency
Author(s) -
Tan Xiaohui,
Anzick Sarah L.,
Khan Sikandar G.,
Ueda Takahiro,
Stone Gary,
DiGiovanna John J.,
Tamura Deborah,
Wattendorf Daniel,
Busch David,
Brewer Carmen C.,
Zalewski Christopher,
Butman John A.,
Griffith Andrew J.,
Meltzer Paul S.,
Kraemer Kenneth H.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22354
Subject(s) - biology , chromosomal translocation , tbx1 , p14arf , genetics , cancer research , gene , promoter , carcinogenesis , gene expression , tumor suppressor gene
Melanoma is the most deadly form of skin cancer and D i G eorge 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 p14 ARF ‐ FAM 230A 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 m RNA s may mediate haploinsufficiency in DGS or dominant negative inhibition of other genes such as those involved in melanoma.