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The article evaluates the effects of cancer diagnosis on endogenous deoxyribonucleic acid (DNA) damage. It assesses the effect of cancer diagnosis among 26 individuals with breast cancer with blood drawn between 2001 and 2003 and again in 2005 and 2006 after a diagnosis of cancer. The comet assay in prediagnostic and postdiagnostic samples from these people shows no effect of cancer diagnosis on the DNA damage and found slight evidence of reverse causation bias being an important concern in case-control studies.

Purpose: To conduct a literature review of candidate protein biomarkers for individual radiation biodosimetry of exposure to ionizing radiation.Materials and methods: Reviewed ?300 publications (1973 – April 2006) that reported protein effects in mammalian systems after either in vivo or in vitro radiation exposure.Results: We found 261 radiation-responsive proteins including 173 human proteins. Most of the studies used high doses of ionizing radiation (>4 Gy) and had no information on dose- or time-responses. The majority of the proteins showed increased amounts or changes in phosphorylation states within 24 h after exposure (range: 1.5- to 10-fold). Of the 47 proteins that are responsive at doses of 1 Gy and below, 6 showed phosphorylation changes at doses below 10 cGy. Proteins were assigned to 9 groups based on consistency of response across species, dose- and time-response information and known role in the radiation damage response.Conclusions: ATM (Ataxia telengiectasia mutated), H2AX (histone 2AX), CDKN1A (Cyclin-dependent kinase inhibitor 1A), and TP53 (tumor protein 53) are top candidate radiation protein biomarkers. Furthermore, we recommend a panel of protein biomarkers, each with different dose and time optima, to improve individual radiation biodosimetry for discriminating between low-, moderate-, and high-dose exposures. Our findings have applications for early triage and follow-up medical assessments. [ABSTRACT FROM AUTHOR]

Understanding the significance of somatic mutations requires knowledge of the mutations that occur in vivo in healthy people. The molecular characterization of mutations in the hypoxanthine phosphoribosyltransferase (hprt) gene in 217 independent T-lymphocyte mutants from 172 donors, including smoking and non-smoking males and females, reveals a broad spectrum of in vivo somatic mutation occurring in a population of healthy people. Identification of the DNA alteration in individual mutant clones was accomplished using either one or a combination of multiplex polymerase chain reaction analysis of genomic DNA, sequencing of cDNA, and genomic DNA sequencing. The total spectrum consists of 59% (128/217) base substitutions: 126 simple and two tandem CC>TT base substitutions; 39% (85/217) deletion/insertion type mutations: 30 frameshifts, 26 small (3–200 basepairs) and 27 large deletions, and two duplications; and the remaining 2% (4/217) complex mutations involving the deletion of one to 11 basepairs which are replaced by 1 to 10 basepairs. No significant difference was detected between the base substitution spectra for the smokers and the non-smokers. Analysis of the number of mutations occurring at any one base position led to the identification of three hotspots for mutations at basepairs 197, 508 and 617, in the hprt gene coding region. Spontaneous deamination of CpG may be implicated in the creation of basepair 508 as a hotspot since all mutations detected are C>T transitions resulting in the nonsense mutation, TAG. At basepairs 197 and 617 both G>T transversions and G>A transitions were found indicating that at least two mechanisms were involved in creating mutations at these positions. Comparison of the mutation spectra from two populations can provide insight into the origin of the mutations. This study provides an excellent base for comparison of mutation spectra in other human populations. [ABSTRACT FROM PUBLISHER]

The repair of damaged DNA requires the function of multiple proteins in generally damage-specific, nonredundant pathways. The relationship of DNA repair to cancer susceptibility is obvious in "cancer families," in which low frequency, high penetrance, loss-of-function variant alleles of genes with roles in the repair of damaged DNA have been associated with a high risk of disease. More important for the cancer incidence in the general population, many individuals exhibit reduced (60-75% of normal) repair capacity phenotypes that have been associated with several-fold increases in individual cancer risk. In a program to identify the molecular basis for the variation in repair capacity and the elevated cancer susceptibility, we have identified 127 amino acid substitution variants in resequencing 37 DNA repair genes in 36-164 unrelated individuals. Over 50% of the substitutions are exchanges of amino acid residues with dissimilar physical or chemical properties, at sites at which the common residue is identical in the human and mouse proteins. Five additional sequence changes resulting in proteins with altered termination of translation and one amino acid insertion variant were detected. The variant allele frequencies average 0.047, with individual variant allele frequencies ranging from <0.01 to 0.43. Homozygous variant individuals and individuals with multiple amino acid substitutions in a gene were observed. Most individuals exhibited variation in multiple genes in a repair pathway. Ten variant alleles accounted for 52% of the genetic variation among individuals, but a striking 23% of the total variation is associated with 108 variants with allele frequencies of less than 5%. Screening generally healthy individuals generates a catalogue of common variants that is a resource for molecular epidemiology studies endeavoring to use a genotype to phenotype paradigm to estimate the role of genetic variation and individual susceptibility in disease risk from environmental and lifestyle exposures in the general population of the United States.