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D J Schaid

Publications and source records attributed to D J Schaid.

At least 19 recordsLinked to original sources
PubMed1996

Increased mutation frequency and altered spectrum in one of four thymic lymphomas derived from tumor prone p53/Big Blue double transgenic mice.

p53 (-/-), lacI (+/-) double transgenic (p53/Big Blue3) mice provide an opportunity to examine the relationship in vivo between somatic mutation and tumorigenesis. Previously, the frequency and spectra of lacI mutations were found to be similar in normal tissues of 6 week old p53 (-/-) lacI (+/-) and p53 (+/+) lacI (+/-) mice. Herein, p53 (-/-), lacI (+/-) mice were used to examine the frequency and spectrum of spontaneous mutation in thymic lymphomas. Four mice with thymic lymphomas were sacrificed at 2.5, 3, 4 and 4.5 months of age. Normal thymus harvested from two p53 (+/+) lacI (+/-) mice and two p53 (-/-) lacI (+/-) mice served as controls. The mutation frequency in tumor 108 (6.8 x 10(-5)) was elevated 2.3-fold relative to the p53 (-/-) control (P<0.0001; chi2 test). The mutation spectra were also different (P=0.0009; Fisher exact test); in particular, A:T-->G:C transitions were prominently overrepresented in tumor 108. In addition, there were two examples of unusual deletions with inversions. In tumors 44 and 115, but not 110, there were trends toward increased mutation frequencies and altered spectra, but, within the constraints of present sample sizes, the results are not statistically significant. In conclusion, these findings suggest that altered frequencies and spectra exist in a subset of thymic lymphomas, perhaps due to somatic mutation in one or more DNA repair genes.

Animals↗
PubMed1996

Molecular epidemiology of breast cancers in northern and southern Japan: the frequency, clustering, and patterns of p53 gene mutations differ among these two low-risk populations.

Comparison of acquired mutations in the p53 tumor suppressor gene can illuminate factors contributing to carcinogenesis among cancer cohorts. Japan has an ethnically homogeneous population with a low incidence of breast cancer. Previously we reported an unusual frequency, allelic status, and clustering of mutations in breast cancers from the northern part of the main Japanese island. To extend these findings, exons 2-11 and adjacent intronic sequences were analysed in tumors of women from northern (Hokkaido) and southern (Tokushima) Japan. The frequency of breast cancers with p53 gene mutations in the Hokkaido group is the highest reported (81%) while that in Tokushima (28%) is similar to most other populations. Thirteen of the 19 mutations (68.4%) in the Hokkaido cohort were heterozygous, an unusually high frequency for p53 mutations in any tumor type. There were three missense mutations at codon 175, a known hotspot for alterations in the p53 gene, and three missense mutations at codon 179, a rare site for p53 changes. In addition, the patterns of p53 gene mutation differed between the two Japanese cohorts (P=0.04). The multiple differences in acquired p53 mutations suggest unsuspected biological differences among breast cancers in northern and southern Japan. In addition, the high frequency of p53 mutations in breast cancers from Hokkaido predicted a poorer prognosis for this population which was confirmed on examination of mortality data.

Adult↗
PubMed1996

Allelic imbalance and microsatellite instability in prostatic adenocarcinoma.

