National Cancer Institute®
Last Modified: November 21, 2001
UI - 21240459
AU - Tiribelli M; Michelutti A; Damante G; Pellizzari L; Martinelli G;
TI - Amabile M; Russo D Screening of Bcr-Abl transcripts in Philadelphia negative essential thrombocythemia.
SO - Leuk Lymphoma 2000 Oct;39(3-4):339-41
AD - Chair and Division of Hematology, Department of Medical and Morphological Research, University of Udine, Italy.
Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterised by the absence of the Philadelphia (Ph+) chromosome. Recent studies have reported controversial results relating to BCR-ABL rearrangements in ET patients. We studied 44 Ph-negative ET patients with the RT-PCR technique at diagnosis or during the follow-up. None of them showed any of the BCR-ABL transcript actually described by others in ET; neither the "classical" P210 nor the P190 or P230 variants. Our results confirm the absence of BCR-ABL abnormalities in Ph-negative ET patients.
UI - 21257654
AU - Aguilar-Martinez P; Esculie-Coste C; Bismuth M; Giansily-Blaizot M;
TI - Larrey D; Schved JF Transferrin receptor-2 gene and non-C282Y homozygous patients with hemochromatosis.
SO - Blood Cells Mol Dis 2001 Jan-Feb;27(1):290-3
AD - Laboratory of Hematology, CHU de Montpellier, Montpellier, France. firstname.lastname@example.org
More than 80% of the patients affected by hereditary hemochromatosis, a common inherited iron disorder, are homozygotes for the 845G --> A (C282Y) mutation of the HFE gene. However, depending on the population, 10-20% of hereditary hemochromatosis can be linked either to other HFE genotypes, particularly the compound heterozygous state for C282Y and the 187 C --> G (H63D) mutation, or to mutations of new other genes. Recently, Camaschella et al. (Nat. Genet. 25, 14-15, 2000) identified a stop mutation (exon 6 nt 750 C --> T, Y250X) on the transferrin receptor-2 (TFR2) gene in two unrelated Sicilian families with hereditary hemochromatosis. The TFR2 gene is a transferrin receptor gene homologue that seems to be involved in iron metabolism. Moreover, one of the patients described by Camaschella et al. was a H63D homozygote. H63D homozygosity can be associated with various phenotypes from asymptomatic subjects to patients with a typical form of hereditary hemochromatosis. Thus, the Y250X mutation could be the molecular defect responsible for hereditary hemochromatosis in subjects with atypical HFE genotypes. We have searched for the Y250X mutation in 63 unrelated French subjects. Forty-three had a diagnosis of hereditary hemochromatosis based on classical criteria. This group included 12 H63D homozygotes, 3 C282Y heterozygotes, and 3 patients with none of the two most prevalent HFE mutants. These 18 patients had no other HFE sequence change and were subsequently subjected to DNA sequencing of the 15 last exons and flanking sequences of the TFR2 gene. The 25 remaining hereditary hemochromatosis patients who were tested for the Y250X mutant were compound heterozygotes for the C282Y and H63D mutations. Finally, we also tested for this TFR2 mutation 20 H63D homozygotes with milder manifestations of iron overload and no acquired cause of iron overload. None of the 63 tested subjects had the Y250X mutation. Concurrently, none of the 18 hereditary hemochromatosis patients who had their TFR2 gene sequenced had any deleterious mutation. Thus, TFR2 mutations are not responsible for hemochromatosis in non-C282Y homozygous patients of our area. Copyright 2001 Academic Press.
UI - 21281776
AU - Rapp B; Haberle J; Linnebank M; Wermuth B; Marquardt T; Harms E; Koch HG
TI - Genetic analysis of carbamoylphosphate synthetase I and ornithine transcarbamylase deficiency using fibroblasts.
SO - Eur J Pediatr 2001 May;160(5):283-7
AD - Universitats-Kinderklinik Munster, Germany.
