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NCI CANCERLIT^® Search: Genetic Counseling and Screening - July 2002

National Cancer Institute^®
Last Modified: July 1, 2002

Collagenase-1 (MMP-1) and HLA-DRB1 gene polymorphisms in rheumatoid arthritis: a prospective longitudinal study.
Lack of association between juvenile idiopathic arthritis and fas gene polymorphism.
Tumor necrosis factor-alpha gene polymorphism in severe and mild-moderate rheumatoid arthritis.
Hereditary factors in pancreatic cancer.
What is the impact of genetic counselling in women at increased risk of developing hereditary breast cancer? A meta-analytic review.
Prenatal genetic screening.
Genetic testing and mental health: the model of Huntington disease.
Heart stopper genes: would you recognize a high risk patient?
The genetics of hereditary nonmedullary thyroid carcinoma.
Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians.
Why mutation analysis does not always predict clinical consequences: explanations in the era of genomics.
Benign mental health consequences of screening for mutations of BRCA1/BRCA2.
Psychosocial dimensions of BRCA testing: an overshadowed issue.
Have p53 gene mutations and protein expression a different biological significance in colorectal cancer?
The complexity of KIT gene mutations and chromosome rearrangements and their clinical correlation in gastrointestinal stromal (pacemaker cell)
Why do women attend familial breast cancer clinics?
Genetic counselling: evolution or involution?
Cytokine polymorphisms in men with chronic prostatitis/chronic pelvic pain syndrome: association with diagnosis and treatment response.
What do women really want to know? Motives for attending familial breast cancer clinics.
Coding for change: the power of the human genome to transform the American Health Insurance System.
[Screening for 6-pyruvoyl-tetrahydrobiopterin synthase (PTPS) deficiency: clinical analysis of 9 patients with PTPS deficiency]
Cancer genetics.
Factors affecting genetic testing and decisions about prophylactic surgery.
Cancer genetics and women's health.
Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification
[Genetic analysis in familial adenomatous polyposis]
A current perspective on genetic testing for breast and ovarian cancer: the oral contraceptive decision.
A -174G/C polymorphism of the interleukin-6 gene in patients with lacunar infarction.
Apolipoprotein E genotype does not predict decline in intelligence in healthy older adults.
Apolipoprotein E4 and tau allele frequencies among Choctaw Indians.
A polymorphism within intron 11 of the tau gene is not increased in frequency in patients with sporadic Alzheimer's disease, nor does it
Testing for genetic traits: the need for a new legal doctrine of informed consent.
Genetics and ethics.
Some modern responsa on medico-moral problems.
Human genome mapping: a Jewish perspective.
When racial sensitivities clash with research.
A change in policy: genetic testing threatens to fundamentally alter the whole notion of insurance.
Recurrent fetal loss associated with bilineal inheritance of type 1 autosomal dominant polycystic kidney disease.
Molecular analysis, mutation screening, and association study of adenylate cyclase type 9 gene (ADCY9) in mood disorders.
Genetic testing for hereditary disease: attending to relational responsibility.
Controversies and guidelines in tissue-based HER-2/neu testing in breast cancer.
Population screening for cancer-related germline gene mutations.
Improved clinical management of retinoblastoma through gene testing.
Dominant negative ATM mutations in breast cancer families.
Applications of advances in molecular biology and genomics to clinical cancer care.
Clinical utility of a genetic susceptibility test for severe chronic periodontitis: a critical evaluation.
Factors influencing intention to obtain a genetic test for colon cancer risk: a population-based study.
Interest in BRCA1/2 testing in a primary care population.
When is molecular genetic testing for colorectal cancer indicated?
Language-impaired children: No sign of the FOXP2 mutation.
Genetic counseling, testing, and screening for breast and ovarian cancer: practical and social considerations.
Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas.
ATM mutations in Finnish breast cancer patients.
Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany.
Investigation of the GRB2, GRB7, and CSH1 genes as candidates for the Silver-Russell syndrome (SRS) on chromosome 17q.
[Behavior in familial breast carcinoma]
APO(a) variants and lipoprotein(a) in men with or without myocardial infarction.
Human genetics. A rational view of insurance and genetic discrimination.
Human genetics. Before it's too late--addressing fear of genetic information.

1
UI - 11824952
AU - Constantin A; Lauwers-Cances V; Navaux F; Abbal M; van MJ; Mazieres B;
TI - Cambon-Thomsen A; Cantagrel A Collagenase-1 (MMP-1) and HLA-DRB1 gene polymorphisms in rheumatoid arthritis: a prospective longitudinal study.
SO - J Rheumatol 2002 Jan;29(1):15-20
AD - Department of Rheumatology and Immunology, CHU Rangueil, France.
OBJECTIVE: Rheumatoid arthritis (RA) is characterized by chronic synovitis leading to permanent damage of the joints. Collagenase-1 (MMP-1) is a matrix metalloproteinase involved in articular cartilage degradation. We investigated the association between a biallelic polymorphism in the MMP-1 gene promoter and the susceptibility to, and severity of, RA. We also investigated the association between HLA-DRB1 gene polymorphism and severity of RA. METHODS: One hundred and three patients with early RA were included in this prospective longitudinal study. A radiographic damage score was used to quantify disease severity at baseline and after 4 years of followup. MMP-1 polymorphism genotyping was analyzed using a fluorescent-based polymerase chain reaction (PCR). HLA-DRB1 genotypes were determined by PCR sequence-specific oligonucleotide probes. One hundred and thirty-three healthy individuals were used as controls. RESULTS: MMP-1 allele and genotype frequencies did not differ between RA patients and controls. The radiographic damage or its progression over the 4 years of followup did not differ across MMP-1 genotypes. The radiographic damage score and its progression over the 4 years of followup differed across HLA-DRB1 genotypes. The HLA-DRB I shared epitope +/+ genotype was associated with the highest radiographic damage score and the highest progression, while the shared epitope -/- genotype was associated with the lowest. CONCLUSION: Our results do not support the hypothesis of an association between this particular polymorphism in the MMP-1 gene promoter and susceptibility to, or severity of, RA. This study confirms the previous reports of an association between the HLA-DRB1 gene polymorphism and severity of RA.

