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Open Access 01-12-2009 | Research

The tumor suppressor gene TRC8/RNF139 is disrupted by a constitutional balanced translocation t(8;22)(q24.13;q11.21) in a young girl with dysgerminoma

Authors: Stefania Gimelli, Silvana Beri, Harry A Drabkin, Claudio Gambini, Andrea Gregorio, Patrizia Fiorio, Orsetta Zuffardi, Robert M Gemmill, Roberto Giorda, Giorgio Gimelli

Published in: Molecular Cancer | Issue 1/2009

Abstract

Background

RNF139/TRC8 is a potential tumor suppressor gene with similarity to PTCH, a tumor suppressor implicated in basal cell carcinomas and glioblastomas. TRC8 has the potential to act in a novel regulatory relationship linking the cholesterol/lipid biosynthetic pathway with cellular growth control and has been identified in families with hereditary renal (RCC) and thyroid cancers. Haploinsufficiency of TRC8 may facilitate development of clear cell-RCC in association with VHL mutations, and may increase risk for other tumor types. We report a paternally inherited balanced translocation t(8;22) in a proposita with dysgerminoma.

Methods

The translocation was characterized by FISH and the breakpoints cloned, sequenced, and compared. DNA isolated from normal and tumor cells was checked for abnormalities by array-CGH. Expression of genes TRC8 and TSN was tested both on dysgerminoma and in the proposita and her father.

Results

The breakpoints of the translocation are located within the LCR-B low copy repeat on chromosome 22q11.21, containing the palindromic AT-rich repeat (PATRR) involved in recurrent and non-recurrent translocations, and in an AT-rich sequence inside intron 1 of the TRC8 tumor-suppressor gene at 8q24.13. TRC8 was strongly underexpressed in the dysgerminoma. Translin is underexpressed in the dysgerminoma compared to normal ovary.

TRC8 is a target of Translin (TSN), a posttranscriptional regulator of genes transcribed by the transcription factor CREM-tau in postmeiotic male germ cells.

Conclusion

A role for TRC8 in dysgerminoma may relate to its interaction with Translin. We propose a model in which one copy of TRC8 is disrupted by a palindrome-mediated translocation followed by complete loss of expression through suppression, possibly mediated by miRNA.

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Ulbright TM: Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol. 2005, 18: S61-79. 10.1038/modpathol.3800310CrossRefPubMed

Oosterhuis JW, Looijenga LH: Testicular germ-cell tumors in a broader perspective. Nat Rev Cancer. 2005, 5: 210-222. 10.1038/nrc1568CrossRefPubMed

Gemmill RM, West JD, Boldog F, Tanaka N, Robinson LJ, Smith DI, Li F, Drabkin HA: The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. Proc Natl Acad Sci USA. 1998, 95: 9572-9577. 10.1073/pnas.95.16.9572PubMedCentralCrossRefPubMed

Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE: Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996, 85: 841-851. 10.1016/S0092-8674(00)81268-4CrossRefPubMed

Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH, Scott MP: Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996, 272: 1668-1671. 10.1126/science.272.5268.1668CrossRefPubMed

Goodrich LV, Milenkovic L, Higgins KM, Scott MP: Altered neural cell fates and medulloblastoma in mouse patched mutants. Science. 1997, 277: 1109-1113. 10.1126/science.277.5329.1109CrossRefPubMed

Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S, Jacobs SC, Brown RS: Hereditary renal-cell carcinoma associated with a chromosomal translocation. N Engl J Med. 1979, 301: 592-595.CrossRefPubMed

Li FP, Decker HJ, Zbar B, Stanton VP, Kovacs G, Seizinger BR, Aburatani H, Sandberg AA, Berg S, Hosoe S, Brown RS: Clinical and genetic studies of renal cell carcinomas in a family with a constitutional chromosome 3;8 translocation. Genetics of familial renal carcinoma. Ann Intern Med. 1993, 118: 106-111.CrossRefPubMed

Poland KS, Azim M, Folsom M, Goldfarb R, Naeem R, Korch C, Drabkin HA, Gemmill RM, Plon SE: A constitutional balanced t(3;8)(p14;q24.1) translocation results in disruption of the TRC8 gene and predisposition to clear cell renal cell carcinoma. Genes Chromosomes Cancer. 2007, 46: 805-812. 10.1002/gcc.20466CrossRefPubMed

10.

Brauweiler A, Lorick KL, Lee JP, Tsai YC, Chan D, Weissman AM, Drabkin HA, Gemmill RM: RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene. Oncogene. 2007, 26: 2263-2271. 10.1038/sj.onc.1210017CrossRefPubMed

11.