Deficiencies of carbamoylphosphate synthetase or of ornithine transcarbamylase, two urea cycle enzymes located within mitochondria, often present as severe neonatal hyperammonaemic crises and have a poor prognosis. While genetic analysis of the X-chromosomal transmitted ornithine transcarbamylase deficiency (OTC) is performed by exon-wise mutation screening of genomic DNA in most cases, identification of mutations in the autosomal inherited carbamoylphosphate synthetase (CPS 1) deficiency requires analysis of transcripts due to the unknown genomic structure. We tested the hypothesis that CPS 1 and OTC are expressed at low levels in fibroblasts and indeed were able to amplify full-length cDNA from that source. Using a reverse transcriptase polymerase chain reaction based procedure we completely characterised the genetic background in five patients and identified three novel mutations and a novel polymorphism of the CPS 1 gene (deletion/insertion 2170delGCTCinsCCA, nonsense mutation 2359C > T, missense mutation 3161T > G and Thr1406Asn, respectively), as well as the missense mutations 482A > G and 994T > A of the OTC gene. CONCLUSION: Cultured fibroblasts are an easily accessible source for genetic analysis of inborn errors of urea cycle enzymes which are functionally expressed only in liver and gut.
UI - 21280916
AU - Chen F; Collin GB; Liu KC; Beier DR; Eccles M; Nishina PM; Moshang T;
TI - Epstein JA Characterization of the murine Lbx2 promoter, identification of the human homologue, and evaluation as a candidate for Alstrom syndrome.
SO - Genomics 2001 Jun 1;74(2):219-27
AD - Cardiology Division, Department of Medicine, University of Pennsylvania Health System, Philadelphia, Pennsylvania 19104, USA.
The murine Lbx2 gene is a member of the ladybird family of homeobox genes, which is expressed in the developing urogenital system, eye, and brain. Using transgenic mice, we demonstrate that 9 kb of the 5' flanking region of mouse Lbx2 is able to direct expression of a reporter gene in a tissue-specific manner recapitulating the endogenous expression pattern. This regulatory region provides a novel reagent allowing for transgenic expression in the developing urogenital ridge. In addition, we describe the identification of the human homologue, LBX2. Comparison of the human LBX2 and mouse Lbx2 sequences upstream of the coding regions reveals sequence conservation suggesting conserved regulatory regions. Both the human LBX2 and the mouse Lbx2 genes have similar genomic structures and are composed of two exons separated by an intron. We mapped the mouse Lbx2 gene to 35 cM on chromosome 6 and the human LBX2 gene to a homologous region of chromosome 2p13. This is a candidate region for several inherited disorders, including Alstrom syndrome, a disorder that includes ocular, urogenital, and renal abnormalities. Given the expression pattern of Lbx2, the chromosomal location in humans, and the potential function of mammalian ladybird genes, we have begun to analyze patients with ocular disorders and those with Alstrom syndrome for mutations in LBX2. Although polymorphisms were identified, our results indicate that mutations in the coding region of LBX2 do not account for Alstrom syndrome in the six kindreds analyzed. Copyright 2001 Academic Press.
UI - 21415702
AU - Klein I; Esik O; Homolya V; Szeri F; Varadi A
TI - Molecular genetic diagnostic program of multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma syndromes in Hungary.
