Penn Medicine
   
 

Frederick G. Barr, M.D., Ph.D.

Department of Pathology and Laboratory Medicine

Contact Information

Department of Pathology and Laboratory Medicine
505C Stellar-Chance Laboratories (BRB-1)
422 Curie Boulevard
Philadelphia, PA 19104-6082
Phone: (215) 898-0884
Fax: (215) 898-4227
E-mail: barrfg@mail.med.upenn.edu
Position: Associate Professor

Expertise

My research program focuses on cancer-associated chromosomal rearrangements. Alveolar rhabdomyosarcoma is an aggressive pediatric soft tissue tumor with a characteristic translocation involving chromosomes 2 and 13. Previous work in my laboratory demonstrated that this translocation juxtaposes the coding regions of the PAX3 gene on chromosome 2 and the FKHR gene on chromosome 13 to produce a chimeric transcript and protein product. My laboratory has also determined that a less frequent variant translocation fuses FKHR with the PAX7 gene on chromosome 1. These genes encode members of the paired box and fork head transcription factor families, and the chimeric products are postulated to function as aberrant transcription factors. My laboratory is now investigating the structural basis of the genomic rearrangements, the transcriptional activity of the chimeric products, and their role in tumorigenesis.

Molecular diagnostic assays are being devised for detection of genetic alterations in clinical samples. We are currently focusing on the translocations in alveolar rhabdomyosarcoma and Ewing sarcoma. PCR, Southern blot, and in situ hybridization approaches are being adapted to assay for these fusion events at the DNA or RNA levle. The utility of these molecular diagnostic assays for differential diagnosis of small round cell tumors of childhood is being explored. We are also exploring the application of highly sensitive PCR assays for detection of minimal disease; these minimal disease assays may impact on initial cancer staging, evaluation of therapeutic interventions, and monitoring for relapse.

To dissect the process of genomic rearrangement, a cell culture system was developed in which carcinogen exposure induces rearrangement of a quiescent endogenous gene. We have adapted PCR technology to facilitate isolation of the rearrangement breakpoints and wild-type rearrangement partners. Multiple independent rearrangements generated by this inducible system are being studied by sequence, methylation, and chromatin analyses to test the hypothesis that both genetic and epigenetic features influence the propensity of a region to rearrange. Furthermore, this system will be employed to compare the ability of different carcinogenic agents to induce genomic rearrangements. Ultimately, this system will be used to develop general methodologies for analysis of rearrangement mechanisms in more complex systems.