2
UI - 11824955
AU - Donn R; Zeggini E; Shelley E; Ollier W; Thomson W; The British
TI - Paediatric Rheumatology Study Group Lack of association between juvenile idiopathic arthritis and fas gene polymorphism.
SO - J Rheumatol 2002 Jan;29(1):166-8
AD - ARC Epidemiology Unit, University of Manchester, UK.
OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a complex genetic disease of autoimmune etiology. Fas is a molecule with a pivotal role in apoptosis and hence in immune regulation. Elevated transcriptional levels of Fas in the synovial fluid of patients with JIA suggest that it might be implicated in disease etiopathogenesis. We investigated whether a polymorphism in the Fas promoter region (-670) confers susceptibility to JIA. METHODS: In this association study, 342 UK patients with JIA and 255 healthy individuals were genotyped for the polymorphism using polymerase chain reaction restriction fragment length polymorphism. Comparisons of the genotypic frequencies were made using chi-square analysis. RESULTS: No statistically significant differences were found when the genotype frequencies of the -670 Fas polymorphism were compared between the JIA cases and the control panel. Similarly, no differences were seen between the JIA subgroups, or when the patients were divided on the basis of rheumatoid factor or antinuclear antibody positivity. CONCLUSION: The -670 polymorphism of Fas does not appear to be associated with susceptibility to JIA.

3
UI - 11824966
AU - Fabris M; Di PE; D'Elia A; Damante G; Sinigaglia L; Ferraccioli G
TI - Tumor necrosis factor-alpha gene polymorphism in severe and mild-moderate rheumatoid arthritis.
SO - J Rheumatol 2002 Jan;29(1):29-33
AD - From the Division of Rheumatology, DPMSC, School of Medicine, University of Udine, Italy.
OBJECTIVE: To examine whether severe rheumatoid arthritis (RA) carries a -238 or +489 tumor necrosis factor-alpha (TNF-alpha) genotype different from mild-moderate RA. METHODS: We investigated 163 patients (66 with severe disease) and 67 healthy blood donor controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Patients with severe RA (all active disease despite disease modifying antirheumatic drug combination therapy) disclosed the -238 GG genotype in 100% of cases versus 92.8% of the mild-moderates and 92.5% of controls (OR 11.7, Cl 0.6-216, p = 0.03). The +489 AA genotype was seen less often in patients than in controls (OR 4.2. CI 0.97-18.4, p = 0.045), and the contribution to this trend appeared predominant in the anti-TNF treated subgroup. CONCLUSION: The -238 AG genotype was absent in severe RA; in contrast, patients with mild-moderate RA disclosed the same frequency as controls. Thus -238 GG homozygosity is associated with severe RA. The +489 AA genotype might instead protect against worse outcome in RA.

4
UI - 12021894
AU - Lynch HT; Brand RE; Lynch JF; Fusaro RM; Kern SE
TI - Hereditary factors in pancreatic cancer.
SO - J Hepatobiliary Pancreat Surg 2002;9(1):12-31
AD - Department of Preventive Medicine and Public Health, Creighton University School of Medicine, 2500 California Plaza, Omaha NE 68178, USA.
The incidence and the mortality rates for pancreatic cancer are the same, indicating its dismal outlook. Its natural history remains elusive. Cigarette smoking appears to be the most significant environmental culprit. Hereditary factors may account for approximately 5% of the total pancreatic cancer burden. However, when its extant heterogeneity and the reduced penetrance of causal germline mutations are considered, the hereditary incidence may significantly exceed this estimate. Even when endoscopic ultrasound (EUS), the gold standard for pancreatic cancer screening, is utilized, early detection with surgical cure has rarely been accomplished. Needed to ameliorate this problem is research into genetic and environmental risk factors and their interaction. The identification of tumor biomarkers which signal early pathogenetic events, thereby enabling pancreatic cancer to be diagnosed at its earliest possible stage before it has spread to regional lymph nodes or to more distant sites, will improve the outlook. We discuss our research approaches to this problem. Members of families with the p16 germline mutation will undergo EUS coupled with the collection of pancreatic juice for the study of a possible gradient for telomerase activity, K- ras mutations, and cytology. If changes in these putative biomarkers are observed, endoscopic retrograde cholangiopancreatography (ERCP) would be the next diagnostic step. We conclude with a discussion of ethical concerns about this research.