SO - J Endocrinol 2001 Sep;170(3):661-6
AD - Institute of Enzymology of the Hungarian Academy of Sciences, Budapest, Hungary. email@example.com
Medullary thyroid carcinoma (MTC) occurs usually in sporadic form, but about a quarter of the cases are hereditary and appear as part of one of the multiple endocrine neoplasia type 2 (MEN2) syndromes. Mutations in the RET protooncogene are known to be the cause of the MEN2A and familial medullary thyroid carcinoma (FMTC) syndromes in the majority of the families. Direct DNA testing allows prophylactic thyroidectomy to be offered to individuals carrying a mutation in the above codons, and in mutation-negative cases it reduces the yearly screening-related burden on family members at risk of the disease. By DNA sequencing and PCR-restriction fragment length polymorphisms, 65 MTC probands were examined for mutations in residues 609, 611, 618, 620 of exon 10, and in residues 634, 768, 804 of exons 11, 13, and 14 respectively of the RET protooncogene. In our study, mutations in the above codons were detected in all of the 14 clinically MEN2A and FMTC families. One of these mutations, TGC609 TCC has not been reported previously. Of the 14 probands with the mutation, 25 relatives also had the identified mutation and 18 relatives proved to be non-carriers. Among the 51 probands with clinically sporadic MTC, none was found to carry a mutation in the above positions even if indirect signs of MTC, pheochromocytoma or hyperparathyroidism could be detected in some families. The frequency of the TGC634AGC mutation is unexpectedly high in our samples, which can probably be attributed to a founder effect. We conclude that screening for mutations in these codons is effective in families fulfilling the strict clinical criteria of MEN2A or FMTC.
UI - 21417631
AU - Chae J; Minami N; Jin Y; Nakagawa M; Murayama K; Igarashi F; Nonaka I
TI - Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy.
SO - Neuromuscul Disord 2001 Sep;11(6-7):547-55
AD - Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8502, Japan.
Mutations in the calpain 3 gene have been proven to be responsible for limb-girdle muscular dystrophy (LGMD) type 2A. To determine the incidence and genotypes of the calpain 3 (p94) gene mutations in Japanese LGMD patients, we sequenced the gene in 80 patients with clinical characteristics of autosomal recessive or sporadic LGMD. We identified 13 distinct pathogenic mutations in 21 patients (26%), including seven missense mutations, four splice-site mutations and two insertions in which six were novel mutations. Among the 21 patients, 15 (71%) had three types of the common missense (G233V, R461C, D707G) and one insertion (1795-1796insA) mutation. The patients had slowly progressive muscle weakness with age of onset of the disease varying from 6 to 52 years, averaging 20.9. The most striking pathologic findings were the presence of lobulated fibers in 14 patients, especially in the advanced stages. Differing from Duchenne and Becker muscular dystrophy, opaque (hypercontracted) fibers were very rarely seen. These findings may be helpful in establishing diagnostic screening strategies in Japanese LGMD patients.
UI - 21436642
AU - Coulson AS; Glasspool DW; Fox J; Emery J
TI - RAGs: A novel approach to computerized genetic risk assessment and decision support from pedigrees.
SO - Methods Inf Med 2001;40(4):315-22
AD - Advanced Computation Laboratory, Imperial Cancer Research Fund, London, United Kingdom.
OBJECTIVES: To assist general practitioners in evaluating patients' genetic risk of cancer on the basis of family history data. METHODS: A new computer application, RAGs (Risk Assessment in Genetics), has been developed to help doctors create graphical family trees and assess the genetic risk of breast and colorectal cancer. RAGs possesses two features that distinguish it from similar software: (i) a user-centred design, which takes into account the requirements of the doctor-patient encounter; (ii) effective and accessible risk reporting by employing qualitative evidence for or against increased risk, which is more easily understood than numerical probabilities. The system allows any rule-based genetic risk guideline to be implemented, and may be readily modified to cater for the varying degrees of information required by different specialists. RESULTS: RAGs permits fast, accurate data entry, and results in more appropriate management decisions than those made via other techniques. In addition, RAGs enables both the clinician and the patient to understand how it arrives at its conclusions, since the use of qualitative evidence allows the program to provide explanations for its reasoning. CONCLUSIONS: The RAGs system promises to help practitioners be more effective gatekeepers to genetic services. It may empower doctors both to make an informed choice when deciding to refer patients who are at increased genetic risk of breast or colorectal cancer, and to reassure those who are at low risk.
