Dr. Barry A. Finette
Mutagenic Mechanisms in Pediatric DiseasesThe major research focus of my laboratory involves investigating the association between somatic mutational events during normal human development and the evolution of multigenetic, multifactorial diseases in children. Included in these objectives are human biomonitoring studies in pediatric populations following genotoxic exposure to chemicals, drugs and radiation to access disease risk.
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.