5
UI - 12061481
AU - Meiser B; Halliday JL
TI - What is the impact of genetic counselling in women at increased risk of developing hereditary breast cancer? A meta-analytic review.
SO - Soc Sci Med 2002 May;54(10):1463-70
AD - Department of Psychological Medicine, Royal North Shore Hospital, St Leonard, NSW, Sydney, Australia. b.meiser@unsw.edu.au
Meta-analytic methods were used to determine the impact of genetic counselling on women with a family history of breast cancer. Published studies with prospective designs and randomized controlled trials were included in the review, and the psychological outcomes assessed were generalized psychological distress, generalized anxiety, depression, and breast cancer anxiety. Other outcomes investigated were the accuracy of perceived risk of developing breast cancer, breast cancer genetics knowledge and breast cancer screening uptake. A meta-analysis was performed to estimate effect size, where sufficient data were available. A total of 12 studies, most of which measured several outcomes, met at least one of the inclusion criteria. A sufficiently large number of studies were available to assess the magnitude of effects on three outcomes: generalized psychological distress, generalized anxiety and accuracy of perceived risk of developing breast cancer. The quantitative synthesis showed that genetic counselling leads to statistically significant decreases in generalized anxiety, with an average weighted effect sizes of r = - 0.17 (p<0.01). In contrast, the reduction in psychological distress exhibited a trend towards statistical significance only, with r = -0.074 (p = 0.052). The impact of genetic counselling on the accuracy of perceived risk was associated with an effect size of r = 0.56 (p<0.01). Thus in this meta-analysis, we demonstrated the efficacy of genetic counselling in meeting two of its objectives: reducing women's anxiety levels and improving the accuracy of their perceived risk. This review highlighted that most research so far focused on generalized distress and anxiety and accuracy of perceived risk, to the exclusion of other, perhaps equally important, types of outcomes. Future studies are likely to lead to more comprehensive assessments if additional emotional, cognitive and behavioural outcomes are included in the assessment.

6
UI - 11380268
AU - Grant SS
TI - Prenatal genetic screening.
SO - Online J Issues Nurs 2000;5(3):2
AD - University of Iowa Hospitals and Clinics, Iowa, USA. stanley-grant@uiowa.edu
This article presents a discussion of screening principles and techniques available to screen for common birth defects during pregnancy. Sixty-five to 70% of women have serum screening and /or ultrasound during pregnancy to evaluate the health and well-being of the developing fetus. The most common birth defects identified by screening include neural tube defects and chromosome abnormalities. Nurses employed in prenatal care settings need to have accurate information they can provide to women so they understand the benefits and limitations of screening. Timely presentation of information and identification of available resources will help nurses minimize confusion and provide support for women as they proceed with pregnancy screening.

7
UI - 11380269
AU - Williams JK; Schutte DL
TI - Genetic testing and mental health: the model of Huntington disease.
SO - Online J Issues Nurs 2000;5(3):3
AD - The University of Iowa, College of Nursing, Iowa, USA. Janet-williams@uiowa.edu
Genetic aspects of mental health disorders are being identified through human genome and family research. Gene discovery makes diagnostic and presymptomatic testing possible. The discovery of a gene mutation for Huntington Disease (HD) enables at-risk persons to request presymptomatic genetic testing. When HD genetic testing is offered through HD testing centers, a multi-visit protocol is followed in which education and counseling are provided for persons considering the option to have HD gene testing. A case study illustrates the clinical and ethical issues regarding privacy and disclosure as well as the personal and family consequences of gene mutation knowledge. Analysis of the impact of genetic knowledge on persons being tested for HD provides a model for the integration of emerging genetic information into mental health nursing practice for other mental health disorders.

8
UI - 11380270
AU - Greco K; Bayan M
TI - Heart stopper genes: would you recognize a high risk patient?
SO - Online J Issues Nurs 2000;5(3):4
Coronary artery disease (CAD) is one of the leading causes of death in the United States. Eighty percent of people having heart attacks have normal cholesterol levels. A quarter of the population have a condition called low-density lipoprotein (LDL) pattern B that has been associated with a threefold risk of myocardial infarction. Although early intervention can often prevent an otherwise fatal event, these patients often go unrecognized until after a myocardial infarction has occurred because they may not have the usual risk factors associated with cardiovascular disease. In patients with LDL pattern B, the standard lipid panel may be normal and inadequate for diagnosis and treatment of the condition. This article discusses how to identify a potentially high risk patient, available laboratory tests, management options, and the role of nurses in identifying high risk patients. The second author tells his personal story of surviving multiple cardiac arrests at a young age before being diagnosed with this condition.