UI - 21446332
AU - Green MJ; Biesecker BB; McInerney AM; Mauger D; Fost N
TI - An interactive computer program can effectively educate patients about genetic testing for breast cancer susceptibility.
SO - Am J Med Genet 2001 Sep 15;103(1):16-23
AD - Department of Humanities, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA. firstname.lastname@example.org
As genetic testing for susceptibility to breast cancer becomes more widespread, alternative methods for educating individuals prior to testing will be needed. Our objective was to compare face-to-face education and counseling by a genetic counselor with education by an interactive computer program, assessing the effects of each on knowledge of breast cancer genetics and intent to undergo genetic testing. We used a randomized, controlled trial. Seventy-two self-referred women with a first-degree relative with breast cancer received outpatient education and counseling at the Clinical Center of the National Institutes of Health (NIH). Twenty-nine received individualized counseling from a genetic counselor (counseling group), 29 received education from an interactive computer program followed by individualized counseling (computer group), and 14 were controls. Both pre- and postintervention assessment of knowledge about breast cancer genetics and intent to undergo genetic testing were measured. The control group participants correctly answered 74% of the knowledge questions; the counselor group, 92%; and the computer group, 96% (P <.0001). Unadjusted mean knowledge scores were significantly higher in the computer group than the counselor group (P =.048), but they were equivalent when adjusted for demographic differences (P = 0.34). Intent to undergo genetic testing was influenced by the interventions: preintervention, a majority in all groups (69%) indicated that they were likely (definitely and most likely) to undergo testing; after either intervention coupled with counseling, only 44% indicated that they were likely to do so (P =.0002; odds ratio = 2.8, 95% CI = 1.7-4.9). We concluded that a computer program can successfully educate patients about breast cancer susceptibility, and, along with genetic counseling, can influence patients' intentions to undergo genetic testing. Copyright 2001 Wiley-Liss, Inc.
UI - 21446333
AU - Green MJ; McInerney AM; Biesecker BB; Fost N
TI - Education about genetic testing for breast cancer susceptibility: patient preferences for a computer program or genetic counselor.
SO - Am J Med Genet 2001 Sep 15;103(1):24-31
AD - Department of Humanities, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA. email@example.com
The purpose of this study was to describe and compare patient preferences for a genetic counselor or an interactive computer program for various components of genetic education and counseling for breast cancer susceptibility. As part of a randomized intervention study on genetics education and counseling for breast cancer risk, 29 women at moderate risk were educated by both a genetic counselor and an interactive computer program. After both educational interventions, participants completed Likert-style and open-ended questionnaires about what they liked most and least about each intervention, and whether they preferred the counselor or computer for a variety of tasks. Participants were largely satisfied with both the computer program and the genetic counselor. A majority preferred the genetic counselor for addressing their concerns, discussing options and alternatives, being sensitive to emotional concerns, helping to make a decision, being a good listener, assuring understanding, helping to make a good choice, helping to understand genes and breast cancer, telling them what they needed to know, being respectful, setting a relaxed tone, and putting them at ease. However, a majority of the women either preferred the computer program or were neutral about allowing patients to learn at their own pace, helping to avoid embarrassment, making good use of time, explaining genes and breast cancer, and treating the patient as an adult. Qualitative analysis of open-ended questions affirmed that patients valued the personal interactions with the counselors, and liked having their specific questions answered. They liked that the computer was self-paced, informative and private, and could be used without causing embarrassment. We concluded that a computer literate, mostly white group of women at moderate risk for inherited susceptibility to breast cancer preferred interacting with a genetic counselor for personal, individualized components of the genetic counseling process, but accepted or preferred a computer program for being self-paced, private, and informative. By incorporating such a computer program into the genetic education process, it is possible that genetic counselors would be able to spend more time performing the personal, individualized components of genetic counseling.
UI - 21446331
AU - Esplen MJ; Madlensky L; Butler K; McKinnon W; Bapat B; Wong J; Aronson
TI - M; Gallinger S Motivations and psychosocial impact of genetic testing for HNPCC.