Although prostate cancer is one of the most common malignancies of males in Western countries, relatively little is known about the molecular mechanisms involved in tumor initiation and progression. Allelic loss studies have suggested the involvement of multiple tumor suppressor genes (TSGs), but few detailed studies of all chromosomes have been performed. In an effort to localize and identify candidate TSGs, we performed allelic imbalance (AI) studies on 55 prostate cancers, using 135 polymorphic microsatellite markers. For the entire chromosome. AI ranged from a low of 0% on chromosomes 14 and 20 to a high of 71% on chromosome 8. Chromosomal regions demonstrating at least twice the background frequency of AI (ranging from 20 to 69%) included 5q, 6q, 7q, 8p, 13, l6q, l8q, and 21. In addition, AI was examined for association with a number of clinicopathological parameters. AI on chromosomes 7 and 16 were each associated with greater age at diagnosis (P = 0.009 and 0.001, respectively), and AI on chromosomes 10, 16, and 18 was associated with aneuploidy/tetraploidy (P = 0.037, 0.013, and 0.054, respectively). Furthermore, AI on chromosome 5 was associated with a higher pathological stage (P = 0.021) and on chromosome 8 and 16 with a higher Gleason score (P = 0.027 and 0.041, respectively). No tumor exhibited a phenotype of widespread microsatellite instability. These results indicate that there likely exist multiple sites harboring candidate TSG in prostate cancer, some of which may have important clinical implications, and which argue against widespread microsatellite instability.

Adenocarcinoma↗
PubMed1996

Tumor necrosis factor-alpha allelic frequency and chromosome 6 allelic imbalance in patients with colorectal cancer.

The human tumor necrosis factor (TNF) locus is located on chromosome 6p21.3 and contains at least five polymorphic microsatellites. In this study, we compared the allelic frequencies derived from 50 normal controls to 64 patients with colorectal cancer at one of these loci, TNF alpha. No differences in allelic frequencies were observed between these two groups (P = 0.47). However, sequencing of the TNF alpha PCR product revealed two populations of TNF alpha alleles; alleles with the expected DNA sequence (i.e., the expected number of AC/GT repeats) and alleles that contained 8-bp deletions adjacent to the microsatellite repeat. In addition, we also examined paired normal and tumor DNA from the colorectal cancer group for microsatellite alterations at the TNF alpha locus, including allelic loss of heterozygosity and microsatellite instability. Of the 64 tumors examined, 13 (20%) demonstrated microsatellite instability, and 14 (42%) of 33 informative cases demonstrated allelic imbalance. Analysis of 10 additional chromosome 6 loci for allelic loss showed that 23 (47%) of 49 informative cases exhibited allelic imbalance with at least one chromosome 6p marker, 23 (47%) of 49 with at least one 6q marker, and 29 (59%) of 49 with at least one marker on chromosome 6. Examination of tumors for the minimal region of deletion overlap suggests the presence of tumor suppressor genes on both 6p and 6q.

Alleles↗
PubMed1996

General score tests for associations of genetic markers with disease using cases and their parents.

Association studies of genetic markers with disease play a critical role in the dissection of genetically complex traits because they are relatively easy to conduct and are useful for fine-scale mapping of genetic traits. The advantage of family-based controls has recently received much attention because spurious associations caused by population structure can be controlled for, and marker genotype information on diseased cases and their parents can be used to test the compound hypothesis of both linkage and linkage disequilibrium. However, debate still exists regarding the statistical methods of analysis. Herein are presented statistical methods to test for linkage (in the presence of linkage disequilibrium) between multiallelic genetic markers and disease when diseased subjects (cases) and their parents are sampled. Theoretical considerations for the development of general statistical tests are presented as well as asymptotic formulas to compute their power when planning a study. Furthermore, simulation results for nine specific statistics are used to contrast the power of these methods under different genetic mechanisms leading to disease (dominant vs. recessive, one vs. two high-risk alleles). These results demonstrate substantial gains in power for specific statistical tests designed to detect specified genetic mechanisms. However, without a priori knowledge of the likely genetic mechanism, it is desirable to rely on a fairly robust statistical method, robust so that power is not drastically lost when either dominant or recessive mechanisms are acting, and when either one or more than one marker alleles are associated with disease. Based on both theoretical and simulation results, a general score statistic, which generalizes the transmission/disequilibrium test, tends to offer sufficient power for a variety of genetic mechanisms, so that it is worth considering for broad use in studies which use genetic marker information from both diseased cases and their parents.