9
UI - 12050199
AU - Malchoff CD; Malchoff DM
TI - The genetics of hereditary nonmedullary thyroid carcinoma.
SO - J Clin Endocrinol Metab 2002 Jun;87(6):2455-9
AD - Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1850, USA. malchoff@nso2.uchc.edu

10
UI - 12050208
AU - Wang H; Chu WS; Hemphill C; Elbein SC
TI - Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians.
SO - J Clin Endocrinol Metab 2002 Jun;87(6):2520-4
AD - Division of Endocrinology and Metabolism, John L. McClellan Jr. Memorial Veterans Hospital, 4300 West 7th Street, Little Rock, AR 72205, USA.
Insulin resistance is strongly associated with obesity, but even among obese subjects insulin sensitivity varies widely. Recently, a new adipocyte hormone, resistin, was identified, shown to reduce insulin-mediated glucose uptake, and shown to be increased in obese mice. We used the chromosome 19 draft sequence to determine the genomic structure of human resistin and to screen the exons, introns, and flanking sequences for variation. We screened 44 subjects with type 2 diabetes and 20 nondiabetic family members who were at the extremes of insulin sensitivity. We identified eight noncoding single nucleotide polymorphisms (SNPs) and one GAT microsatellite repeat. Three SNPs, which were in incomplete linkage disequilibrium with each other and had allelic frequencies exceeding 5%, were selected for further study. No SNP was associated with type 2 diabetes, but the SNP in the promoter region was a significant determinant of insulin sensitivity index (P = 0.04) among nondiabetic family members who had undergone iv glucose tolerance tests. The three common SNPs showed statistical significance as determinants of insulin sensitivity index (P < 0.01) in interaction with body mass index. Noncoding SNPs in the resistin gene may influence insulin sensitivity in interaction with obesity, but this finding will need to be confirmed in other populations.

11
UI - 12032513
AU - Scriver CR
TI - Why mutation analysis does not always predict clinical consequences: explanations in the era of genomics.
SO - J Pediatr 2002 May;140(5):502-6
AD - Department of Human Genetics, McGill University, Montreal, Quebec, Canada. charles.scriver@mcgill.ca

12
UI - 11840496
AU - Coyne JC; Kruus L; Kagee A; Thompson R; Palmer S; Kruus L
TI - Benign mental health consequences of screening for mutations of BRCA1/BRCA2.
SO - Am J Med Genet 2002 Feb 1;107(4):346-9

13
UI - 11829055
AU - Bredart A; Autier P; Riccardo A; Audisio A; Geraghty JG
TI - Psychosocial dimensions of BRCA testing: an overshadowed issue.
SO - Eur J Cancer Care (Engl) 2001 Jun;10(2):96-9
AD - Psycho-Oncology Research Unit, European Institute of Oncology, Milan, Italy.
Routine cancer susceptibility testing will soon be feasible in clinical practice. However, to date, this new technology has entailed many limitations, including potential adverse psychosocial consequences. Empirical studies examining these psychosocial aspects are strikingly scarce, especially in continental European countries. Are we prepared for managing the psychosocial problems that emerge from widespread introduction of this practice? Current research do not take into account cross-cultural variations in attitudes and reactions towards genetic testing. This paper points to the urgent need for obtaining a more accurate picture on the psychosocial aspects of breast cancer gene testing and disclosure in order to design recommendations for implementation in populations with highly variable cultural and legal background.

14
UI - 12064467
AU - Bazan V; Migliavacca M; Tubiolo C; Macaluso M; Zanna I; Corsale S; Amato
TI - A; Calo V; Dardanoni G; Morello V; La Farina M; Albanese I; Tomasino RM; Gebbia N; Russo A Have p53 gene mutations and protein expression a different biological significance in colorectal cancer?
SO - J Cell Physiol 2002 May;191(2):237-46
AD - Department of Oncology, Regional Reference Center for Biomolecular Characterization of Neoplasms and Genetics Screening of Hereditary Tumors of Sicily, University of Palermo, Italy.
p53 alterations are considered the most common genetic events in many types of neoplasms, including colorectal carcinoma (CRC). These alterations include mutations of the gene and/or overexpression of the protein. The aim of our study was to assess whether in 160 patients undergoing resective surgery for primary operable CRC there was an association between p53 mutations and protein overexpression and between these and other biological variables, such as cell DNA content (DNA-ploidy) and S-phase fraction (SPF), and the traditional clinicopathological variables. p53 mutations, identified by PCR-SSCP-sequencing analysis, were found in 68/160 patients (43%) and positive staining for p53 protein, detected with the monoclonal antibody DO-7, was present in 48% (77/160) of the cases, with agreement of 57% (91/160). In particular, a significant association was found between increased p53 expression and genetic alterations localized in the conserved regions of the gene or in the L3 DNA-binding domain and the specific type of mutation. Furthermore, both overexpression of p53 and mutations in the conserved areas of the gene were found more frequently in distal than in proximal CRCs, suggesting that they might be "biologically different diseases." Although p53 mutations in conserved areas were associated with flow cytometric variables, overexpression of p53 and mutations in its L3 domain were only related respectively to DNA-aneuploidy and high SPF. These data may reflect the complex involvement of p53 in the different pathways regulating cell-cycle progression. In conclusion, the combination of the mutational status and immunohistochemistry of p53, and flow cytometric data may provide an important insight into the biological features of CRCs.

