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Biomedical subjects

S L Neuhausen

Publications and source records attributed to S L Neuhausen.

At least 19 recordsLinked to original sources
PubMed2006

Genome-wide linkage analysis of 160 North American families with celiac disease.

Celiac disease (CD) is a common autoimmune disease caused by exposure to the protein gliadin in wheat, and related prolamins in barley and rye. The prevalence of the disease in the US is 1:133. The aim of this study was to identify non-human leukocyte antigen (HLA) loci that predispose to CD. A genome-wide search of 405 microsatellite markers was performed on DNA samples from 160 families with a minimum of two cases of CD. Multipoint, parametric and non-parametric linkage (NPL) analyses were performed. Locations on chromosomes 1q, 3q, 6p, 6q, 7q, 9q and 10q showed linkage statistics (NPL scores or heterogeneity logarithm of the odds (HLOD) scores) of approximately 2.0 or larger. The greatest evidence for linkage outside of chromosome 6 was on 7q and 9q. An NPL score of 2.60 occurred at position 151.0 on 7q and a HLOD score of 2.47 occurred at position 144.8 on 9q under a recessive model. As expected, there was highly significant linkage to the HLA region on 6p, with NPL and HLOD scores exceeding 5.50. In conclusion, this genome-wide linkage analysis represents one of the largest such studies of CD. The most promising region is a putative locus on 7q, a region reported independently in previous genome-wide searches.

Celiac Disease↗
PubMed2001

A strategy for high throughput HLA-DQ typing.

We have developed a high throughput HLA typing methodology that is a modification of the standard sequence-specific primer method. This approach is distinct from other methods using an automated DNA analyzer, as more than one gene is typed in a single lane. We have optimized the method for use on an ABI 373 automated genotyping machine. Primers were designed to preferentially amplify DNA fragments of the generic allelic groups of the DQA1 and DQB1 loci. PCR products representing alleles at the DQA1 locus were amplified using a different fluorescent dye than the PCR products from the DQB1 locus. Only three PCR reactions are required for low resolution typing of DQA1 and DQB1. Use of different labeled primers enables genotyping for both loci in a single gel lane, allowing for 64 samples to be typed at low resolution for both DQA1 and DQB1 on a single gel. Automated allele assignments were determined based on DNA migration distance through a polyacrylamide gel using a standard genotype allele-calling program. Accuracy of this method is greater than 98% for both loci. The strategy described here may be adapted to include more loci or to produce higher resolution typing of alleles encoded by these loci. It can be readily optimized for use on other slab gel or capillary electrophoresis systems.

Alleles↗
PubMed2001

Linkage analysis of HLA and candidate genes for celiac disease in a North American family-based study.

BACKGROUND: Celiac disease has a strong genetic association with HLA. However, this association only explains approximately half of the sibling risk for celiac disease. Therefore, other genes must be involved in susceptibility to celiac disease. We tested for linkage to genes or loci that could play a role in pathogenesis of celiac disease. METHODS: DNA samples, from members of 62 families with a minimum of two cases of celiac disease, were genotyped at HLA and at 13 candidate gene regions, including CD4, CTLA4, four T-cell receptor regions, and 7 insulin-dependent diabetes regions. Two-point and multipoint heterogeneity LOD (HLOD) scores were examined. RESULTS: The highest two-point and multipoint HLOD scores were obtained in the HLA region, with a two-point HLOD of 3.1 and a multipoint HLOD of 5.0. For the candidate genes, we found no evidence for linkage. CONCLUSIONS: Our significant evidence of linkage to HLA replicates the known linkage and association of HLA with CD. In our families, likely candidate genes did not explain the susceptibility to celiac disease.

Journal Article↗
PubMed2001

Genomewide multipoint linkage analysis of seven extended Palauan pedigrees with schizophrenia, by a Markov-chain Monte Carlo method.