Adult↗
PubMed1996

Etoposide-cisplatin and thoracic radiation therapy salvage of incomplete responders to a noncisplatin induction regimen for limited and extensive small-cell carcinoma of the lung.

Our purpose was to determine the ability of an etoposide-cisplatin (EP )-based regimen to salvage patients with limited and extensive small-cell lung cancer who are incomplete responders to cyclophosphamide-Adriamycin-vincristine-etoposide (CAVE) chemotherapy, and to determine the ability of thoracic radiation therapy (TRT) to salvage CAVE and EP incomplete responders. Fifty-eight patients with small-cell lung cancer (33, limited disease; 25, extensive disease) were entered on this Phase II study between November 1984 and December 1987. Patients received three cycles of CAVE chemotherapy, followed by two cycles of CEPi (cyclophosphamide-etoposide-cisplatin (infusional) and two cycles of CE (cyclophosphamide-etoposide) in conjunction with TRT and prophylactic cranial irradiation (PCI). The overall response rate to CAVE was 62% [5% complete response (CR), 57% partial response (PR) + regression (REGR)]. Of the patients who failed to achieve a CR with CAVE, 81% responded to CEPi (44% CR, 36% PR). Of the patients who did not achieve a CR with either CAVE or CEPi, 89% responded to TRT (65% CR, 24% PR + REGR). For the 33 patients with limited disease, the median survival time and 2-year survival rate were 16.1 months and 24%, respectively. The corresponding figures for the 25 patients with extensive disease were 9.8 months and 4%, respectively. Eleven of these 25 patients were "downstaged" to "limited disease" with CAVE + CEPi and then received TRT + PCI + CE. Their median survival time and 2-year survival rate were 12.6 months and 9%, respectively. The EP-based regimen CEPi and TRT were able to convert 44 to 65% of patients to a complete response who had failed to do so with non-EP induction chemotherapy. This study supports the use of an EP regimen with TRT as initial therapy for newly diagnosed small-cell lung cancer.

Adult↗
PubMed1996

Anticipation in familial Parkinson's disease: a reanalysis of 13 United Kingdom kindreds.

Several authors reported anticipation for age at onset in familial Parkinson's disease (PD) and postulated the involvement of an unstable trinucleotide repeat gene. We reanalyzed 13 previously reported multiple generation kindreds with familial PD to investigate anticipation and related biases. Although initial review of 33 informative parent-child and aunt/uncle-niece/nephew pairs revealed a mean anticipation interval of 9.3 years (p = 0.0001), exclusion of probands, in an effort to limit referral bias, reduced this to 4.1 years (p = 0.09). This reduced figure is still an overestimate of the true anticipation interval because of residual referral bias and because of incomplete information on the most recent generation. Our analyses did not demonstrate the effects of recall bias or of reduced fertility. We conclude that the observed anticipation in familial PD may partly or completely result from referral and other biases. Caution should be exercised in assuming an unstable trinucleotide repeat gene as the cause of familial PD.

Adolescent↗
PubMed1996

Alpha-1-antitrypsin phenotypes among patients with intracranial aneurysms.

A deficiency of alpha 1-antitrypsin has been implicated in the development of arterial aneurysms, including intracranial aneurysms. The authors determined the prevalence of alpha 1-antitrypsin deficiency of different phenotypes in 100 consecutive patients with intracranial aneurysms and compared the distribution of alpha 1-antitrypsin phenotypes to that in the general population (904 people). The study population consisted of 44 men and 56 women with a mean age of 52 years (range 15-81 years). The heterozygous alpha 1-antitrypsin deficiency states (PiMS and PiMZ) were more common in patients (16%) than in the general population (7%), providing an odds ratio of 2.56 (95% confidence interval (CI) 1.32-4.75; p = 0.005). In addition, one patient (1%) was homozygous for the deficient allele (PiZZ) compared to an expected number of 0.015, providing an odds ratio of 67.0 (95% CI 2.0-363.3; p = 0.015). These findings lead the authors to suggest that the heterozygous and homozygous alpha 1-antitrypsin deficiency states are genetic risk factors for the development of intracranial aneurysms.