15
UI - 11786393
AU - Andersson J; Sjogren H; Meis-Kindblom JM; Stenman G; Aman P; Kindblom LG
TI - The complexity of KIT gene mutations and chromosome rearrangements and their clinical correlation in gastrointestinal stromal (pacemaker cell) tumors.
SO - Am J Pathol 2002 Jan;160(1):15-22
AD - Department of Pathology, Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, Goteborg University, Goteborg, Sweden.
Gastrointestinal stromal (pacemaker cell) tumors (GIST/GIPACTs) are frequently associated with activating KIT mutations, primarily of exon 11 and rarely of exons 9 and 13, as well as certain chromosome rearrangements. Reports regarding the frequency and prognostic significance of KIT mutations are conflicting and few cases have been completely sequenced. Furthermore, there are few detailed analyses of chromosome alterations in GIST/GIPACTs. In a detailed analysis of 14 GIST/GIPACTs from 12 patients, we found a wider spectrum of KIT mutations than previously reported, including 11 different in-frame mutations involving exons 11, 14, and 15. No mutations were detected in four malignant tumors. The shorter (GNNK-) KIT isoform was preferentially expressed. Cytogenetic and spectral karyotype analyses of 10 tumors revealed clonal abnormalities in eight tumors; the most common were terminal 1p deletions and losses of chromosomes 14 and/or 22. Neither KIT mutation status nor chromosome aberrations correlated with tumor phenotype or clinical behavior in our series. Collectively, these findings indicate that the role of KIT mutations and chromosomal rearrangements in the pathogenesis of GIST/GIPACTs are more complex than previously recognized.

16
UI - 10699056
AU - Brain K; Gray J; Norman P; Parsons E; Clarke A; Rogers C; Mansel R;
TI - Harper P Why do women attend familial breast cancer clinics?
SO - J Med Genet 2000 Mar;37(3):197-202
AD - Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK.
The increasing demand for genetic assessment for familial breast cancer has necessitated the development of cancer genetics services. However, little is known about the factors motivating the client population likely to approach these services. A cross sectional questionnaire survey of 1000 women with a family history of breast cancer was conducted to identify self-reported reasons for attending a familial breast cancer clinic and possible differences in the characteristics of women who were attending for diverse reasons. Before attendance at clinic, 833 women completed a baseline questionnaire (83% response rate). Women who gave personal risk (n=188), awareness of a family history (n=120), risk to family members (n=84), reassurance (n=69), genetic testing (n=65), breast screening (n=46), or prevention (n=39) as their main reason for attending were compared on demographic and medical variables, and on psychological variables including general anxiety, cancer worry, perceived risk, and attitudes towards prophylactic surgery and genetic testing. Important differences in the psychological characteristics of these groups were found, which were unrelated to reported family history. In particular, women who primarily wanted genetic testing felt extremely vulnerable to developing breast cancer, were more likely to be considering prophylactic surgery, and perceived fewer limitations of testing. Those who primarily wanted reassurance were highly anxious about the disease. We recommend that cancer genetics services take into consideration the informational and psychological needs and concerns of their client group.

17
UI - 11878343
AU - Frontali M; Jacopini AG
TI - Genetic counselling: evolution or involution?
SO - Community Genet 2000 May;3(4):175-8
AD - Instituto di Medicina Sperimentale CNR, Via Fosso del Cavaliere, I-00044 Frascati, Rome (Italy). Marina.Frontali@ims.rm.cnr.it
The need for genetic counselling derives from the peculiarities of genetic information, as compared to other biomedical tests, with particular reference to (a) its predictive character; (b) the existing gap between the ability to diagnose and to treat an inherited disorder, and (c) the psychological, social and ethical problems that genetic testing can raise. Counselling is traditionally performed by healthcare professionals, specifically trained to help individuals to develop ways of dealing with genetic information and gain a better understanding of the problems related with it. The growing number of genetic tests (for rare Mendelian as well as for common disorders), the development of easier and cheaper molecular techniques, the increasing tendency of physicians to have recourse to genetic tests, by-passing alternative diagnostic procedures, are all factors that contribute to the vast increase in the demand for genetic tests, a demand which is significantly out of step with the available numbers of trained counsellors. This paper discusses possible solutions, including the institution of committees with regulatory powers on genetic testing, the promotion of studies on models of genetic services, on programmes to monitor the services currently offered by test providers, and the expansion of training programmes and of employment opportunities for genetic counsellors.

19
UI - 12070250
AU - Van Asperen CJ; Van Dijk S; Zoeteweij MW; Timmermans DR; De Bock GH;
TI - Meijers-Heijboer EJ; Niermeijer MF; Breuning MH; Kievit J; Otten W What do women really want to know? Motives for attending familial breast cancer clinics.
SO - J Med Genet 2002 Jun;39(6):410-4

20
UI - 12025537
AU - Geetter JS
TI - Coding for change: the power of the human genome to transform the American Health Insurance System.
SO - Am J Law Med 2002;28(1):1-76
AD - McDermott, Will & Emery, Boston, Massachusetts, USA.