Palauans are an isolated population in Micronesia with lifetime prevalence of schizophrenia (SCZD) of 2%, compared to the world rate of approximately 1%. The possible enrichment for SCZD genes, in conjunction with the potential for reduced etiological heterogeneity and the opportunity to ascertain statistically powerful extended pedigrees, makes Palauans a population of choice for the mapping of SCZD genes. We have used a Markov-chain Monte Carlo method to perform a genomewide multipoint analysis in seven extended pedigrees from Palau. Robust multipoint parametric and nonparametric linkage (NPL) analyses were performed under three nested diagnostic classifications-core, spectrum, and broad. We observed four regions of interest across the genome. Two of these regions-on chromosomes 2p13-14 (for which, under core diagnostic classification, NPL=6.5 and parametric LOD=4.8) and 13q12-22 (for which, under broad diagnostic classification, parametric LOD=3.6, and, under spectrum diagnostic classification, parametric LOD=3.5)-had evidence for linkage with genomewide significance, after correction for multiple testing; with the current pedigree resource and genotyping, these regions are estimated to be 4.3 cM and 19.75 cM in size, respectively. A third region, with intermediate evidence for linkage, was identified on chromosome 5q22-qter (for which, under broad diagnostic classification, parametric LOD=2.5). The fourth region of interest had only borderline suggestive evidence for linkage (on 3q24-28; for this region, under broad diagnostic classification, parametric LOD=2.0). All regions exhibited evidence for genetic heterogeneity. Our findings provide significant evidence for susceptibility loci on chromosomes 2p13-14 and 13q12-22 and support both a model of genetic heterogeneity and the utility of a broader set of diagnostic classifications in the population from Palau.

Chromosome Mapping↗
PubMed2001

Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history.

Women who have inherited a germ-line mutation in the BRCA1 or BRCA2 (BRCA1/2) genes have a greatly increased risk of developing breast cancer compared with the general population. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1/2 mutation carriers. We hypothesize that genes involved in endocrine signaling may modify the BRCA1/2-associated age-specific breast cancer penetrance. We studied the effect of alleles at the AIB1 gene using a matched case-control sample of 448 women with germ-line BRCA1/2 mutations. We found that these women were at significantly higher breast cancer risk if they carried alleles with at least 28 or 29 polyglutamine repeats at AIB1, compared with women who carried alleles with fewer polyglutamine repeats [odds ratio (OR), 1.59; 95% confidence interval (CI), 1.03-2.47 and OR, 2.85; 95% CI, 1.64-4.96, respectively]. Late age at first live birth and nulliparity have been associated with increased breast cancer risk. We observed increases in BRCA1/2-associated breast cancer risk in women who were either nulliparous or had their first live birth after age 30 (OR, 3.06; 95% CI, 1.52-6.16). Women were at significantly increased risk if they were nulliparous or had a late age at first live birth and had AIB1 alleles no shorter than 28 or 29 or more AIB1 polyglutamine repeats (OR, 4.62; 95% CI, 2.02-10.56 and OR, 6.97; 95% CI, 1.71-28.43, respectively) than women with none of these risk factors. Our results support the hypothesis that pathways involving endocrine signaling, as measured through AIB1 genotype and reproductive history, may have a substantial effect on BRCA1/2-associated breast cancer risk.

Adult↗
PubMed2001

Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study.

BACKGROUND: In several case-control and prospective studies, tubal ligation has been associated with a decreased risk of invasive epithelial ovarian cancer. We aimed to assess the potential of tubal ligation in reducing the risk of ovarian cancer in women who carry predisposing mutations in the BRCA1 or BRCA2 genes. METHODS: We did a matched case-control study among women from Canada, the USA, and the UK who had undergone genetic testing and who carried a pathogenic mutation in BRCA1 or BRCA2. Cases were 232 women with a history of invasive ovarian cancer, and controls were 232 women without ovarian cancer, and who had both ovaries intact. Cases and controls were matched for year of birth, country of residence, and mutation (BRCA1 or BRCA2). The odds ratio for developing ovarian cancer was estimated for tubal ligation, adjusting for oral contraceptive use, parity, history of breast cancer, and ethnic group. FINDINGS: In an unadjusted analysis among BRCA1 carriers, significantly fewer cases than controls had ever had tubal ligation (30 of 173 [18%] vs 60 of 173 [35%], odds ratio 0.37 [95% CI 0.21-0.63]; p=0.0003). After adjustment for oral contraceptive use, parity, history of breast cancer and ethnic group, the odds ratio was 0.39 (p=0.002). Combination of tubal ligation and past use of an oral contraceptive was associated with an odds ratio of 0.28 (0.15-0.52). No protective effect of tubal ligation was seen among carriers of the BRCA2 mutation. INTERPRETATION: Tubal ligation is a feasible option to reduce the risk of ovarian cancer in women with BRCA1 mutations who have completed childbearing.