Adolescent↗
PubMed1996

The influence of the HLA-DRB1*13 allele on measles vaccine response.

BACKGROUND: Measles remains a public health threat in the United States with over 50,000 cases being reported from 1989 through 1991 with continued smaller outbreaks. Measles vaccine failure is in part to blame for these large-scale outbreaks. The human leukocyte antigen (HLA) genes are important determinants of immune response to measles virus and vaccine. To examine the influence that HLA polymorphisms may have on measles vaccine antibody response, we compared the distribution of HLA-DRB1 alleles between measles vaccine nonresponders and hyper-responders. METHODS: We determined the seroprevalence of measles antibody in 881 school children immunized with measles-mumps-rubella-II at age 15 months using a whole virus IgG EIA. We performed class II HLA-DR typing by PCR with sequence specific primers (PCR-SSP) on 81 nonresponders (IgG seronegative) and 65 hyper-responders (from the upper 10th percentile of IgG levels of all subjects). We then compared the distribution of alleles between nonresponders and hyper-responders. RESULTS: The distribution of HLA-DRB1 alleles among nonresponders compared to hyper-responders was significantly different (p = 0.014). Nonresponders were significantly less likely to carry the HLA-DRB1*13 alleles than were hyper-responders (7.4% vs 16.2%;p = 0.02). Nonresponders also had an excess of HLA-DRB1*07 alleles (15.4% vs 6.2%; p = 0.015). CONCLUSIONS: The absence of HLA-DRB1*13 alleles is associated with measles vaccine nonresponse. The absence of this allele has also been associated with susceptibility to other infectious diseases. The role of this gene in the immunogenetic response to infectious diseases requires further study.

Alleles↗
PubMed1995

Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals.

OBJECTIVE: The outcome of patients with mild cognitive impairment is not known, yet these patients present a difficult dilemma for the clinician. This study was designed to characterize the outcome of a group of patients with mild cognitive impairment and to determine whether the presence of the epsilon 4 allele on the apolipoprotein E gene (APOE) is a predictor of that outcome. DESIGN: A prospective, longitudinal inception cohort. SETTING: General community clinic. PARTICIPANTS: A consecutive sample of 66 patients who met criteria for a diagnosis of a mild cognitive impairment and who had at least one clinical reevaluation was identified from the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry. INTERVENTIONS: We evaluated patients initially and at 12- to 18-month intervals up to 54 months using standard neurological and neuropsychological measures such as the Mini-Mental State Examination, the Dementia Rating Scale, the Wechsler Adult Intelligence Scale--Revised, the Wechsler Memory Scale--Revised, and the Free and Cued Selective Reminding Test. The APOE status of study patients was determined. MAIN OUTCOME MEASURE: The development of dementia as determined by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria. RESULTS: Sixty-six individuals had been reevaluated once (mean of 18 months), 36 individuals twice (mean of 36 months), and 22 individuals on three occasions (mean of 54 months), with conversion rates to dementia at these intervals of 24%, 44%, and 55%, respectively. A multivariate Cox regression model demonstrated that possession of an APOE epsilon 4 allele was the strongest predictor of clinical outcome. CONCLUSIONS: These data suggest the following: (1) patients with mild cognitive impairment can be clinically defined, (2) many members of this group progress to Alzheimer's disease, and (3) APOE epsilon 4 allele status appears to be a strong predictor of clinical progression.

Aged↗
PubMed1995

Relative-risk regression models using cases and their parents.