21
UI - 11798810
AU - Ye J; Liu X; Huang X
TI - [Screening for 6-pyruvoyl-tetrahydrobiopterin synthase (PTPS) deficiency: clinical analysis of 9 patients with PTPS deficiency]
SO - Zhonghua Yi Xue Za Zhi 2000 Jul;80(7):513-5
AD - Shanghai Institute for Pediatric Research, Shanghai 200092, China.
OBJECTIVE: To show the incidence of 6-Pyruvoyl-tetrahydrobiopterin synthase (PTPS) deficiency among hyperphenylalaninemia and conclude the clinical outcome of patients with PTPS deficiency. METHODS: The urinary neopterin (N) and biopterin (B) were determined by HPLC in 69 PKU cases. BH(4) loading test and mutation analysis of PTPS were performed in patients who had abnormal urinary pterin patterns. Three patients with PTPS deficiency were placed on treatment with combined synthetic BH(4) and neurotransmitter precursors such as Dopa and 5-hydroxytryptophan. RESULTS: 9 out of 69 patients, whose urinary N/B exceed 38 [normal: 1.17 (1.4)] and B% were less than 5% [normal: 55.9 (18.6)], were diagnosed as having PTPS deficiency. Four kinds of PTPS gene mutations (P87S, N52S, D96N and G144R) were detected from 4 out of 9 cases with PTPS deficiency. The last mutation was a new mutation. The three typical PTPS-deficient patients had satisfactory physical development, their intelligence quotient (IQ) were 70 approximately 80 after treatment and one partial PTPSD had normal growth and mental development. CONCLUSION: The screening for BH(4) deficiency should be carried out among all patients with hyperphenylalaninemia in order to avoid misdiagnosis.

22
UI - 11827271
AU - Murphy AE
TI - Cancer genetics.
SO - Eur J Cancer Care (Engl) 2001 Mar;10(1):66-8
AD - Geneva University Hospital, Switzerland.

23
UI - 11899370
AU - Mahon SM
TI - Factors affecting genetic testing and decisions about prophylactic surgery.
SO - Clin J Oncol Nurs 2001 May-Jun;5(3):117-20
AD - St. Louis University, Division of Hematology/Oncology, St. Louis, MO, USA.
Both of the articles reviewed here as well as the references, suggest that very little is actually known about the impact of many aspects of genetic testing. How decision are made about genetic testing in people who do not have cancer, how the results of testing are used used to guide care, and ultimately how people adjust to prophylactic surgery, which is the most effective form of prevention currently available to those who do have a mutation are not completely clear. This has many implications for practice in general. Oncology nurses who build relationships with those diagnosed with cancer and their families may be one of the best groups of professionals to provide the education and counseling individuals and families need prior to making any decision about genetic testing. Just as many responses to cancer exist, so do many responses to finding out the results of mutation status. Oncology nurses are challenged to help facilitate adjustment to learning that one carries a mutation that significantly increases risk of developing cancer. More nursing research needs to be conducted on how to facilitate this adjustment. Dealing with the unknown can be a frightening experience. Little is known about the long-term effectiveness of prophylactic mastectomy and oophorectomy in unaffected mutation-positive individuals. Most of what is known is based on retrospective review. Nurses are challenged to interpret this information, along with its inherent strengths and weaknesses, to individuals so they can make the best possible decisions. The psychosocial needs of those who undergo prophylactic surgery are not clearly understood. Surgery can have many psychological outcomes, and how individuals adjust to these changes is not clear. More nursing research is needed not only to understand these needs but also to design interventions to facilitate and improve adjustment to not only the information that one is mutation positive but also to prophylactic surgery. People who do not have cancer but have a high risk for cancer because of their genetic background need comprehensive and consistent care by knowledgeable healthcare providers. Although these individuals have not been diagnosed with cancer, they have complex psychosocial needs related to their family history and the decisions being made about prevention strategies. Oncology nurses can help fill this gap in care and provide the necessary support these individuals need.

24
UI - 11926405
AU - Zawacki KL; Phillips M
TI - Cancer genetics and women's health.
SO - J Obstet Gynecol Neonatal Nurs 2002 Mar-Apr;31(2):208-16
AD - School of Nursing, The Johns Hopkins University School of Nursing, Baltimore, MD 21205, USA. kzawadzki@son.jhmi.edu
It is now known that all cancer is genetic in origin. Although most cancer occurs by chance, approximately 5% of individuals inherit specific genetic mutations that predispose them to cancer. The genetic characteristics of some cancers are known. Such information can be useful to health care providers in the clinical setting for treatment, early detection, and prevention. This article reviews basic carcinogenesis as well as genetic syndromes that predispose women to breast, ovarian, colorectal, and endometrial cancer. Knowledge of hereditary cancer syndromes and familiarity with them will assist the advanced practice nurse in the management of patients who are at risk. Cancer continues to contribute substantially to the mortality of women in all age groups. Knowledge of these syndromes provides an excellent opportunity to decrease mortality by early detection and prevention.