SO - Am J Med Genet 2001 Sep 15;103(1):9-15
AD - Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. firstname.lastname@example.org
A type of hereditary colorectal cancer (CRC) known as hereditary nonpolyposis colorectal cancer (HNPCC) is associated with MLHI and MSH2 gene mutations. This study consists of a pilot, cross-sectional study of 50 individuals who were engaged in the genetic testing process for HNPCC. The study investigated the motivations and attitudes around genetic testing and current psychosocial functioning through the use of standardized measures, as well as obtained information on disclosure patterns associated with test results. The mean age of the sample was 44.3 years. (SD = 15.0). Twenty-three individuals were identified as "carriers" (13 had a previous history of CRC), seven were "non-carriers" and 20 individuals were still awaiting test results. The primary motivations for participating in genetic testing were similar to previous reports and included: wanting to know if more screening tests were needed, obtaining information about the risk for offspring and increasing certainty around their own risk. The psychosocial scores demonstrated that a subgroup of individuals exhibited distress, with greater distress for those individuals awaiting results or testing positive. There was a high level of satisfaction associated with the experience of testing. Individuals in this study tended to disclose their test results to a variety of family and non-family members. Disclosure was primarily associated with positive experiences however, some individuals reported regret around disclosure of their results. These preliminary findings should be further explored in a larger prospective study design over multiple time points.
UI - 21444716
AU - Varnava AM; Elliott PM; Baboonian C; Davison F; Davies MJ; McKenna WJ
TI - Hypertrophic cardiomyopathy: histopathological features of sudden death in cardiac troponin T disease.
SO - Circulation 2001 Sep 18;104(12):1380-4
AD - Department of Cardiological Sciences, St George's Hospital Medical School, Cranmer Terrace, London, UK.
BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) are at increased risk of premature death; this is particularly apparent for patients with mutations of the troponin T gene. Myocyte disarray and interstitial fibrosis, pathological features of HCM, may be determinants in these deaths. The relation between genotype, pathological phenotype, and mode of death has not been explored. METHODS AND RESULTS: Seventy-five hearts with HCM were examined. DNA was available in 50 for screening of the troponin T gene. The macroscopic findings, percentage of disarray, percentage of fibrosis, and percentage of small-vessel disease were correlated with the genotype. A troponin T mutation was identified in 9 of the 50 patients, 8 of whom died suddenly. Patients with a troponin T mutation were younger (mean age, 21.0 years [range, 6 to 37] versus 39.1 years [range, 14 to 72]; P<0.0001), had more sudden death (P=0.02), and had lower heart weights, less fibrosis, and greater disarray than other HCM patients (mean heart weight, 380.3+/-105.4 versus 585.0+/-245.7 g, P=0.002; mean fibrosis, 0.7+/-0.4% versus 2.6+/-2.8%, P=0.001; mean disarray, 46.2+/-7.2% versus 24.1+/-15.9%, P<0.0001; and mean small-vessel disease, 11.7+/-14.6 versus 14.1+/-8.7, P=0.6, respectively). Similarly, patients with troponin T mutations who died suddenly had lower heart weights and greater disarray than patients who died suddenly with unknown genotype (ie, troponin T mutation excluded) (mean heart weight, 429.8+/-75.4 versus 559.6+/-204.43 g, P=0.04, and mean disarray, 40.1+/-9.4% versus 20.2+/-12.6%, P=0.002, respectively). CONCLUSIONS: Patients with troponin T mutations had severe disarray, with only mild hypertrophy and fibrosis. These patients died suddenly and at an especially early age. We propose that extensive myocyte disarray in the absence of marked hypertrophy is the pathological substrate for sudden death in these patients.
UI - 21450459
AU - Lahti-Domenici J; Rapakko K; Paakkonen K; Allinen M; Nevanlinna H;
TI - Kujala M; Huusko P; Winqvist R Exclusion of large deletions and other rearrangements in BRCA1 and BRCA2 in Finnish breast and ovarian cancer families.