Lee JP, Brauweiler A, Rudolph M, Hooper JE, Drabkin HA, Gemmill RM: TRC8/RNF139, a kidney cancer-associated tumor suppressor gene and E3-ubiquitin ligase, is sterol-regulated and interacts with lipid and protein biosynthetic pathways [abstract]. Proceedings of the 100th Annual Meeting of the American Association for Cancer Research. 2009, 1287-Denver, CO. Philadelphia (PA): AACR

12.

Gemmill RM, Bemis LT, Lee JP, Sozen MA, Baron A, Zeng C, Erickson PF, Hooper JE, Drabkin HA: The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway. Oncogene. 2002, 21: 3507-3516. 10.1038/sj.onc.1205437CrossRefPubMed

13.

Cho YS, Iguchi N, Yang J, Handel MA, Hecht NB: Meiotic messenger RNA and noncoding RNA targets of the RNA-binding protein Translin (TSN) in mouse testis. Biol Reprod. 2005, 73: 840-847. 10.1095/biolreprod.105.042788CrossRefPubMed

14.

Giorda R, Cerritello A, Bonaglia MC, Bova S, Lanzi G, Repetti E, Giglio S, Baschirotto C, Pramparo T, Avolio L, Bragheri R, Maraschio P, Zuffardi O: Selective disruption of muscle and brain-specific BPAG1 isoforms in a girl with a 6;15 translocation, cognitive and motor delay, and tracheo-oesophageal atresia. J Med Genet. 2004, 41: e71- 10.1136/jmg.2003.012260PubMedCentralCrossRefPubMed

15.

Kubota T, Das S, Christian SL, Baylin SB, Herman JG, Ledbetter DH: Methylation-specific PCR simplifies imprinting analysis. Nat Genet. 1997, 16: 16-17.PubMed

16.

Edelmann L, Spiteri E, McCain N, Goldberg R, Pandita RK, Duong S, Fox J, Blumenthal D, Lalani SR, Shaffer LG, Morrow BE: A common breakpoint on 11q23 in carriers of the constitutional t(11;22) translocation. Am J Hum Genet. 1999, 65: 1608-1616. 10.1086/302689PubMedCentralCrossRefPubMed

17.

Spiteri E, Babcock M, Kashork CD, Wakui K, Gogineni S, Lewis DA, Williams KM, Minoshima S, Sasaki T, Shimizu N, Potocki L, Pulijaal V, Shanske A, Shaffer LG, Morrow BE: Frequent translocations occur between low copy repeats on chromosome 22q11.2 (LCR22s) and telomeric bands of partner chromosomes. Hum Mol Genet. 2003, 12: 1823-1837. 10.1093/hmg/ddg203CrossRefPubMed

18.

Kurahashi H, Shaikh TH, Emanuel BS: Alu-mediated PCR artifacts and the constitutional t(11;22) breakpoint. Hum Mol Genet. 2000, 9: 2727-2732. 10.1093/hmg/9.18.2727CrossRefPubMed

19.

Kurahashi H, Shaikh TH, Hu P, Roe BA, Emanuel BS, Budarf ML: Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22). Hum Mol Genet. 2000, 9: 1665-1670. 10.1093/hmg/9.11.1665CrossRefPubMed

20.

Gotter AL, Nimmakayalu MA, Jalali GR, Hacker AM, Vorstman J, Conforto Duffy D, Medne L, Emanuel BS: A palindrome-driven complex rearrangement of 22q11.2 and 8q24.1 elucidated using novel technologies. Genome Res. 2007, 17: 470-481. 10.1101/gr.6130907PubMedCentralCrossRefPubMed

21.

Boldog FL, Gemmill RM, Wilke CM, Glover TW, Nilsson AS, Chandrasekharappa SC, Brown RS, Li FP, Drabkin HA: Positional cloning of the hereditary renal carcinoma 3;8 chromosome translocation breakpoint. Proc Natl Acad Sci USA. 1993, 90: 8509-8513. 10.1073/pnas.90.18.8509PubMedCentralCrossRefPubMed

22.

Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K: The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell. 1996, 84: 587-597. 10.1016/S0092-8674(00)81034-XCrossRefPubMed

23.

Ashley T, Gaeth AP, Inagaki H, Seftel A, Cohen MM, Anderson LK, Kurahashi H, Emanuel BS: Meiotic recombination and spatial proximity in the etiology of the recurrent t(11;22). Am J Hum Genet. 2006, 79: 524-538. 10.1086/507652PubMedCentralCrossRefPubMed

24.

Kurahashi H, Inagaki H, Ohye T, Kogo H, Kato T, Emanuel BS: Palindrome-mediated chromosomal translocations in humans. DNA Repair (Amst). 2006, 5: 1136-1145. 10.1016/j.dnarep.2006.05.035CrossRef

25.

Kuroda-Kawaguchi T, Skaletsky H, Brown LG, Minx PJ, Cordum HS, Waterston RH, Wilson RK, Silber S, Oates R, Rozen S, Page DC: The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet. 2001, 29: 279-286. 10.1038/ng757CrossRefPubMed

26.

