Biomedical subjects

Barry W Brown

Publications and source records attributed to Barry W Brown.

5 recordsLinked to original sources

PubMed2005

Generation or birth cohort effect on cancer risk in Li-Fraumeni syndrome.

Genetic anticipation is the increased incidence, earlier onset, or increased severity of a disease in successive generations. Before the biological basis of anticipation had been demonstrated, the phenomenon was thought to be due to sampling bias, epigenetic effects, gene conversion, or recombinant events. Since then, the biologic basis for anticipation in a number of neurodegenerative disorders has been shown to be attributable to trinucleotide repeat instability, with expansion of repeats clearly correlated with an earlier age of onset. Recently, telomere shortening has been suggested as the mechanism for anticipation in the autosomal dominant form of dyskeratosis congenita, attributable to mutations in the TERC gene, leading to dysfunctional telomeres (Vulliamy et al. 2004). However, the pattern of anticipation has been observed in other disorders, including cancers, for which no genetic defect has been identified. In this study, we assess the apparent generation effect on cancer incidence in ten extended families with P53 germline mutation, identified through probands diagnosed with childhood sarcoma. The probands were from two sets of systematically ascertained sarcoma patients treated at the University of Texas M. D. Anderson Cancer Center between 1944 and 1982. From those overall studies, we have identified ten kindreds having germline P53 mutations in more than one generation. We compared the cancer incidence in members of successive generations of these families with P53 mutations (carriers) and with no P53 mutations (noncarriers). In carriers, cancer incidence increased in succeeding generations; there was no evidence for this effect in noncarriers; however, the noncarrier population was too small to rule it out. The apparent lack of increase in incidence in noncarriers argues against a cohort effect explaining the increase in carriers.

Adult↗

PubMed2005

Microsatellite instability (MSI) increases with age in normal somatic cells.

Small pool PCR (SP-PCR) is a sensitive method for the detection and quantification of microsatellite instability (MSI) in somatic cells. Here we propose that mutant microsatellite fragments accumulate with age in normal somatic cells and that this increase in MSI can be quantified by SP-PCR. MSI at 6 microsatellite loci was determined by SP-PCR in PBL DNA from 17 "normal" blood bank donors. These individuals varied in age from 20 to 67 y/o. MSI phenotypes were plotted against age in a regression analyses. A positive slope indicated a correlation between age and MSI phenotype (p=0.0006). The mean weighted average mutant frequencies across all loci for all individuals in the age groups (0.009 for 20-30 y/o; 0.019 for 35-50 y/o; 0.034 for 60-70 y/o) were also significantly different from each other (p<0.01). A baseline for increases of MSI with age in human somatic cells was therefore begun and the effectiveness of SP-PCR to evaluate low, but significant, levels of MSI, established.

Adult↗

PubMed2004

Phase I clinical evaluation of near-simultaneous computed tomographic image-guided stereotactic body radiotherapy for spinal metastases.

PURPOSE: To evaluate in a Phase I study the safety, feasibility, and patient-positioning accuracy of treating patients with intensity-modulated, near-simultaneous, computed tomographic (CT) image-guided stereotactic body radiotherapy (SBRT). PATIENTS AND METHODS: Fifteen consecutive patients with metastatic spinal disease who met protocol eligibility criteria were entered into a Phase I clinical trial. Each patient received five treatments of intensity-modulated, near-simultaneous CT image-guided SBRT, for a total of 75 treatments with 90 isocenter setups during the course of the study. Patients uniformly received 30 Gy (if possible) of radiotherapy in 5 fractions to the clinical target volume. The total dose was constrained by limiting the spinal cord to a maximum dose of 10 Gy. To verify correct daily patient positioning before each treatment and to determine the daily treatment setup error after radiation delivery, axial CT scans were taken before and immediately after each treatment without moving the patient from the treatment position, for comparison with the planning CT scan. Toxicity was measured using the Common Toxicity Criteria, the Late Effects of Normal Tissue scoring system and a neurologic function scale. Follow-up was conducted 4 weeks after completion of SBRT, and then 2, 3, 6, 9, 12, and every 6 months thereafter. RESULTS: The procedure was technically feasible to perform in all patients. No neurologic toxicity was observed in any patient. The median follow-up time was 9 months (range 6-16). The Clopper-Pearson upper bound on the probability of paralysis with 95% confidence is no greater than 0.181. The positional setup error was determined to be within 1 mm of planning isocenter. CONCLUSIONS: This Phase I study shows that intensity-modulated, near simultaneous, CT image-guided SBRT is a feasible, and highly precise technique for the noninvasive treatment of spinal metastases. Although no paralysis has developed in the 15 patients treated, continued monitoring for spinal cord toxicity is warranted, as larger numbers of patients will be needed to more precisely define the upper bound on the probability of spinal cord myelopathy.

Adolescent↗

PubMed2004

Estimating mutant microsatellite allele frequencies in somatic cells by small-pool PCR.

Identifying microsatellite instability (MSI) by partitioning DNA into multiple small pools containing only single genome amounts of DNA results in trapping both progenitor and low-frequency mutant alleles into pools where they can be identified and counted following PCR. Statistical approaches determining both the frequencies and the significant differences between frequencies of these Poisson-distributed alleles are presented. Results indicate a level of sensitivity and quantification not possible by standard PCR methods. Using material from colon cancer patients with high levels of MSI in their tumors, we also present the molecular and robotic methods for carrying out such studies. Validation experiments indicated mutants detectable at frequencies >0.03 above background. Frequencies obtained in tumor tissue (>0.25) met the expectations of the approach. Significant levels of MSI were detected in the constitutive tissue of the patient carrying a germ-line mutation for mismatch repair, suggesting both mechanistic and clinical applications of the procedure.

Adult↗

PubMed2004

Power calculations for the transmission/disequilibrium and affected sib pair tests using elementary probability methods.

The transmission/disequilibrium test (TDT) and the affected sib pair test (ASP) both test for the association of a marker allele with some conditions. Here, we present methods for calculating the probability of detecting the association (power) for a study examining a fixed number of families for suitability for the study and for calculating the number of such families to be examined. Both calculations use a genetic model for the association. The model considered posits a bi-allelic marker locus that is linked to a bi-allelic disease locus with a possibly nonzero recombination fraction between the loci. The penetrance of the disease is an increasing function of the number of disease alleles. The TDT tests whether the transmission by a heterozygous parent of a particular allele at a marker locus to an affected offspring occurs with probability greater than 0.5. The ASP tests whether transmission of the same allele to two affected sibs occurs with probability greater than 0.5. In either case, evidence that the probability is greater than 0.5 is evidence for association between the marker and the disease. Study inclusion criteria (IC) can greatly affect the necessary sample size of a TDT or ASP study. IC considered by us include a randomly selected parent at least one parent or both parents required to be heterozygous. It also allows a specified minimum number of affected offspring to be required (TDT only). We use elementary probability calculations rather than complex mathematical manipulations or asymptotic methods (large sample size approximations) to compute power and requisite sample size for a proposed study. The advantages of these methods are simplicity and generality.

Chromosome Mapping↗