SO - Cancer Genet Cytogenet 2001 Sep;129(2):120-3
AD - Department of Clinical Genetics, University of Oulu/Oulu University Hospital, P.O. Box 22, FIN-90220, Oulu, Finland.
In the Finnish population, identified mutations in BRCA1 and BRCA2 account for a less than expected proportion of hereditary breast and ovarian cancer. All previous studies performed in our country have concentrated on finding germ-line mutations in the coding and splice-site regions of these two genes. Therefore, we wanted to use a different methodological approach and search for large genomic rearrangements, to exclude the possibility of biased BRCA1 and BRCA2 mutation spectra due to known limitations of the previously used PCR-based detection methods. Our results support earlier notions that other genes than BRCA1 and BRCA2 will explain a majority of the still unexplained cases of hereditary susceptibility to breast and ovarian cancer.
UI - 21457580
AU - Urwyler A; Deufel T; McCarthy T; West S; European Malignant Hyperthermia
TI - Group Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia.
SO - Br J Anaesth 2001 Feb;86(2):283-7
AD - Department of Anaesthesia and Research, Kantonsspital, University of Basel, Switzerland.
Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disease triggered by several anaesthetic agents. The in vitro muscle contracture test (IVCT) is the standard test to establish an individual's risk of susceptibility to MH. Clinical practitioners and geneticists of the European MH Group have agreed on the present guidelines for the detection of MH susceptibility using molecular genetic techniques and/or IVCT to predict the risk of MH.
UI - 21412328
AU - Wang X; Zuckerman B; Kaufman G; Wise P; Hill M; Niu T; Ryan L; Wu D; Xu
TI - X Molecular epidemiology of preterm delivery: methodology and challenges.
SO - Paediatr Perinat Epidemiol 2001 Jul;15 Suppl 2():63-77
AD - Department of Pediatrics, Boston University School of Medicine, 91 E. Concord Street, Boston, MA 02118, USA. email@example.com
Preterm delivery (PTD) appears to be a complex trait determined by both genetic and environmental factors. Few studies have examined genetic influence on PTD. The overall goal of our study is to examine major candidate genes of PTD and to test gene-environment interactions. Our study includes 500 preterm trios, including 500 preterm babies and their parents and 500 maternal age-matched term controls. We will perform the transmission/disequilibrium test (TDT) on candidate genes thought to be important in each of the four biological pathways of PTD: (1) decidual chorioamionotic inflammation: interleukin 1 (IL-1), IL-6, and tumour necrosis factor (TNF); (2) maternal and fetal stress: corticotropin-releasing hormone (CRH); (3) uteroplacental vascular lesions: methylenetereahydrofolate reductase (MTHFR); and (4) susceptibility to environmental toxins: GSTM1, GSTT1, CYP1A1, CYP2D6, CYP2E1, NAT2, NQO1, ALDH2, and EPHX. We will also perform standard case-control analyses on the 500 preterm cases and 500 term controls to examine gene-environment interactions. The major environmental, nutritional and social factors as well as clinical variables known or suspected to be associated with PTD will be used to test for gene-environment interactions. This study integrates epidemiological and clinical data as well as genetic markers along major pathogenic pathways of PTD. The findings from this study should improve our understanding of genetic influences on PTD and gene-environment interactions.
UI - 21412289
AU - Schwartzman JS; Bernardino A; Nishimura A; Gomes RR; Zatz M
TI - Rett syndrome in a boy with a 47,XXY karyotype confirmed by a rare mutation in the MECP2 gene.
SO - Neuropediatrics 2001 Jun;32(3):162-4
AD - Universidade Mackenzie, Sao Paulo, Brazil.