Adult↗
PubMed2001

Breast cancer after mantle irradiation for Hodgkin's disease: correlation of clinical, pathologic, and molecular features including loss of heterozygosity at BRCA1 and BRCA2.

PURPOSE: Hodgkin's disease patients who receive mantle irradiation have an age-dependent increased risk of developing breast cancer. To determine if genetic factors predispose these patients to develop breast cancer, we evaluated breast cancer specimens for loss of heterozygosity (LOH) at regions where BRCA1 and BRCA2, two breast cancer tumor suppressor genes, are located. We also evaluated whether breast cancers in patients who were previously treated with radiation have a more aggressive phenotype, and whether the clinical course differed from a sporadic group of breast cancer patients. METHODS AND MATERIALS: All females with Hodgkin's disease who were subsequently diagnosed with breast cancer and for whom tissue blocks were available were included. Using a case-control design, case patients (previously treated with radiation therapy) were matched with sporadic control breast cancer patients for age, breast cancer stage, and date of breast cancer diagnosis. After microdissection of tumor and normal tissue from paraffin-embedded tissue blocks, DNA was extracted and samples were examined for LOH at chromosomal segments encompassing BRCA1 and BRCA2. Breast cancer specimens were also evaluated in a blinded fashion for tumor grade and immunoreactivity to estrogen and progesterone receptors, p53, her2-neu, and topoisomerase II alpha. Comparisons were made between the case and control populations using chi2 analysis, and a paired Student's t test. Survival differences were evaluated using a log-rank test. RESULTS: From January 1960 to December 1983, 917 patients were diagnosed with Hodgkin's disease. Twelve patients were subsequently diagnosed with breast cancer and tissue blocks were available on 10 cases. No statistical difference was observed between the case and control populations for LOH at BRCA1 or BRCA2. In the Hodgkin's disease group, LOH was observed in 30% of tumors at BRCA1 and 10% of tumors at BRCA2 vs. 10% and 0% of tumors in the control group at BRCA1 and BRCA2, respectively. Breast tumors from patients who received radiation therapy for Hodgkin's disease displayed greater nuclear pleomorphism (p < 0.02), and an increase in topoisomerase II alpha expression (p < 0.05) vs. the control population. Five of 10 patients were pregnant at the time of their Hodgkin's treatment, and those patients had a shorter time interval to the development of breast cancer compared with the patients who were not pregnant (12.4 years compared with 18.6 years). There was no significant difference in disease-free survival; however, overall survival was inferior in the population previously treated with radiation therapy for Hodgkin's disease (p = 0.01). 80% of patients with a previous Hodgkin's diagnosis died of breast cancer or treatment related effects vs. 30% in the control group. CONCLUSION: We were unable to find statistical evidence for LOH at BRCA1 and BRCA2 in breast cancers from patients previously irradiated for Hodgkin's disease. Breast cancer diagnosed after mantle irradiation may be more biologically aggressive based on the greater nuclear pleomorphism and increase in topoisomerase II alpha staining. This did not translate into a statistical difference in breast cancer disease-free survival; however, overall survival was significantly inferior in the Hodgkin's disease patients.

Adolescent↗
PubMed2001

Prevalence and clinical characteristics of celiac disease in Downs syndrome in a US study.

