Mutagenic Mechanisms in Pediatric Diseases
Dr. Finette received his B.Sci. in Bacteriology at the University of Wisconsin – Madison in 1979 and his Ph.D. in Microbiology in 1984 at the University of Texas – Austin. He subsequently went on to receive his M.D. at the University of Texas Health Science Center-Dallas. He did is residency training in Pediatrics at Children’s Medical Center and Parkland Hospital in Dallas and at the Medical Center Hospital of Vermont-Burlington.
The overall premise of our studies evolves around the observation that cellular, hormonal, and molecular systems during fetal and childhood development are dynamic and change with time; that these events in children are unique compared to adults; and that virtually all human diseases are age specific. We first studied this at the molecular level by determining that the frequency and spectrum of somatic mutational events in children is age dependent and unique compared to adults. Specifically we reported that children have an age – specific frequency of spontaneous somatic mutations from birth to early adolescence. In addition we have determined that the frequency of somatic mutations during human fetal development is in itself distinct compared to full term infants and children. In addition we have also determined that there is a gender specific difference in somatic mutant frequency and mutational spectra during fetal development that is dependent on gestational age. Mutational spectra analysis of genomic mutant isolates from healthy children has also revealed a developmentally specific mutational spectrum mediated by a V(D)J recombinase mechanism that correlates clinically with genetic events associated with lymphoid malignancies in children. In addition, age – specific mutational events involving clinically important single base substitutions at CpG dinucleotides has also been demonstrated. In addition, we have also investigated somatic mutational events in children with a variety of diseases, including, juvenile onset dermatomyositis, Down syndrome, and cancer.
Genotoxic biomonitoring studies in our laboratory have focused on determining the genetic effects of transplacental exposure to tobacco smoke on healthy newborns. Molecular analysis of mutant clones from these newborns revealed a striking observation, specifically that newborn infants exposed to transplacental genotoxic agents from tobacco smoke had a significant increase in the proportion and frequency of V(D)J recombinase mediated rearrangements in peripheral T-lymphocytes compared to controls. This study linked for the first time, transplacental tobacco exposure with and increase in the frequency of a molecular event associated with leukemogenesis in children.
Our current studies focus on investigating mutagenic mechanisms associated with the accumulation of somatic mutations in clonal lineages and their association with malignant transformation in children. We are determining the genotoxic effects of antineoplastic therapy in children with a variety of malignancies such as leukemia, sarcomas, neuroblastoma and Hodgkin’s disease. Most recently we have captured the evolution of clonally restricted mutagenic pathways (proliferative mutability and mutator phenotype hypermutability) in children who have received treatment for acute lymphocytic leukemia. We are expanding these studies to by investigating the incidence of these mutagenic events in children treated with other malignancies, specifically sarcomas, neuroblastoma and Hodgkin’s disease. In addition we are beginning extensive studies investigating the genetic basis for this hypermutability / genomic instability in these patients. These studies should lead to the first “functional genetic” studies for elucidating the cellular and molecular mechanisms associated with clonal proliferation and genetic instability leading to malignant transformation.
Rice, S., P. Vacek, A.C. Homans, T. Messier, J. Rivers, H. Kendall, and B.A. Finette. 2004. Genotoxicity of therapeutic intervention in children with acute lymphocytic leukemia. Cancer Research.2004. 64: 4464-4471
Finette, B.A., Homans, A.C., and Albertini, R.J. Emergence of genetic instability in children treated for leukemia. Science. 2000.288:514-517
Yoshioka, M., Vacek, P.M., Poseno, T., Silver, R., and Finette, B.A. Gender-specific frequency of background somatic mutations at the hypoxanthine phosphoribosyltransferase locus in cord blood T lymphocytes from preterm newborns. Proc. Natl. Acad. Sci. USA 1999 Jan 19;96(2):586-591.
Finette, B.A., O’Neill, J.P., Vacek, P.M., and Albertini, R.J. Gene mutations with characteristic deletions in cord blood T lymphocytes associated with passive maternal exposure to tobacco smoke. Nat. Med. 1998 Oct;4(10):1144-1151.
Finette, B.A, Poseno, T., and Albertini, R.J. V(D)J recombinase-mediated HPRT mutations in peripheral blood lymphocytes of normal children. Cancer Res. 1996 Mar 15;56(6):1405-1412.
Messier TL, O\’Neill JP, Hou SM, Nicklas JA, Finette BA. In vivo transposition mediated by V(D)J recombinase in human T lymphocytes EMBO J. 2003 Mar 17;22(6):1381-8.
* indicates equal contribution
Nguyen TT, Lakhan SE, Finette BA (2013) Development of a cost-effective high-throughput process of microsatellite analysis involving miniaturized multiplexed PCR amplification and automated allele identification. Hum Genomics 7: 6.
Murray JM, Messier T, Rivers J, O’Neill JP, Walker VE, Vacek PM, Finette BA (2012) VDJ recombinase-mediated TCR β locus gene usage and coding joint processing in peripheral T cells during perinatal and pediatric development. J Immunol 189(5): 2356-64.
Nguyen T, Vacek PM, O’Neill P, Colletti RB, Finette BA (2009) Mutagenicity and potential carcinogenicity of thiopurine treatment in patients with inflammatory bowel disease. Cancer Res 69(17): 7004-12.
Pinsonneault RL, Vacek PM, O’Neill JP, Finette BA (2007) Induction of V(D)J-mediated recombination of an extrachromosomal substrate following exposure to DNA-damaging agents. Environ Mol Mutagen 48(6): 440-50.
Murray JM, O’Neill JP, Messier T, Rivers J, Walker VE, McGonagle B, Trombley L, Cowell LG, Kelsoe G, McBlane F, Finette BA (2006) V(D)J recombinase-mediated processing of coding junctions at cryptic recombination signal sequences in peripheral T cells during human development. J Immunol 177(8): 5393-404.
Kendall HE, Vacek PM, Rivers JL, Rice SC, Messier TL, Finette BA (2006) Analysis of genetic alterations and clonal proliferation in children treated for acute lymphocytic leukemia. Cancer Res 66(17): 8455-61.
Messier TL, O’Neill JP, Finette BA (2006) V(D)J recombinase mediated inter-chromosomal HPRT alterations at cryptic recombination signal sequences in peripheral human T cells. Hum Mutat 27(8): 829.
Leukemia and Lymphoma Society of America Translational Research Scholar (1997-present)
National Cancer Institute Howard Temin Award (1998-2003)
Exemplary Scholar, University of Vermont (2000)
Burroughs Wellcome Fund Clinical Scientist Award in Translational Research (2002-present)
Department of Pediatrics
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