Rett syndrome (RTT) is an X-linked condition which affects almost exclusively females. Here we report the first case of RTT syndrome in a boy with an XXY chromosomal constitution. Mutation analysis of the MECP2 gene in the affected patient revealed a 423 C-->G substitution in exon 4, resulting in a new stop codon (Y141 X). This change was not present in both his parents or in his older sister. Taking into account the incidence of both RTT syndrome as well as of Klinefelter syndrome, the probability for the simultaneous occurrence of these two events is very low (about approximately 1 in 10 to 15,000,000 births). However, the recent identification of mutations in the MECP2 gene in affected males indicates that screening of the MECP2 gene should be considered also in males with severe mental retardation (MR) in whom the most common forms of MR have been excluded.
UI - 21459805
AU - Giarelli E
TI - Ethical issues in genetic testing. The experiences of one family diagnosed with an inherited cancer syndrome.
SO - J Infus Nurs 2001 Sep-Oct;24(5):301-10
AD - University of Pennsylvania School of Nursing, 420 Guardian Drive, Philadelphia, PA 19104, USA. IMLNG@aol.com
This article describes selected ethical issues faced by members of a family with genetic predisposition to the cancer syndrome multiple endocrine neoplasia type 2a. The bioethical principles of autonomy, nonmaleficence, beneficence, and justice are the moral guides for nurses and other health professionals, who may apply them to help patients, family members and peers resolve ethical issues and moral dilemmas. Sometimes, however, issues that are morally problematic cannot be settled by simply referring to standards of practice and bioethical norms. In these cases all stakeholders must struggle together to resolve the conflict.
UI - 21463150
AU - Percesepe A; Borghi F; Menigatti M; Losi L; Foroni M; Di Gregorio C;
TI - Rossi G; Pedroni M; Sala E; Vaccina F; Roncucci L; Benatti P; Viel A; Genuardi M; Marra G; Kristo P; Peltomaki P; Ponz de Leon M Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study.
SO - J Clin Oncol 2001 Oct 1;19(19):3944-50
AD - Department of Internal Medicine, University of Modena, Modena, Italy. firstname.lastname@example.org
PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer. PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1. RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P <.01), high mucinous component (P <.01), and poor differentiation (P =.002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations. CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.
UI - 21113004
AU - Keen RW; Snieder H; Molloy H; Daniels J; Chiano M; Gibson F; Fairbairn
TI - L; Smith P; MacGregor AJ; Gewert D; Spector TD Evidence of association and linkage disequilibrium between a novel polymorphism in the transforming growth factor beta 1 gene and hip bone mineral density: a study of female twins.
SO - Rheumatology (Oxford) 2001 Jan;40(1):48-54
AD - Twin & Genetic Epidemiology Research Unit, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.
OBJECTIVE: Bone mineral density (BMD) in later life is a major determinant of osteoporotic fracture risk and has been shown to be under strong genetic influence. Transforming growth factor beta 1 (TGF-beta 1) is an important regulatory cytokine, is found in high concentrations in the bone matrix, and is a plausible candidate for the genetic regulation of BMD. METHODS: This study investigated whether a novel polymorphism within the TGF-beta 1 gene is associated with BMD in a large normal female population of 1706 dizygotic (DZ) twins (age range 18-76 yr). RESULTS: A C--->T [corrected] polymorphism was identified in intron 5, the T [corrected] allele having a frequency of 0.25. Subjects homozygous for the presence of the TGF-beta 1 T [corrected] allele had a 4% reduction in femoral neck BMD compared with the other two genotype groups (P<0.025). No effect was seen at the lumbar spine or ultradistal radius, or with calcaneal ultrasound measurements. Results were unaffected after adjustment for potential confounders. These findings were predominantly seen in pre-menopausal subjects, suggesting that this locus has an effect on the attainment of peak BMD. In pre-menopausal women, subjects who were homozygous for the T [corrected] allele had a 5-fold excess risk of having osteoporosis at the femoral neck compared with the other genotype groups. A within-pair analysis using the sibling transmission disequilibrium test confirmed these findings in pre-menopausal women and supported the candidacy of the TGF-beta 1 locus in the genetic regulation of hip BMD. CONCLUSIONS: These results indicate that allelic variation at the TGF-beta 1 gene contributes to the development of osteoporosis at the hip. The study also highlights the power of candidate gene analysis in twins, in whom loci having modest effects on disease risk can be identified.