Celiac disease is an autoimmune gastrointestinal disorder characterized by mucosal atrophy of the jejunum on exposure to gluten, a protein found in grains. The purpose of our study was to determine the prevalence of celiac disease in children with Downs syndrome in a U.S.-based Caucasian population. The 97 Downs syndrome children were screened for celiac disease using serum IgA-anti-endomysial antibody testing, which is highly specific and sensitive for the disorder. Children with titers greater than 1:5 (using the IgA endomysial antibody [EMA] test; EMA+) were considered affected. Ten children (10.3%) were EMA+. We examined their HLA DQA1 DQB1 genotype, karyotype, clinical characteristics, and the prevalence of celiac disease in their first-degree relatives. The nine available karyotypes were trisomy 21. Downs syndrome-specific mean height percentile was 64%+/-26% (range <5-99%) and weight percentile was 43%+/-28% (range 5-95%). Presence of diarrhea, constipation, vomiting, and abdominal pain was similar for children with and without celiac disease. Only bloating symptoms were significantly more frequent in those with celiac disease (EMA+). Seven of eight (88%) genotyped EMA+ children had the celiac disease-associated high-risk HLA DQA1*0501 DQB1*0201 genotype as compared with 13/ 80 (16%) of EMA- children. Five of 48 (10%) first-degree relatives of the celiac disease (EMA+) children were EMA+. In conclusion, celiac disease, as diagnosed by positive endomysial antibody tests, has an increased prevalence in children with Downs syndrome in the U.S. as compared with the general population (1/250). Clinical and growth characteristics do not distinguish between children with and without celiac disease. Based on these observations, it is recommended that children with Downs syndrome be screened for celiac disease.

Adolescent↗
PubMed2001

Knowledge, attitudes, and interest in breast-ovarian cancer gene testing: a survey of a large African-American kindred with a BRCA1 mutation.

BACKGROUND: This study assessed counseling and testing needs from the perspective of adult members of a large African-American kindred with a BRCA1 mutation. METHODS: Interviews were conducted with 95 male and female kindred members to elicit information on sociodemographics, attitudes toward health care providers, breast cancer screening behaviors, and religious/spiritual beliefs, as well as to evaluate psychological distress, beliefs, knowledge, and attitudes related to genetic testing. RESULTS: Knowledge about breast and ovarian cancer genetics was limited. Adherence to screening recommendations was low among females with no personal breast or ovarian cancer history. The majority (67%) wished to discuss risk factors with a health care provider. Most participants (82%) indicated that they would have a genetic test if it were available. Significant predictors of intent to undergo testing were having at least one first-degree relative with breast and/or ovarian cancer (OR = 5.1; 95% CI = 1.2-20.9) and perceived risk of being a gene carrier > or =50% (OR = 64.3; 95% CI = 5.1-803.9) or reporting that they did not know their risk of being a gene carrier (OR = 10.9; 95% CI = 2.1-57.7). Cited barriers to testing included cost and availability. CONCLUSION: There is a high interest level in genetic testing despite limited knowledge about cancer genetics among these high-risk African Americans. Our study provides information for designing a genetic education and counseling intervention for this and similar families.

Adult↗
PubMed2000

Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group.

BACKGROUND: Women with a mutation in BRCA1 or BRCA2 have a high risk of developing breast cancer and of contralateral cancer after the initial diagnosis of breast cancer. Tamoxifen protects against contralateral breast cancer in the general population, but whether it protects against contralateral breast cancer in BRCA1 or BRCA2 mutation carriers is not known. METHODS: We compared 209 women with bilateral breast cancer and BRCA1 or BRCA2 mutation (bilateral-disease cases), with 384 women with unilateral disease and BRCA1 or BRCA2 mutation (controls) in a matched case-control study. Age and age at diagnosis of breast cancer (range 24-74 years) were much the same in bilateral-disease cases and controls, and both groups had been followed up for the same time for a second primary breast cancer. History of tamoxifen use for first breast cancer was obtained by interview, or by self-administered questionnaire. FINDINGS: The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 (95% CI 0.28-0.89). Tamoxifen protected against contralateral breast cancer for carriers of BRCA1 mutations (odds ratio 0.38, 95% CI 0.19-0.74) and for those with BRCA2 mutations (0.63, 0.20-1.50). In women who used tamoxifen for 2-4 years, the risk of contralateral breast cancer was reduced by 75%. A reduction in risk of contralateral cancer was also seen with oophorectomy (0.42, 0.22-0.83) and with chemotherapy (0-40, 0.26-0.60). INTERPRETATION: Tamoxifen use reduces the risk of contralateral breast cancer in women with pathogenic mutations in the BRCA1 or BRCA2 gene. The protective effect of tamoxifen seems independent of that of oophorectomy.

