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Constitutional 9P22q Translocation in a Patient with Melanoma, Deafness and DNA Repair Deficiency Disrupts P14arf and Down-Regulates TBX1

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Constitutional 9P22q Translocation in a Patient with Melanoma, Deafness and DNA Repair Deficiency Disrupts P14arf and Down-Regulates TBX1 Constitutional 9p22q translocation in a patient with melanoma, deafness and DNA repair deficiency disrupts p14arf and down-regulates TBX1 Xiaohui Tan1, Sarah Anzick2, Sikandar G. Khan1, Takahiro Ueda1,3, Gary Stone2, John J. DiGiovanna1,4, Deborah Tamura1, Daniel Wattendorf5, Carmen Brewer6, Chris Zalewski6, Robert Walker2, John A Butman7, Andrew Griffith6, Paul Meltzer2, Paul Bergstresser8 and Kenneth H. Kraemer1 1DNA Repair Section, Dermatology Branch, CCR, NCI 2Genetics Branch, NCI 3Pharm/ Medical Device Agency, Tokyo, Japan 4 Derm, Brown Med School, Providence, RI 5Office of the Air Force Surgeon General 6Otolaryngology Br, NIDCD 7Radiology, CC 8Derm, Univ of Texas SW, Dallas, TX DNA REPAIR DEFICIENCY, MELANOMA, DEAFNESS, AND CHROMOSOME 9p22q TRANSLOCATION – A NEW SYNDROME? Low set ears Contractures Posterior fifth toes 12 y/o Patient DD129BE Sensorineural deafness, DiGeorge Syndrome / Velo-cardio-facial Syndrome like features Melanoma 0.25 mm 14 y/o CLINICAL EXAMINATION • Audiologic assessment No measureable hearing bilaterally and absent vestibular reactivity • CT and MRI Bilaterally symmetric cochlear hypoplasia and vestibular dysplasia with absence of the cochlear nerve. KARYOTYPE ANALYSIS t(9;22)(p21;q11.2) Reciprocal translocation between the short arm of chromosome 9 and the long arm of chromosome 22 THE AIM 1. To map the chromosome breakpoints in cells from patient DD129BE 2. To develop a detailed molecular characterization of the candidate genes for his clinical syndrome of melanoma, defective DNA repair and deafness. FISH analysis of t(9;22) with whole chromosome painting Chromosome 9 Chromosome 22 CHROMOSOME 9 and 22 PROBES ARE SPLIT BY THE TRANSLOCATION der 22 Normal 9 der 9 p24.2 p24.1 p22.3 p21.3 p21.1 TRANSLOCATION p12 9p21 LSI p16 q12 q21.13 q21.33 q31.1 q33.1 FISH analysis of the translocation on chr9 q34.3 9p11-q11CEP CHROMOSOME 9 p16 PROBE IS SPLIT BY THE Array Comparative Genome Hybridization (aCGH) of Total Genomic DNA No detectable changes BIVARIATE FLOW SORTING TO ISOLATE DERIVATIVE CHROMOSOMES Normal chromosomes Patient chromosomes derivative chromosome 9 derivative chromosome 22 Derivative Chromosomes can be Separated By Bivariate Flow Sorting Breakpoint Located Within CDKN2A Gene Using aCGH On Flow Sorted Derivative Chromosome 9 Area 1 derivative BREAKPOINT chromosome 9 Break on Chromosome 9 splits CDKN2A gene BREAKPOINT TEL CEN Intron 1 Breakpoint on Chromosome 9 Interrupts p14/ARF Protein Leading to Melanoma Laser Capture Microdissected Melanoma Tissue from patient DD129BE Two UV-type Missense Mutations in Exon 1 β of p14arf Gene Wild type gCAG>CGG pQ57R gAGA>GGA pR62G Knudson Model for Cancer The melanoma in patient DD129BE may have resulted when one copy of p14arf was disrupted by the translocation followed by somatic mutations in the other copy. DNA REPAIR DEFICIENCY IN PATIENT DD129BE FIBROBLASTS Reduced HCR is not corrected by any of the known XP complementation groups Increased HCR by Co-transfection with p14 DNA repair defect improved by transfection with p14 cDNA vector FISH Analysis of DiGeorgechr22:17,300,000-20,000,000 Syndrome Critical Region on Chr22 3 megabase DiGeorge Syndrome Critical Region 17500000 18,000,000 18,500,000 GAP 19,000,000 19,500,000 3090o16 278E23 VCFS probe 138C22 3148D21 586I18 562F10 - - - + + + 586I18 Normal 22 3090o16 562F10 Der 9 Der 22 Der 22 Der 22 Normal 9 Der 9 Normal 22 Normal 9 Normal 22 Der 9 562F10, 3090o16 and 586I18 PROBES ARE SPLIT BY TRANSLOCATION Array CGH On Flow Sorted Derivative 22 Areas 3-8 BREAKPOINT pooled derivative chromosome 22 980kb CHROMOSOME 22 BREAKPOINT LIES WITHIN A BREAKPOINT HOTSPOT REGION IN A GAP IN THE HUMAN GENOME MAP Breakpoint hotspot 22d 22c 