Chimeric Negative Regulation ofp14ARFandTBX1by a t(9;22) Translocation Associated with Melanoma, Deafness, and DNA Repair Deficiency

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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.We studied a patient with melanoma, DNA repair deficiency, and deafness due to malformed inner ears who had a novel balanced t(9;22) translocation. Sequencing this break region served as a “Rosetta stone” permitting identification of a new gene, FAM230A, within a gap region on chromosome 22. The chimeric p14ARF-FAM230A gene appears to play an important dominant negative regulatory role in melanoma induction and ear development in this patient.

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