Adult↗
PubMed2000

Absence of evidence for a familial breast cancer susceptibility gene at chromosome 8p12-p22.

Several recent studies indicate that the majority of families with five or fewer cases of breast cancer and no cases of ovarian cancer are not due to BRCA1 or BRCA2. It has been proposed that a further breast cancer susceptibility gene that may account for some of these families is located on chromosome 8p12-p22. We have identified 31 site-specific breast cancer families that have a greater than 80% posterior probability of being due to genes other than BRCA1 or BRCA2. These families have been examined for linkage to 8p12-p22 using markers flanking the putative location of the gene. The overall multi-point LOD score is strongly negative across the whole 44 cM. The individual multi-point LOD score is negative in 23 families and only exceeds 0.5 in a single family (with a multi-point LOD score of 1.22). The maximum heterogeneity LOD score was 0.03 at marker D8S136 with estimated proportion linked (alpha) of 3% (95% CI 0 - 30%). These data do not lend support to the hypothesis that chromosome 8p12-p22 harbours a familial breast cancer susceptibility gene. Oncogene (2000) 19, 4170 - 4173

BRCA2 Protein↗
PubMed2000

Founder populations and their uses for breast cancer genetics.

Numerous founder mutations have been reported in BRCA1 and BRCA2. For genetic screening of a population with a founder mutation, testing can be targeted to the mutation, allowing for a more rapid and less expensive test. In addition, more precise estimates of the prior probability of carrying a mutation and of the likelihood of a mutation carrier developing cancer should be possible. For a given founder mutation a large number of carriers are available, so that focused scientific studies of penetrance, expression, and genetic and environmental modifiers of risk can be performed. Finally, founder populations may be a powerful resource to localize additional breast cancer susceptibility loci, because of the reduction in locus heterogeneity.

Adult↗
PubMed2000

The role of candidate genetic polymorphisms in the etiology of prostate cancer.

Prostate cancer appears to result from complex interactions among genetic, endocrine and environmental factors. Identification of risk factors for development and progression of prostate cancer is needed. This will allow researchers to design strategies to reduce the morbidity and mortality from this cancer and to identify individuals at increased risk of developing the disease. It is probable that common genetic polymorphisms (variants) in genes directly and indirectly involved in androgen biosynthesis, metabolism and regulation are important. Other important genes are likely to be those directly involved in regulation of prostate cell proliferation and apoptosis.Prostate Cancer and Prostatic Diseases (2000) 3, 236-240

Journal Article↗
PubMed2000

The predictive value of BRCA1 and BRCA2 mutation testing.

Genetic testing for mutations in BRCA1 and BRCA2, two genes predisposing to breast and ovarian cancers, is available to women with a relevant family history. The aim of this study was to estimate the positive and negative predictive value of clinical sequence analysis of these genes. A reference graph showing positive and negative predictive values over a range of pre-test risk was derived, taking into account the sensitivity and specificity of a full-sequence analysis test. High positive and negative predictive values were found for women with pre-test risk between 4% and 40%, a range of risk commonly seen in clinical testing. The predictive value of full sequence and single-site analysis of BRCA1 and BRCA2, therefore, compares favorably with other diagnostic medical tests. Our results provide a numerical estimate of the predictive value of BRCA testing, and as such, provide a valuable tool to healthcare providers and families as they interpret BRCA1 and BRCA2 test results.

BRCA1 Protein↗
PubMed1999

Ethnic differences in cancer risk resulting from genetic variation.

