title: Mutational profiling of sporadic versus toxin-associated brain cancer formation: initial findings using loss of heterozygosity profiling.
abstract: The role of environmental and occupational toxin exposure as a cause of or contributing factor for cancer development and progression is incompletely understood. A unique signature of specific mutational change to discriminate toxin-exposed from sporadic cancer is generally sought but not often encountered. We report an approach to better understand cancer causality based on the measurement of the cumulative DNA damage (via loss of heterozygosity) over a defined genomic region (chromosome 3) that is applicable to archival, fixative-treated tissue and cytology specimens of cancer. Our method was applied to (1) a cohort of 10 brain tumor subjects (9 gliomas, 1 hemangioblastoma) with potential exposure to chlorinated solvents and (2) a control cohort of sporadic brain cancer controls (7 gliomas, 1 hemangioblastoma). We show that brain tumors arising in potentially toxin-exposed subjects bear a significantly higher level of passenger LOH mutations compared to sporadic cancer controls. The methodology utilized tissue microdissection, PCR amplification and capillary electrophoresis (fragment analysis for LOH determination, DNA sequencing for specific point mutations), and examined a panel of 15 microsatellite markers distributed along both arms of chromosome 3 that aimed at capturing passenger mutational change accrued during stages of clonal expansion of neoplastic cells. This proof-of-principle study using mutational profiling for passenger LOH mutational damage provides support for the utility of this approach and further studies in order to differentiate between genotoxin-associated versus sporadic (unexposed) cancer development.
authors.affiliation: RedPath Integrated Pathology, Inc, Pittsburgh, PA 15222, USA.
authors.forename: Eric M G
authors.initials: EM
authors.lastname: Ellsworth
authors.forename: John F
authors.initials: JF
authors.lastname: Palma
authors.forename: W Christine
authors.initials: WC
authors.lastname: Spence
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Bleicher
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Smith
authors.forename: Sydney D
authors.initials: SD
authors.lastname: Finkelstein
mesh_terms: D001932:Brain Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D002274:Carcinogens, Environmental / Q000633:toxicity*; D017606:Chlorine Compounds / Q000633:toxicity; D015331:Cohort Studies; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004781:Environmental Exposure; D006801:Humans; D019656:Loss of Heterozygosity; D009153:Mutagens / Q000633:toxicity*; D012997:Solvents / Q000633:toxicity
chemical_list: D002274:Carcinogens, Environmental; D017606:Chlorine Compounds; D009153:Mutagens; D012997:Solvents