UI - 21295695
AU - Simpson SA; Harper PS; United Kingdom Huntington's Disease Prediction
TI - Consortium Prenatal testing for Huntington's disease: experience within the UK 1994-1998.
SO - J Med Genet 2001 May;38(5):333-5
UI - 21406034
AU - Wolford JK; Thameem F; Bogardus C; Prochazka M
TI - Polymorphism screening of the insulin receptor-related receptor gene (INSRR) on 1q in Pima Indians.
SO - Mol Cell Probes 2001 Aug;15(4):223-7
AD - Clinical Diabetes and Nutrition Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 4212 North 16th Street, Phoenix, AZ 85016, USA.
INSRR coding for the insulin receptor-related receptor (IRR) is located within the 1q21-q23 region linked with type-2 diabetes mellitus in Pima Indians and Caucasians. Although the ligand and biological function of this receptor are not yet known, its tyrosine kinase phosphorylates proteins involved in insulin signaling, and IRR may also play a role in the control of the insulin producing beta-cell mass. Therefore, defects in INSRR could contribute to susceptibility to type-2 diabetes. By screening the 22 exons, 5' and 3' flanking sequences, and most introns in 20 Pima Indians and one Caucasian control, we detected nine diallelic variants, including eight single nucleotide polymorphisms (SNPs), and a length polymorphism involving a 26-nt motif. In this study sample, four of the identified SNPs were rare, while the remaining five common variants located within 4.5 kb from the 3' end of the gene were in linkage disequilibrium. When analysed in selected diabetic and non-diabetic Pimas, none of the markers was associated with the disease. We conclude that INSRR has no detectable mutations contributing to diabetes in the Pima Indians. However, information on the novel markers may prove useful for association studies of this candidate gene in other populations. Copyright 2001 Academic Press.
UI - 21421258
AU - Chalmers KI; Luker KA; Leinster SJ; Ellis I; Booth K
TI - Information and support needs of women with primary relatives with breast cancer: development of the Information and Support Needs Questionnaire.
SO - J Adv Nurs 2001 Aug;35(4):497-507
AD - Helen Glass Centre for Nursing, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2. email@example.com
AIMS OF THE STUDY: The aim was to develop and pilot test a newly developed measure, The Information and Support Needs Questionnaire (ISNQ), for use with women with primary relatives with breast cancer. BACKGROUND/RATIONALE: Breast cancer is a major risk to the health of women in the United Kingdom (UK). Increasingly, research is documenting women's needs for information and support, particularly at the time of diagnosis. However, to date there is little understanding of the information and support needs of women who have a family history of breast cancer. Contributing to the dearth of understanding of female relatives' needs is the lack of valid and reliable instruments for use in descriptive and intervention research with this population. DESIGN/METHODS: The ISNQ and survey items documenting family history, sources of information and support for breast cancer risk, breast self-care practices, and other variables were pilot tested for the acceptability of the measures, appropriateness of the data collection methods, initial psychometric properties of the ISNQ, and time and financial costs of administration. Data were collected from 39 women living in the North-west of England who had primary relatives with breast cancer using mailed questionnaires and follow-up telephone interviews. FINDINGS: The items on the ISNQ were reported to be clear, acceptable to women and to yield relevant data. The psychometric properties of the new measure were satisfactory with a high reliability coefficient alpha. Descriptive findings indicate that women had moderate to high needs for information and support, but reported that these needs were not well met. CONCLUSIONS: The results of this pilot are guiding the development of a larger study in which the information and support needs of women with a family history of breast cancer are explored.