Representative Publications

  1. Biegel JA, Nycum LM, Valentine V, Barr FG, and Shapiro DN. 1995. Detection of the t(2;13)(q35;q14) and PAX3-FKHR fusion in alveolar rhabdomyosarcoma by fluorescence in situ hybridization. Genes Chromosomes Cancer. 12:186-92.
  2. Barr FG, Chatten J, D'Cruz CM, Wilson AE, Nauta LE, Nycum LM, Biegel JA, and Womer RB. 1995. Molecular assays for chromosomal translocations in the diagnosis of pediatric soft tissue sarcomas. JAMA. 273:553-557.
  3. Hol FA, Hamel BC, Geurds MP, Mullaart RA, Barr FG, Macina RA, and Mariman EC. 1995. A frameshift mutation in the gene for PAX3 in a girl with spina bifida and mild signs of Waardenburg syndrome. J Med Genet. 32:52-6.
  4. Fredericks WJ, Galili N, Mukhopadhyay S, Rovera G, Bennicelli J, Barr FG, and Rauscher FJ 3rd. 1995. The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3. Mol Cell Biol. 15:1522-35.
  5. Macina RA, Barr FG, Galili N, and Riethman HC. 1995. Genomic organization of the human PAX3 gene: DNA sequence analysis of the region disrupted in alveolar rhabdomyosarcoma. Genomics. 26:1-8.
  6. Bennicelli JL, Fredericks WJ, Wilson RB, Rauscher FJ 3rd, and Barr FG. 1995. Wild type PAX3 protein and the PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma contain potent, structurally distinct transcriptional activation domains. Oncogene. 11:119-30.
  7. Davis RJ, Bennicelli J, Macina RA, Nycum LM, Biegel JA, and Barr FG. 1995. Structural characterization of the FKHR gene and its rearrangement in alveolar rhabdomyosarcoma. Hum Mol Genet. 4:2355-2362.
  8. Barr FG, Xiong QB, and Kelly K. 1995. A consensus polymerase chain reaction-oligonucleotide hybridization approach for the detection of chromosomal translocations in pediatric bone and soft tissue sarcomas. Am J Clin Pathol. 104:627-33.
  9. Barr FG, Nauta LE, Davis RJ, Schafer BW, Nycum LM, and Biegel JA. 1996. In vivo amplification of the PAX3-FKHR and PAX7-FKHR fusion genes in alveolar rhabdomyosarcoma. Hum Mol Genet. 5:15-21.
  10. Bennicelli JL, Edwards RH, and Barr FG. 1996. Mechanism for transcriptional gain of function resulting from chromosomal translocation in alveolar rhabdomyosarcoma. Proc Natl Acad Sci U S A. 93:5455-9.
  11. Kelly KM, Womer RB, and Barr FG. 1996. Minimal disease detection in alveolar rhabdomyosarcoma using a reverse transcriptase-polymerase chain reaction method. Cancer. 78:1320-1327.
  12. Scheidler S, Fredericks WJ, Rauscher FJ 3rd, Barr FG, and Vogt PK. 1996. The hybrid PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma transforms fibroblasts in culture. Proc Natl Acad Sci U S A. 93:9805-9.
  13. Benjamin LE, Fredericks WJ, Barr FG, and Rauscher FJ 3rd. 1996. Fusion of the EWS1 and WT1 genes as a result of the t(11;22)(p13;q12) translocation in desmoplastic small round cell tumors. Med Pediatr Oncol. 27:434-9.
  14. Edwards RH, Chatten J, Xiong QB, and Barr FG. 1997. Detection of gene fusions in rhabdomyosarcoma by reverse transcriptase-polymerase chain reaction assay of archival samples. Diagn Mol Pathol. 6:91-7.
  15. Kelly KM, Womer RB, Sorensen PH, Xiong QB, and Barr FG. 1997. Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol. 15:1831-6.
  16. Davis RJ and Barr FG. 1997. Fusion genes resulting from alternative chromosomal translocations are overexpressed by gene-specific mechanisms in alveolar rhabdomyosarcoma. Proc Natl Acad Sci U S A. 94:8047-51.
  17. Chalk JG, Barr FG, and Mitchell CD. 1997. Translin recognition site sequences flank chromosome translocation breakpoints in alveolar rhabdomyosarcoma cell lines. Oncogene. 15:1199-205.
  18. van de Rijn M, Barr FG, Xiong QB, Salhany KE, Fraker DL, and Fisher C. 1997. Radiation-associated synovial sarcoma. Hum Pathol. 28:1325-8.
  19. Massuda ES, Dunphy EJ, Redman RA, Schreiber JJ, Nauta LE, Barr FG, Maxwell IH, and Cripe TP. 1997. Regulated expression of the diphtheria toxin A chain by a tumor-specific chimeric transcription factor results in selective toxicity for alveolar rhabdomyosarcoma cells. Proc Natl Acad Sci U S A. 94:14701-6.
  20. Barr FG, Nauta LE, and Hollows JC. 1998. Structural analysis of PAX3 genomic rearrangements in alveolar rhabdomyosarcoma. Cancer Genet Cytogenet. 102:32-9.
  21. de Alava E, Kawai A, Healey JH, Fligman I, Meyers PA, Huvos AG, Gerald WL, Jhanwar SC, Argani P, Antonescu CR, Pardo-Mindan FJ, Ginsberg J, Womer R, Lawlor ER, Wunder J, Andrulis I, Sorensen PH, Barr FG, and Ladanyi M. 1998. EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma. J Clin Oncol. 16:1248-55.
  22. Ginsberg JP, Davis RJ, Bennicelli JL, Nauta LE, and Barr FG. 1998. Up-regulation of MET but not neural cell adhesion molecule expression by the PAX3-FKHR fusion protein in alveolar rhabdomyosarcoma. Cancer Res. 58:3542-6.
  23. van de Rijn M, Barr FG, Xiong QB, Hedges M, Shipley J, and Fisher C. 1999. Poorly differentiated synovial sarcoma: an analysis of clinical, pathologic, and molecular genetic features. Am J Surg Pathol. 23:106-12.
  24. Tang ED, Nunez G, Barr FG, and Guan KL. 1999. Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chem. 274:16741-6.