25
UI - 12036858
AU - Thiede C; Steudel C; Mohr B; Schaich M; Schakel U; Platzbecker U; Wermke
TI - M; Bornhauser M; Ritter M; Neubauer A; Ehninger G; Illmer T Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis.
SO - Blood 2002 Jun 15;99(12):4326-35
AD - Medizinische Klinik und Poliklinik I, Universitatsklinikum Carl Gustav Carus der Technischen Universitat, Dresden, Germany. thiede@mk1.med.tu-dresden.de
Constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplication (ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (TKD), has been described in patients with acute myelogenous leukemia (AML). We analyzed the prevalence and the potential prognostic impact of FLT3 mutations in 979 AML patients. Results were correlated with cytogenetic data and the clinical response. FLT3-ITD mutations were found in 20.4% and FLT3-TKD mutations in 7.7% of the patients. Each mutation was associated with similar clinical characteristics and was more prevalent in patients with normal karyotype. Significantly more FLT3 aberrations were found in patients with FAB M5, and fewer were found in patients with FAB M2 and M6. Although less frequent in patients with cytogenetic aberrations, FLT3-ITDs were found in 13 of 42 patients with t(15;17) and in 9 of 10 patients with t(6;9). The prevalence of the ITD allele on the DNA level was heterogeneous, ranging from faint mutant bands in some patients to predominant mutant bands in others. Based on quantitative analysis, the mutant-wild-type (wt) ratio ranged from 0.03 to 32.56 (median, 0.78). Patients with a high mutant/wt ratio (ie, greater than 0.78) had significantly shorter overall and disease-free survival, whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations. Multivariate analysis confirmed a high mutant/wt ratio to be a strong independent prognostic factor. Taken together, these data confirm that FLT mutations represent a common alteration in adult AML. Constitutive activation may be associated with monocytoid differentiation. A high mutant/wt ratio in ITD-positive patients appears to have a major impact on the prognostic relevance.

26
UI - 12013617
AU - Andresen PA; Gedde-Dahl T Jr; Fausa O; Eide TJ; Heiberg A
TI - [Genetic analysis in familial adenomatous polyposis]
SO - Tidsskr Nor Laegeforen 2001 Jan 10;121(1):64-8
AD - Patologisk-anatomisk avdeling 9038 Regionsykehuset i Tromso. per.arne.andresen@rikshospitalet.no
BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder caused by germline mutations in the APC gene. FAP is characterised by a variable, but normally large number of colorectal adenomas and variations in extracolonic manifestations. These variations are associated with specific mutations of the APC gene. MATERIAL AND METHODS: Representatives from 70 Norwegian families are under molecular investigation. Analyses have so far been concentrated on the part of the APC gene associated with classic FAP. RESULTS: Germline mutations causing FAP have been identified in 36 of the 70 families examined. All mutations identified are confined to the first half of the gene and correlate to classic FAP. INTERPRETATION: Because of the mutation heterogeneity in FAP, the size of the APC gene and variations in phenotype, it is a laborious task to identify the causative mutations. Better approaches to the analysis of the whole APC have now been established and will result in a higher degree of mutation detection independent of phenotype. Family history and phenotype-genotype correlations are still important guidelines for efficient molecular genetic analysis of the APC gene. Genetic surveillance, personal and socio-economic benefits from presymptomatic and predictive testing of members of FAP families are discussed.

27
UI - 11965197
AU - Friedenson B
TI - A current perspective on genetic testing for breast and ovarian cancer: the oral contraceptive decision.
SO - MedGenMed 2001 Nov 2;3(6):2
AD - Department of Biochemistry and Molecular Biology at the University of Illinois at Chicago, Chicago, Illinois, USA. molmeddoc@Yahoo.com.
A clinician faces a problem in how best to counsel the woman with a family history of breast or ovarian cancer about her options for pregnancy prevention. The physician must guide her as she makes new and complex decisions. Recent data strongly support an amplified effect of the estrogens in oral contraceptives for the woman with a genetic risk for breast cancer. Nonetheless, a woman's immediate need to prevent pregnancy may be much more important to her than worrying about the long-term risk of breast cancer. Another factor is that oral contraceptives prevent ovarian cancer, so the physician may wish to prescribe them to protect her from ovarian cancer. In some genetic backgrounds, however, oral contraceptives not only do not prevent ovarian cancer, but they may raise the risk of breast cancer so significantly that they should not be taken. With other genetic backgrounds, oral contraceptives will protect the woman from ovarian cancer without much effect on her breast cancer risk. When does each of these cancer risks or benefits become significant? The clinician can provide an important benefit to a woman who must prevent pregnancy yet worries about her cancer risk. The physician can help her evaluate the evidence, with its gaps and uncertainties, in the context of her own preferences. To assist in this evaluation, this decision aid provides base-line estimates of the cancer risk that accompanies each of a woman's options. In some cases, genetic testing is likely to provide valuable information as she makes choices about contraception and the risks vs. benefits of different alternatives available to her.

28
UI - 11983287
AU - Revilla M; Obach V; Cervera A; Davalos A; Castillo J; Chamorro A
TI - A -174G/C polymorphism of the interleukin-6 gene in patients with lacunar infarction.
SO - Neurosci Lett 2002 May 10;324(1):29-32
AD - Service of Neurology, Hospital Clinic Universitari, Villarroel 170, 08036 Barcelona, Spain.
Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a central role in the pathogenesis of stroke. A base pair substitution -174G/C in the promoter region of the IL-6 gene regulates IL-6 gene expression. We compared the prevalence of this polymorphism in patients with lacunar stroke and in an age- and sex-matched cohort of asymptomatic controls. Eighty-two patients with lacunar stroke and 82 asymptomatic controls were prospectively assessed and genotyped for the -174G/C polymorphism in the promoter region of the IL-6 gene. Demographics and vascular risk factors were recorded in both groups. A brain computed tomography scan/magnetic resonance imaging confirmed the clinical diagnosis of lacunar stroke in all patients. The prevalence of CC genotype (18.3 vs. 7.3%, P=0.03), and the frequency of C allele (42.7 vs. 31.1%, P=0.03) were statistically significantly higher in patients with lacunar stroke than in asymptomatic controls. Expectedly, patients with lacunar stroke had a higher prevalence of vascular risk factors than asymptomatic controls. A logistic regression model showed that independent variables associated with lacunar stroke included history of hypertension (odds ratio (OR), 7.02; 95% confidence interval (95% CI), 3.11-15.81), diabetes (OR, 5.37; 95% CI, 1.52-8.89), hyperlipidemia (OR, 3.43; 95% CI, 1.04-11.25), smoking (OR, 5.84; 95% CI, 2.15-15.84), and CC genotype of the -174G/C IL-6 gene polymorphism (OR, 4.28; 95% CI, 1.22-15.00). These findings suggest that lacunar stroke might result from genetic susceptibility to inflammation-mediated damage in concert with atherosclerotic risk factors.

29
UI - 11983298
AU - Pendleton N; Payton A; van den Boogerd EH; Holland F; Diggle P; Rabbitt
TI - PM; Horan MA; Worthington J; Ollier WE Apolipoprotein E genotype does not predict decline in intelligence in healthy older adults.
SO - Neurosci Lett 2002 May 10;324(1):74-6
AD - Clinical Gerontology Group, Clinical Division I, University of Manchester, Hope Hospital, Stott Lane, Salford, M6 8HD, UK. npendlet@fs1.ho.man.ac.uk
There is evidence of a genetic influence on the decline in cognitive performance of older adults, although the mechanisms responsible are unknown. A group of 767 subjects of the Manchester University Age and Cognitive Performance longitudinal study volunteer group, followed up from 1985 to the present, were genotyped for apolipoprotein E (APOE). The data from this were related to cross-sectional and longitudinal trends in the Heim intelligence test score (AH4-1) using previously reported random-effects models (Neuropsychologia 39 (2001) 532). There were no significant differences in mean scores for presence compared with absence of the APOE4 or APOE2 genotypes (P=0.48 and P=0.51, respectively). This research does not demonstrate a link between intelligence and APOE genotype in older adults.

30
UI - 11983299
AU - Henderson JN; Crook R; Crook J; Hardy J; Onstead L; Carson-Henderson L;
TI - Mayer P; Parker B; Petersen R; Williams B Apolipoprotein E4 and tau allele frequencies among Choctaw Indians.
SO - Neurosci Lett 2002 May 10;324(1):77-9
AD - Department of Health Promotion Sciences, University of Oklahoma, Oklahoma City 73190, USA.
Apolipoprotein genotyping and tau haplotyping were carried out on a series of cases with dementia and controls from the Choctaw Nation of Oklahoma. Both the Apolipoprotein E4 allele frequency and the tau H2 haplotype frequency were low in the Choctaw compared with Caucasians and there was the possibility that the association between dementia and the E4 allele was weaker than in Caucasians.

31
UI - 11988340
AU - Green EK; Thaker U; McDonagh AM; Iwatsubo T; Lambert JC; Chartier-Harlin
TI - MC; Harris JM; Pickering-Brown SM; Lendon CL; Mann DM A polymorphism within intron 11 of the tau gene is not increased in frequency in patients with sporadic Alzheimer's disease, nor does it influence the extent of tau pathology in the brain.
SO - Neurosci Lett 2002 May 17;324(2):113-6
AD - Department of Psychiatry, University of Birmingham, Birmingham B15 2QZ, UK
There are numerous polymorphisms within the tau gene but these are in complete linkage disequilibrium and exist as two common extended haplotypes H1 and H2. We have investigated the frequency of these haplotypes in 83 cases of sporadic Alzheimer's disease (AD) using the +34 polymorphism in intron 11 of the tau gene as a marker of H1 and H2 haplotypes. The total amount of hyperphosphorylated tau protein (tau load), present as neurofibrillary tangles, neuropil threads or plaque neurites, was quantified in the frontal cortex of these patients and related to tau haplotype. We found no increase in H1H1 haplotype in this autopsy population of cases with AD compared to published control data. Stratification of cases for apolipoprotein E (APO E) genotype showed a slight, but not statistically significant, overrepresentation of epsilon 4 allele amongst bearers of H2 haplotype. There were no overall differences in tau load between haplotype groups though cases within each haplotype group bearing APO E epsilon 4 allele had a significantly higher tau load than those without epsilon 4 allele. Neither age at onset or duration of illness differed according to tau haplotype. We conclude that the frequency of tau gene H1 haplotype is not elevated in AD and possession of this has no impact upon the amount of tau pathology in AD.

32
UI - 11660778
AU - Cooper EB
TI - Testing for genetic traits: the need for a new legal doctrine of informed consent.
SO - MD Law Rev 1999;58(2):346-422

33
UI - 7886138
AU - Schutzer PJ
TI - Genetics and ethics.
SO - Pharos Alpha Omega Alpha Honor Med Soc 1995 Winter;58(1):26-31

34
UI - 12083151
AU - Jakobovits I
TI - Some modern responsa on medico-moral

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