Barbouti A, Stankiewicz P, Nusbaum C, Cuomo C, Cook A, Hoglund M, Johansson B, Hagemeijer A, Park SS, Mitelman F, Lupski JR, Fioretos T: The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large, palindromic, low-copy repeats. Am J Hum Genet. 2004, 74: 1-10. 10.1086/380648PubMedCentralCrossRefPubMed

27.

Tanaka H, Bergstrom DA, Yao MC, Tapscott SJ: Widespread and nonrandom distribution of DNA palindromes in cancer cells provides a structural platform for subsequent gene amplification. Nat Genet. 2005, 37: 320-327. 10.1038/ng1515CrossRefPubMed

28.

Kato T, Inagaki I, Kogo H, Ohye T, Yamada K, Emanuel BS, Kurahashi H: Two different forms of palindrome resolution in the human genome: deletion or translocation. Hum Mol Genet. 2008, 17: 1184-1191. 10.1093/hmg/ddn008CrossRefPubMed

29.

Gemmill RM, Lee JP, Chamovitz DA, Segal D, Hooper JE, Drabkin HA: Growth suppression induced by the TRC8 hereditary kidney cancer gene is dependent upon JAB1/CSN5. Oncogene. 2005, 24: 3503-3511. 10.1038/sj.onc.1208509CrossRefPubMed

30.

Yu Z, Hecht NB: The DNA/RNA-binding protein, translin, binds microRNA122a and increases its in vivo stability. J Androl. 2008, 29: 572-579. 10.2164/jandrol.108.005090CrossRefPubMed

31.

Aoki K, Suzuki K, Sugano T, Tasaka T, Nakahara K, Kuge O, Omori A, Kasai M: A novel gene, Translin, encodes a recombination hotspot binding protein associated with chromosomal translocations. Nat Genet. 1995, 10: 167-174. 10.1038/ng0695-167CrossRefPubMed

32.

Wu XQ, Gu W, Meng X, Hecht NB: The RNA-binding protein, TBRBP, is the mouse homologue of translin, a recombination protein associated with chromosomal translocations. Proc Natl Acad Sci USA. 1997, 94: 5640-5645. 10.1073/pnas.94.11.5640PubMedCentralCrossRefPubMed

33.

Morales CR, Wu XQ, Hecht NB: The DNA/RNA-binding protein, TB-RBP, moves from the nucleus to the cytoplasm and through intercellular bridges in male germ cells. Dev Biol. 1998, 201: 113-123. 10.1006/dbio.1998.8967CrossRefPubMed

34.

Morales CR, Lefrancois S, Chennathukuzhi V, El-Alfy M, Wu X, Yang J, Gerton GL, Hecht NB: A TB-RBP and Ter ATPase complex accompanies specific mRNAs from nuclei through the nuclear pores and into intercellular bridges in mouse male germ cells. Dev Biol. 2002, 246: 480-494. 10.1006/dbio.2002.0679CrossRefPubMed

35.

Chennathukuzhi V, Morales CR, El-Alfy M, Hecht NB: The kinesin KIF17b and RNA binding protein TB-RBP transport specific cAMP responsive element modulator-regulated mRNAs in male germ cells. Proc Natl Acad Sci USA. 2003, 100: 15566-15571. 10.1073/pnas.2536695100PubMedCentralCrossRefPubMed

36.

Kasai M, Matsuzaki T, Katayanagi K, Omori A, Maziarz RT, Strominger JK, Aoki K, Suzuki K: The translin ring specifically recognizes DNA ends at recombination hot spots in the human genome. J Biol Chem. 1997, 272: 11402-11407. 10.1074/jbc.272.17.11402CrossRefPubMed

37.

Chennathukuzhi V, Stein JM, Abel T, Donlon S, Yang C, Miller J, Allman D, Simmons RA, Hecht NB: Mice deficient for testis-brain RNA-binding protein exhibit a coordinate loss of TRAX, reduced fertility, altered gene expression in the brain, and behavioral changes. Mol Cell Biol. 2003, 23: 6419-6434. 10.1128/MCB.23.18.6419-6434.2003PubMedCentralCrossRefPubMed

Title: The tumor suppressor gene TRC8/RNF139 is disrupted by a constitutional balanced translocation t(8;22)(q24.13;q11.21) in a young girl with dysgerminoma
Authors: Stefania Gimelli
Silvana Beri
Harry A Drabkin
Claudio Gambini
Andrea Gregorio
Patrizia Fiorio
Orsetta Zuffardi
Robert M Gemmill
Roberto Giorda
Giorgio Gimelli
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: Molecular Cancer / Issue 1/2009
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/1476-4598-8-52

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Abstract

Background

Methods

Results

Conclusion

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