  25. Ginsberg JP, de Alava E, Ladanyi M, Wexler LH, Kovar H, Paulussen M, Zoubek A, Dockhorn-Dworniczak B, Juergens H, Wunder JS, Andrulis IL, Malik R, Sorensen PH, Womer RB, and Barr FG. 1999. EWS-FLI1 and EWS-ERG gene fusions are associated with similar clinical phenotypes in Ewing's sarcoma. J Clin Oncol. 17:1809-14.
  26. van de Rijn M, Barr FG, Collins MH, Xiong QB, and Fisher C. 1999. Absence of SYT-SSX fusion products in soft tissue tumors other than synovial sarcoma. Am J Clin Pathol. 112:43-9.
  27. Durham SK, Suwanichkul A, Scheimann AO, Yee D, Jackson JG, Barr FG, and Powell DR. 1999. FKHR binds the insulin response element in the insulin-like growth factor binding protein-1 promoter. Endocrinology. 140:3140-6.
  28. Bennicelli JL, Edwards RH, and Barr FG. 1996. Mechanism for transcriptional gain of function resulting from chromosomal translocation in alveolar rhabdomyosarcoma. Proc Natl Acad Sci USA. 93:5455-5459.
  29. Trupiano JK, Machen SK, Barr FG, and Goldblum JR. 1999. Cytokeratin-negative desmoplastic small round cell tumor: a report of two cases emphasizing the utility of reverse transcriptase-polymerase chain reaction. Mod Pathol. 12:849-53.
  30. Ayala JE, Streeper RS, Desgrosellier JS, Durham SK, Suwanichkul A, Svitek CA, Goldman JK, Barr FG, Powell DR, and O'Brien RM. 1999. Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence. Diabetes. 48:1885-9.
  31. Barr FG, Fitzgerald JC, Ginsberg JP, Vanella ML, Davis RJ, and Bennicelli JL. 1999. Predominant expression of alternative PAX3 and PAX7 forms in myogenic and neural tumor cell lines. Cancer Res. 59:5443-8.
  32. del Peso L, Gonzalez VM, Hernandez R, Barr FG, and Nunez G. 1999. Regulation of the forkhead transcription factor FKHR, but not the PAX3-FKHR fusion protein, by the serine/threonine kinase Akt. Oncogene. 18:7328-33.
  33. Fitzgerald JC, Scherr AM, Barr FG. 2000. Structural analysis of PAX7 rearrangements in alveolar rhabdomyosarcoma. Cancer Genet Cytogenet. 117:37-40.
  34. de Alava E, Panizo A, Antonescu CR, Huvos AG, Pardo-Mindan FJ, Barr FG, and Ladanyi M. 2000Association of EWS-FLI1 type 1 fusion with lower proliferative rate in Ewing's sarcoma. Am J Pathol. 156:849-55.
  35. Margue CM, Bernasconi M, Barr FG, Schafer BW. 2000. and Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR. Oncogene. 19:2921-9.
  36. Zhao HH, Herrera RE, Coronado-Heinsohn E, Yang MC, Ludes-Meyers JH, Seybold-Tilson KJ, Nawaz Z, Yee D, Barr FG, Diab SG, Brown PH, Fuqua SA, and Osborne CK. 2001. Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions. J Biol Chem. 276:27907-12.
  37. Collins MH, Zhao H, Womer RB and Barr FG. 2001. Proliferative and apoptotic differences between alveolar rhabdomyosarcoma subtypes: a comparative study of tumors containing PAX3-FKHR or PAX7-FKHR gene fusions. Med Pediatr Oncol. 37:83-9.
  38. Ladanyi M, Antonescu CR, Leung DH, Woodruff JM, Kawai A, Healey JH, Brennan MF, Bridge JA, Neff JR, Barr FG, Goldsmith JD, Brooks JS, Goldblum JR, Ali SZ, Shipley J, Cooper CS, Fisher C, Skytting B, and Larsson O. 2002. Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients. Cancer Res. 62:135-40.
  39. Bridge JA, Liu J, Qualman SJ, Suijkerbuijk R, Wenger G, Zhang J, Wan X, Baker KS, Sorensen P, and Barr FG. 2002. Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chromosomes Cancer. 33:310-21.
  40. Trupiano JK, Rice TW, Herzog K, Barr FG, Shipley J, Fisher C, and Goldblum JR. 2002. Mediastinal synovial sarcoma: report of two cases with molecular genetic analysis. Ann Thorac Surg. 73:628-30.
  41. Barber TD, Barber MC, Tomescu O, Barr FG, Ruben S, Friedman TB. 2002. Identification of target genes regulated by PAX3 and PAX3-FKHR in embryogenesis and alveolar rhabdomyosarcoma. Genomics. 79:278-84.
  42. Sorensen PH, Lynch JC, Qualman SJ, Tirabosco R, Lim JF, Maurer HM, Bridge JA, Crist WM, Triche TJ, and Barr FG. 2002. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol. 20:2672-9.
  43. Barr FG, Qualman SJ, Macris MH, Melnyk N, Lawlor ER, Strzelecki DM, Triche TJ, Bridge JA, and Sorensen PH. 2002. Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res. 62:4704-10.
  44. Sanders ME, Mick R, Tomaszewski JE, and Barr FG. 2002. Unique patterns of allelic imbalance distinguish type 1 from type 2 sporadic papillary renal cell carcinoma. Am J Pathol. 161:997-1005.
  45. Libura J, Drukala J, Majka M, Tomescu O, Navenot JM, Kucia M, Marquez L, Peiper SC, Barr FG, Janowska-Wieczorek A, and Ratajczak MZ. 2002. CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood. 100:2597-606.
  46. Goldsmith JD, Pawel B, Goldblum JR, Pasha TL, Roberts S, Nelson P, Khurana JS, Barr FG, and Zhang PJ. 2002. Detection and diagnostic utilization of placental alkaline phosphatase in muscular tissue and tumors with myogenic differentiation. Am J Surg Pathol. 26:1627-33.
  47. Zhang PJ, Goldblum JR, Pawel BR, Fisher C, Pasha TL, Barr FG. 2003. Immunophenotype of Desmoplastic Small Round Cell Tumors as Detected in Cases with EWS-WT1 Gene Fusion Product. Mod Pathol. 16:229-35.

 

 
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