Ethnic differences in cancer incidence and mortality exist and are probably the result of genetic and epidemiological risk factors. Genetic differences caused by founder mutations are reviewed, with special emphasis on mutations in BRCA1 and BRCA2. Germline mutations in cancer susceptibility genes have been identified in individuals of all races and ethnic groups. Differences among ethnic groups for cancer risks have been recognized, and a proportion of the differences may be the result of founder mutations within these genes. The BRCA2 999del5 mutation in Iceland and the three BRCA1 and BRCA2 mutations in Ashkenazic Jews have been well characterized and were easy to study because the patient population and anonymous samples were readily available and ethnicity was known. Mutations in BRCA1 and BRCA2 probably account for approximately 3 to 10% of breast cancer in the general population and a much higher proportion in those with a strong family history of breast and ovarian cancers and in those of Ashkenazic Jewish descent. However, no overall increased risk of breast or ovarian cancers exists among Ashkenazic Jewish women compared with non-Jewish Caucasians. Some ethnic variation in cancer risk may be explained by founder mutations identified in cancer-predisposing genes. Knowledge acquired by studying the effect of a single mutation in a well defined population may be applied to larger, more heterogeneous populations. Individuals from all racial and ethnic groups carry deleterious mutations. Mutations are simply easier to find and characterize when identified in a specific ethnic group.

BRCA1 Protein↗
PubMed1999

Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers.

BACKGROUND: The availability of genetic testing for inherited mutations in the BRCA1 gene provides potentially valuable information to women at high risk of breast or ovarian cancer; however, carriers of BRCA1 mutations have few clinical management options to reduce their cancer risk. Decreases in ovarian hormone exposure following bilateral prophylactic oophorectomy (i.e., surgical removal of the ovaries) may alter cancer risk in BRCA1 mutation carriers. This study was undertaken to evaluate whether bilateral prophylactic oophorectomy is associated with a reduction in breast cancer risk in BRCA1 mutation carriers. METHODS: We studied a cohort of women with disease-associated germline BRCA1 mutations who were assembled from five North American centers. Surgery subjects (n = 43) included women with BRCA1 mutations who underwent bilateral prophylactic oophorectomy but had no history of breast or ovarian cancer and had not had a prophylactic mastectomy. Control subjects included women with BRCA1 mutations who had no history of oophorectomy and no history of breast or ovarian cancer (n = 79). Control subjects were matched to the surgery subjects according to center and year of birth. RESULTS: We found a statistically significant reduction in breast cancer risk after bilateral prophylactic oophorectomy, with an adjusted hazard ratio (HR) of 0.53 (95% confidence interval [CI] = 0.33-0.84). This risk reduction was even greater in women who were followed 5-10 (HR = 0. 28; 95% CI = 0.08-0.94) or at least 10 (HR = 0.33; 95% CI = 0.12-0.91) years after surgery. Use of hormone replacement therapy did not negate the reduction in breast cancer risk after surgery. CONCLUSIONS: Bilateral prophylactic oophorectomy is associated with a reduced breast cancer risk in women who carry a BRCA1 mutation. The likely mechanism is reduction of ovarian hormone exposure. These findings have implications for the management of breast cancer risk in women who carry BRCA1 mutations.

Age Factors↗
PubMed1999

Prostate cancer susceptibility locus HPC1 in Utah high-risk pedigrees.

A prostate cancer susceptibility locus ( HPC1 ) at 1q24-25 has been identified. Subsequent analysis showed that the majority of the evidence for localization was provided by families with relatively young (<65 years) average age at diagnosis. We examined evidence for linkage to this region in a set of 41 extended multi-case prostate cancer pedigrees containing 440 prostate cancer cases. Genotyping of five short tandem repeat markers in the region was performed on DNA from 1724 individuals, including 284 prostate cancer cases. In comparison with the families reported in the initial localization, the Utah pedigrees are generally much larger (average of 10.7 versus 5.1 cases) and have an older average age at diagnosis (69 versus 65 years). Two- and three-point linkage analyses were conducted using a previously reported model and provided replication for HPC1 (two-point: LOD = 1.73, P = 0.005 at D1S196; three-point: LOD = 2.06, P = 0.002 for the interval D1S196-D1S416 ). The youngest quartile (by median age at diagnosis) yielded a maximum LOD of 2.82, P = 0. 0003 (at D1S215-D1S222 ), compared with a maximum LOD of 0.73, P = 0. 07 for the oldest quartile pedigrees at the same locus. Further analysis with an age-dependent model, specifying higher sporadic rates for older cases, suggests that the linkage evidence may be lower than expected given the power of the resource due to a high sporadic rate in the large Utah pedigrees.

Aged↗