22b 22b 22c 22a PATRR22 GAP GAP PATRR22(1kb) 22q11.2 17500000 18,000,000 18,500,000 19,000,000 19,500,000 VCFS probe 138C22 3148D21 586I18 562F10 278E23 BACs - - + + ISOLATION OF TRANSLOCATION JUNCTION FROM Derivative 9 BY PCR Normal Chr9-1R Chr9-5R Chr9-6R Chr9-5F Chr9-6F Chr9-1F Chromosome 9 Centromere telomere Derivative 9 Chr9-1R Chr9-5R Chr9-6R 22b 22c 22d Centromere telomere TA repeat variable palindrome in PATRR22 TA-rich region flanking the TA repeat variable region on chr 22 Breakpoint JunctionPATRR22 is present region on chr 9 Lymphoblast Genomic DNA Genomic DNA only in cells from patient DD129BE (bp) (bp) 2000 2000 1000 1000 300 300 100 (bp) 800 300 100 Junction Fragment Sequences of Der9 Chr9-1R Chr9-5R Chr9-6R 5F3R 6F 4R 4F 3F Chr9-1F Chr 9 Centromere Chr9-1R Chr9-5R Chr9-6R 22b22c 22d telomere Der 9 SINE (88% similarity to regions TA repeat variable region on chr 22 palindrome in PATRR22 on PATRR22 and chr9) TA repeat variable region on chr 9 TA-rich region flanking TA-rich region flanking the TRANSLOCATION BREAKPOINTthe PATRR22 LIES PATRR22WITHIN AT-RICH REGIONS ON CHR 9 AND CHR 22 Sequence of normal chromosome 9 Sequence of der 9 Bold lettering indicates the sequence on der(9) Localization of Translocation Breakpoints Within PATRR22 t(11;22) t(9;22) -31 9,22 TRANSLOCATION BREAKPOINT IS IN A BREAKPOINTKurahashi, HOTSPOT et al. REGIONGenome Research, WITHIN (2007) PATRR22 17:461-469 22q11.2 50kb GAP 22q11.2 17500000 18,000,000 18,500,000 19,000,000 19,500,000 18,890,000 800 KB 18,940,000 18,077,328 2655G7 18,325,388 19,057,981 TBX1 probe 1057H19 186o8 138C22 3148D21 586I18 562F10 278E23 BACs 17,690,710 18,259,187 18,444,588 18,859,173 19,809,922 18,259,187 18,696,552 19,022,374 18068734-18,298734 PATRR22(1kb) 22d 22c 22b 22b 22c 22a PATRR22 Breakpoint t(X;22) t(1;22) t(4;22) t(11;22) t(17;22) hotspot NT-011519 Genes CLTCL17,546,987 HIRA 17,698,224-17799219HIRA LOC150185-17,918,882 C22orf25 18,388,637 DGCR6L 18,682,046 AK129567 18,962,132 KIAA1666 18,835,994 AK129567 18,706,399 C22orf29 18,213,661 DGCR8 18,453,210 RTN4R 18,608,938 HTF9C 18,479,398 PI4KAP2 18,763,731 LZTR1 19,663,751 USP41 19,047,911 TBX1 18,124,226 ZNF74 19,078,480 DKF2p761 18,404,283 RTN4R 19,257,965 KLHL22 19,125,806 SERPIND1 19,458,383 PI4KA 19, 391,979 19, PI4KA AK129567 19,852,118 PCQAP 19, 191,886PCQAP AK12956719,985,286 DKF2p434k 19119, 802,941 SCAF2 19,108,875 BCR 19,787,305 3 megabase DiGeorge Syndrome Critical Region TBX1 is 800kb away from the breakpoint in the gap FISH analysis of the translocation on chr22 with TBX1 probe Chromosome 9 Chromosome 22 Der 9 Der 22 TBX1 PROBE IS NOT SPLIT BY THE TRANSLOCATION No mutations in promoter or exons in three isoforms of TBX1 Semiquantitative RT-PCTDramatically reduced TBX1 Expression TBX1 β actin Real Time T-PCT No detectable in Patient’s cells Water Lymphoblast Patient Mother TBX1 Father by PCR or qRT-PCR Normal expression in DD129BE cells Patient Fibroblast Fold Change Relative to Mother Normal Fibroblasts (AG13354) Father Patient Normal Marker Mother 650bp 300bp Father Microarray Analysis of Expression of the Genes Around the Translocation Low expression of CDKN2A and TBX1 by microarray SUMMARY • We have demonstrated that the constitutional t(9;22) translocation occurs in AT-rich repeat intervals on both chromosomes 9 and 22 • The rearrangement was mediated by a 6 bp CACGTG palindromic sequence between the breakpoints. Chromosome 9 had a deletion of 71 bp in an AT-rich repeat region in intron 1 of CDKN2A gene, and chromosome 22 had a deletion of 62 bp in PATRR22 in an uncloned gap. • The melanoma in this patient may have arisen according to the Knudson model in which one copy of p14arf is disrupted by the translocation followed by a somatic mutations in the other copy CONCLUSIONS These rearrangements on chromosomes 9 and 22 in patient DD129BE resulted in: 1. down regulation of CDKN2A on chr 9 that contributes to the melanoma susceptibility and reduced DNA repair and 2. down regulation of TBX1 on chr 22 that contributes to his deafness..
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