Relative-risk regression models are presented for studies of the association of genetic markers with disease status when the study design uses affected cases and their parents, with or without unaffected sibs. These models generalize the "haplotype relative-risk" method and allow for censored unaffected sibs; in this sense, these models resemble proportional hazards models that are commonly used in survival analysis. A critical distinction between these models and the usual Cox proportional hazards model is that the frequencies of the genotypes of the cases are compared to controls based on Mendelian expectations, and not simply to the genotypes of the sib controls who are at risk of disease. These models allow modeling of the contribution of specific alleles to the relative risk of disease, as well as interactions of allelic effects with environmental risk factors. To demonstrate the application of these models, we have fit them to the binary affection status of the Problem 2 data set. Four candidate-gene loci were found to have a significant association with affection status, after allowance for relative risks that decrease with age; two of these associations correctly identified two of the major gene loci, and the other two were false-positive associations.

Aging↗
PubMed1995

Exclusion of a primary gene defect at the HLA locus in familial idiopathic dilated cardiomyopathy.

Case control studies have reported associations between specific HLA class II antigens and idiopathic dilated cardiomyopathy (DCM), suggesting that genetically regulated immune response factors may be involved in the pathogenesis of this disease. In this study, families with DCM were used to test the hypothesis that a heritable gene defect in the HLA region is the primary genetic determinant for a subset of cases. Twelve families with DCM were identified. By formal segregation analysis, the inheritance of the disease was most consistent with an autosomal dominant gene defect with incomplete penetrance. Genotyping was performed with five highly polymorphic linked dinucleotide repeat markers that span the HLA locus. Linkage analysis was used to determine whether or not these genetic markers cosegregated with the disease phenotype. Genetic linkage between the disease phenotype and a 21 cM region spanning the HLA was excluded (lod score < or = -2) in at least 60% of our families. These results indicate that a gene defect in the HLA locus region is not the primary genetic determinant of DCM in a series of familial cases. However, our data do not exclude the possibility that HLA regulated immune response factors may have a modifying effect on disease penetrance and expression.

Cardiomyopathy, Dilated↗
PubMed1995

Novel pattern of P53 mutation in breast cancers from Austrian women.

Since mutagens produce an extraordinary diversity of mutational patterns, differential mutational exposures among populations are expected to produce different patterns of mutation. Classical epidemiological methods have been successful in implicating specific mutagens in cancers such as those of lung and skin in which one mutagen predominates. In breast cancer, however, no mutagens have been implicated in an unequivocal manner. In an attempt to facilitate epidemiological studies, we have been studying the pattern of p53 gene mutations in breast cancers from multiple populations with high and low breast cancer incidences. We previously reported that breast cancers from Midwest United States, predominantly rural Caucasian women, have a different pattern of p53 gene mutation from populations of Western European women. Herein, we analyze patterns of p53 mutations from Graz, Austria, another population with a high incidence of breast cancer. Among the 60 Austrian breast cancers analyzed, 14 (23%) have a p53 gene mutation in exons 5-9 or in adjacent splice junctions. Analysis of the patterns of mutation shows differences between the "Western European" profile and the Austrian and Midwest United States groups (P = 0.027 and 0.024, respectively). The Austrian pattern is characterized by a high frequency of A:T-->T:A transversions (P = 0.006). The presence of distinct patterns of mutation among the limited number of analyzed populations of Western European origin supports the idea that differential mutagenic exposure and/or genetic differences contribute to breast cancer mutagenesis among geographically distinct Caucasians of Western European origin.

Aged↗
PubMed1995

Familial medullary thyroid cancer and prominent corneal nerves: clinical and genetic analysis.

