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NCI CANCERLIT® Search: Genetic Counseling and Screening - September 2001
Last Modified: November 1, 2001

Table of Contents

CancerMail from the National Cancer Institute

1
UI - 21336783
AU - Bale SJ
TI - The morbid anatomy of the dermatologic genome: an update for the third millennium.
SO - J Cutan Med Surg 2001 Mar-Apr;5(2):117-25
AD - GeneDx, Inc., Rockville, Maryland 20850, USA. sherrib@genedx.com
BACKGROUND: Much progress has been made in recent years in the identification of genes underlying many hereditary skin diseases. OBJECTIVE: To provide an update on the status of the identification of genes involved in hereditary skin disorders and to compare the current standing with that in the last decade. METHODS: A review of the literature is presented here in a series of lists describing the chromosomal location, specific gene, clinical relevance, and availability of molecular-based genetic tests for each genodermatosis. RESULTS: Progress has been made in identifying the genes underlying many disorders of cornification, genodermatoses with malignant potential, bullous disorders, pigmentary disorders, disorders affecting the epidermal appendages and the dermis, and other miscellaneous genodermatoses. CONCLUSION: The great progress made toward the completion of the human gene sequence and the continued efforts of many clinical and molecular scientists to identify disease genes will make diagnosis of hereditary dermatological disorders more precise and allow accurate family counseling as well as possibly leading to more targeted therapies during this millennium.

2
UI - 21367597
AU - Lichanska AM; McGibbon D; Silvestri G; Hughes AE
TI - A physical and expression map of the D17S1810-D17S1353 region spanning the central areolar choroidal dystrophy locus.
SO - Cytogenet Cell Genet 2001;93(1-2):43-7
AD - Department of Medical Genetics, The Queen's University of Belfast, Belfast, Northern Ireland, UK. A.Lichanska@qub.ac.uk
Central areolar choroidal dystrophy (CACD) causes bilateral irreversible central visual loss in the 5th to 7th decades. The authors previously described a large pedigree with the disorder, which showed linkage to chromosome 17p13.2-->p13.1 between microsatellite markers D17S1353 and D17S1810. 17p13 is very rich in genes that cause retinal diseases. We have now constructed a detailed and ordered physical map of the critical CACD region which spans up to 2.4 Mb. The new transcript map contains thirteen genes and seven expressed sequence tags (ESTs) that are eye-expressed, and therefore are positional candidates. Several of these have been screened, but no disease-causing mutations were found in CACD patients. Copyright 2001 S. Karger AG, Basel

3
UI - 21341875
AU - Thomas G
TI - [Genetic counselling in Gastroenterology]
SO - Gastroenterol Clin Biol 2001 Apr;25(4 Suppl):B18-9
AD - INSERM U434, Fondation Jean-Dausset - CEPH, 27, rue Juliette-Dodu, 75010 Paris.

4
UI - 21341877
AU - Olschwang S
TI - [Digestive polyposes: genetic aspects]
SO - Gastroenterol Clin Biol 2001 Apr;25(4 Suppl):B26-30
AD - INSERM U434, Fondation Jean-Dausset-CEPH, 27, rue Juliette-Dodu, 75010 Paris.

5
UI - 21376189
AU - Severin DM; Leong T; Cassidy B; Elsaleh H; Peters L; Venter D; Southey M; McKay M
TI - Novel DNA sequence variants in the hHR21 DNA repair gene in radiosensitive cancer patients.
SO - Int J Radiat Oncol Biol Phys 2001 Aug 1;50(5):1323-31
AD - Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia.
PURPOSE: Radiation therapy is an important treatment modality for oncology patients. DNA sequence variants have so far been identified in only a few genes in radiosensitive cancer patients. Patients known to be clinically radiosensitive were tested for mutation of a gene involved in DNA double-strand break repair and sister chromatid cohesion--hHR21. METHODS AND MATERIALS: Clinically radiation-sensitive patients were accrued to the study after giving informed consent. Blood samples were obtained and lymphoblastoid cell lines established. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to amplify the hHR21 gene, and the DNA product was sequenced to identify any genetic abnormalities. Northern blot analysis, cell survival, and growth assays were performed on control cells and cells with hHR21 variants, and a restriction digest assay was developed to screen for carriers of a detected gene variant. RESULTS: The DNA sequence of the hHR21 gene was determined in 19 radiation-sensitive cancer patients. In 6 of the 19 patients, a thymidine (T) to cytosine (C) transition was detected at position 1440 of the hHR21 open reading frame (T1440C). This variant did not alter the amino acid sequence and was likely to be a polymorphism. One patient with a particularly severe radiation reaction had a second sequence variant immediately adjacent to the first. This was a guanine (G) to adenine (A) transition (G1441A), resulting in a change of the amino acid sequence (glycine --> arginine) in a portion of the protein conserved in evolution. This suggests that this DNA alteration may be biologically significant. Restriction digest with the HpaII enzyme confirmed the presence of both sequence variants on the same allele. CONCLUSIONS: We describe the first two DNA sequence variants ever found in the hHR21 gene, in patients with clinical radiation hypersensitivity. Although no direct evidence for the involvement of hHR21 alterations in the radiosensitivity of the cancer patients examined has been demonstrated, the possibility exists that homozygous mutations or other mutations of this gene could contribute to radiosensitivity. A simple test is described that could be applied to screening for these variants in relevant populations.

6
UI - 21395050
AU - Hemminki K
TI - Genetic Epidemiology--science and ethics on familial cancers.
SO - Acta Oncol 2001;40(4):439-44
AD - Department of Biosciences, Karolinska Institute, Huddinge, Sweden. kari.hemminki@cnt.ki.se
Genetic epidemiology provides data on cancer etiology, familial risks and genotype-specific risks. These data are useful for clinical counselling and gene identification. The studies require large, unbiased sample sizes and collaboration between research teams, nationally and internationally. A recent study on Nordic twins suggests that in colorectal, breast and prostate cancer, the inherited component ranges between 27 and 42%, far in excess of the known susceptibility genes. The data from the Swedish Family-Cancer Database, particularly on second cancers, also suggest that a main genetic component in cancer is polygenic. The results have implications for design of genetic studies and for clinical counselling.

7
UI - 21395051
AU - