Nijmegen breakage syndrome (NBS, OMIM 251260) is a rare hereditary disease, characterized by immune deficiency, microcephaly, and an extremely high incidence of lymphoid tissue malignancies. The gene mutated in NBS, NBS1, was recently cloned from its location on chromosome 8q21. The encoded protein, nibrin (p95), together with hMre11 and hRad50, is involved in the double-strand DNA break repair system. We screened two Russian cohorts for the 657del5 NBS1 mutation and found no carriers in 548 controls and two carriers in 68 patients with lymphoid malignancies: one with acute lymphoblastic leukemia (ALL) and one with non-Hodgkin lymphoma (NHL). Several relatives of the second patient, who were carriers of the same mutation, had cancer (ALL, breast cancer, GI cancers). These preliminary data suggest that NBS1 mutation carriers can be predisposed to malignant disorders.
Genetic testing for a variety of diseases is becoming more available to primary care physicians, but it is unclear how useful physicians perceive these tests to be. We examined academic family physicians' perception of and experiences with clinical genetic testing and direct-to-consumer genetic testing.
This study is an analysis of a survey conducted as part of the Council of Academic Family Medicine Educational Research Alliance (CERA). Academic family physicians in the United States and Canada were queried about their perception of genetic testing's utility, how frequently patients ask about genetic testing, and the importance of genetic testing in future practice and education of students and residents.
The overall survey had a response rate of 45.1% (1,404/3,112). A majority (54.4%) of respondents felt that they were not knowledgeable about available genetic tests. Respondents perceived greater utility of genetic tests for breast cancer (94.9%) and hemochromatosis (74.9%) than for Alzheimer's disease (30.3%), heart disease (25.4%), or diabetes (25.2%). Individuals with greater self-perceived knowledge of genetic tests were more likely to feel that genetic testing would have a significant impact on their future practice (23.1%) than those with less knowledge (13.4%). Respondents had little exposure to direct-to-consumer genetic tests, but a majority felt that they were more likely to cause harm than benefit.
Academic family physicians acknowledge their lack of knowledge about genetic tests. Educational initiatives may be useful in helping them incorporate genetic testing into practice and in teaching these skills to medical students and residents.
The aim of the study was to analyze effects of age, education and gender on acceptance of genetic testing. Subjects, n = 1967 aged 15-69, were a stratified random sample of the Finnish population. One thousand, one hundred and sixty nine subjects, 530 men and 639 women, returned the questionnaire. The majority of the respondents approved of the availability of genetic testing. Young, aged 15-24, were more favourable towards testing and more willing to undergo suggested tests, but they were also more worried than others about the misuse of test results. Men aged 45-69 with only basic education were more in favour of mandatory genetic testing than other respondents. Respondents with university education were more critical towards genetic testing and expressed their worry about eugenics more often than other education groups. In conclusion, there are age, education and gender related differences in acceptance of genetic testing which need to be taken into account when considering screening programmes and informing the public.
To assess the accuracy of the calculated risk for trisomy 18 assigned to individual women screened with the second-trimester triple test.
The study was based on 382598 women screened in the Ontario Maternal Serum Screening Programme between October 1993 and September 2000. Of the women screened, 111 cases of trisomy 18 were identified. Originally, 92874 women were screened using a risk cut-off level method. Estimated risks of trisomy 18 were calculated by applying published population parameters for the remaining women screened using a fixed analyte cut-off method. Women were ranked according to their individual risk for trisomy 18 syndrome in decreasing order and divided into 12 groups. The mean calculated risks of having an affected pregnancy at term for each group were compared with the birth prevalence of the corresponding group after allowing for spontaneous fetal losses.
Agreement between the mean calculated risks and the observed prevalence was seen across the entire risk range, although women identified as having high-risk pregnancies had an actual prevalence that was somewhat lower than that estimated by the screen.
The calculated risk for trisomy 18 syndrome assigned to the individual woman on the basis of the risk cut-off method accurately reflects their risk of having a term trisomy 18 syndrome pregnancy.
Renal cell carcinoma (RCC) encompasses different histologic subtypes. Distinguishing between the subtypes is usually made by morphologic assessment, which is not always accurate.
Our aim was to identify microRNA (miRNA) signatures that can distinguish the different RCC subtypes accurately.
A total of 94 different subtype cases were analysed. miRNA microarray analysis was performed on fresh frozen tissues of three common RCC subtypes (clear cell, chromophobe, and papillary) and on oncocytoma. Results were validated on the original as well as on an independent set of tumours, using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis with miRNA-specific primers.
Microarray data were analysed by standard approaches. Relative expression for qRT-PCR was determined using the ??C(T) method, and expression values were normalised to small nucleolar RNA, C/D box 44 (SNORD44, formerly RNU44). Experiments were done in triplicate, and an average was calculated. Fold change was expressed as a log(2) value. The top-scoring pairs classifier identified operational decision rules for distinguishing between different RCC subtypes and was robust under cross-validation.
We developed a classification system that can distinguish the different RCC subtypes using unique miRNA signatures in a maximum of four steps. The system has a sensitivity of 97% in distinguishing normal from RCC, 100% for clear cell RCC (ccRCC) subtype, 97% for papillary RCC (pRCC) subtype, and 100% accuracy in distinguishing oncocytoma from chromophobe RCC (chRCC) subtype. This system was cross-validated and showed an accuracy of about 90%. The oncogenesis of ccRCC is more closely related to pRCC, whereas chRCC is comparable with oncocytoma. We also developed a binary classification system that can distinguish between two individual subtypes.
MiRNA expression patterns can distinguish between RCC subtypes.
Social, ethical and policy analysis of the issues arising from gene patenting and commercial genetic testing is enhanced by the application of science and technology studies, and Actor-Network Theory (ANT) in particular. We suggest the potential for transferring ANT's flexible nature to an applied heuristic methodology for gathering empirical information and for analysing the complex networks involved in the development of genetic technologies. Three concepts are explored in this paper--actor-networks, translation, and drift--and applied to the case of Myriad Genetics and their commercial BRACAnalysis genetic susceptibility test for hereditary breast cancer. Treating this test as an active participant in socio-technical networks clarifies the extent to which it interacts with, shapes and is shaped by people, other technologies, and institutions. Such an understanding enables more sophisticated and nuanced technology assessment, academic analysis, as well as public debate about the social, ethical and policy implications of the commercialization of new genetic technologies.
This study compares adherence to breast and ovarian cancer screening recommendations among a population cohort of women at familial risk of breast and/or ovarian cancer. This cross-sectional study included 1039 first-degree female relatives without breast cancer identified from the Ontario site of the Breast Cancer Family Registry. We compared breast and ovarian cancer screening behaviors, using a telephone-administered questionnaire among three groups of women defined by their familial risk (high, moderate, and low) of breast and/or ovarian cancer. Associations between screening behaviors and familial risk were assessed using multinomial regression models adjusted by familial clustering. Women, 40-49 years of age, at moderate or high familial risk were significantly more likely to have had a screening mammogram within the past 12 months [odds ratio (OR): 2.80; 95% confidence interval (CI): 1.40-5.58], and women of less than 50 years of age were more likely to have a clinical breast examination (OR: 1.84; 95% CI: 1.02-3.31) compared with women at low familial risk. Compared with women at low or moderate familial risk, women at high familial risk were significantly more likely to have ever had a genetic test for the BRCA 1/2 genes (OR: 2.67; 95% CI: 1.76-4.05). Although the overall level of adherence among high-risk women is suboptimal in the community, women at a higher familial risk are adhering more often to cancer screening recommendations than women at a lower familial risk.
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X-linked adrenoleukodystrophy is a peroxisomial disorder caused by mutations in the ABCD1 gene. Adrenomyeloneuropathy is the second most frequent phenotype (25-46%) of this disease and classically presents in adulthood with spastic paraparesis. Female heterozygotes can be symptomatic, but they are frequently misdiagnosed as having multiple sclerosis.
We report a novel missense mutation in the ABCD1 gene in a 47-year-old French-Canadian female with spastic paraparesis and no confirmed family history of X-linked adrenoleukodystrophy. The mutation is located on exon 1 and causes the amino acid substitution of a valine for an alanine in a region of the protein highly conserved between mouse and man.
Adrenomyeloneuropathy must be considered in the differential diagnosis of spastic paraparesis in men or women. This is an initial report of an ABCD1 gene mutation in the French-Canadian population, which should lead to the recognition of other cases in the future.
To estimate survival median and its changes, number of patients over 18 years of age for 1991-2000 and 2001-2010 for 20-year period (1991-2010), to elucidate factors affecting survival for 2001-2010 in mucoviscidosis children living in Moscow and Moscow Region and treated outpatiently in specialized medical centers.
Case records were analysed for mucoviscidosis patients registered in specialized clinics of Moscow on 01.01.01 and 01.01.11. Survival was assessed with Kaplan-Meier curve.
Survival medians for 1991-2000 and 2001-2010 was 25.7 and 35.1 years, respectively In the group of mucoviscidosis patients with Staphylococcus aureus infection survival was significantly higher than in those infected with gram-negative microflora. Longer survival was reported in patients with "soft" mutation (p = 0.06927).
The survival median for mucoviscidosis patients for 2001-2010 was 35.1 years. The percentage of adult patients in the last decade significantly rose from 19.5 to 32%. Gram-negative microflora significantly reduces survival, while 'soft" mutation prolongs survival. Creation of National Register will specify survival of mucoviscidosis patients in all regions of the Russian Federation.