A unique kindred manifesting medullary thyroid carcinoma and corneal nerve thickening without other aspects of the multiple endocrine neoplasia syndrome (MEN) was analyzed by linkage analysis using four highly polymorphic (CA)n repeat markers (sTCL-1, D10S141, ZNF22, and sJRH-1). Additionally, the RET protooncogene was examined for specific mutations by DNA sequence analyses in all affected family members. Screening of 11 family members spanning 4 generations revealed 7 subjects with corneal nerve thickening; of these subjects, 3 had abnormal pentagastrin-stimulated calcitonin studies, and these 3 subjects were each found to have C-cell hyperplasia or medullary thyroid carcinoma at surgery. Linkage analysis showed cosegregation of alleles (as defined by the above markers), with the presence of both corneal nerve thickening and medullary thyroid carcinoma/C-cell hyperplasia (maximum LOD score, 2.69; consistent with, but not proving linkage). DNA sequence analysis showed that none of the affected individuals had mutations in either exon 10 or 11, or in exon 16 of the RET protooncogene, regions where mutations have been described for MEN type 2A (MEN-2A) and MEN-2B families, respectively. Thus, compared to the defined syndromes of MEN-2A and MEN-2B, this kindred appears to represent a true clinical overlap syndrome whose genetic basis may be distinct from these two syndromes.

Aged↗
PubMed1995

Familial aneurysmal subarachnoid hemorrhage: a community-based study.

The familial occurrence of intracranial aneurysms has been well described. However, intracranial aneurysms are not rare and the great majority of reported families consist of only two affected members. Therefore, the familial aggregation of intracranial aneurysms could be fortuitous. The authors investigated the familial occurrence of aneurysmal subarachnoid hemorrhage (SAH) in their community to determine whether family members of patients with a ruptured aneurysm are at an increased risk of developing an SAH. All 81 patients from Rochester, Minnesota, who suffered an SAH between 1970 and 1989 from a proven aneurysmal rupture were identified, and they or their families were contacted and a family history was obtained. The number of expected SAHs among first-degree relatives was calculated using previously established age- and sex-specific incidence rates in the community of Rochester. Of the 81 index patients, 76 had complete follow up for family history. Fifteen (20%) of these 76 patients had a first- or second-degree relative with aneurysmal SAH. The number of observed first-degree relatives with aneurysmal SAH was 11, compared to an expected number of 2.66, giving a relative risk of 4.14 (95% confidence interval 2.06-7.40; p < 0.001). In the authors' community, aneurysmal SAH was familial in one of five patients, and this familial aggregation was not fortuitous. The increase in familial risk of aneurysmal SAH is approximately fourfold among first-degree relatives.

Adolescent↗
PubMed1994

DNA ploidy and the percentage of cells in S-phase as prognostic factors for women with lymph node negative breast cancer.

BACKGROUND: Previous cell kinetic studies have shown that the percentage of cells in S-phase (%S) of the tumor may be an important prognostic factor for relapse-free survival (RFS) and overall survival (OS) in patients with resected lymph node negative breast cancer. METHODS: This study examined DNA ploidy and %S from the paraffin embedded primary tumors of 265 patients who had surgery between 1975 and 1981, had lymph node negative cancer, and had no adjuvant therapy. The %S and %G2M values were calculated using a debris and aggregate subtraction model. RESULTS: The results of the DNA ploidy analysis revealed 130 (49%) DNA diploid tumors and 135 (51%) DNA nondiploid tumors. Ploidy was not significant for either RFS (P = 0.20) or OS (P = 0.13). The total %S (using a cutoff of 8%) was a statistically significant prognostic factor for RFS (P = 0.003) and borderline for OS (P = 0.08). The proliferation fraction (%S + %G2M), using a cutoff of 12.5, was a statistically significant prognostic factor for RFS (P = 0.01) and for OS (P = 0.01). In a Cox multivariate analysis for RFS, the total %S remained significant (P = 0.05) along with tumor size. In the analysis of OS, the proliferation fraction remained significant (P = 0.03) along with tumor size and age. DNA ploidy was not significant in any multivariate analysis. CONCLUSIONS: This study suggests that tumor size and cell proliferation parameters are independent prognostic factors for patients with resected lymph node negative breast cancer. However, the clinical usefulness of the cell kinetic parameters appears limited.

Adult↗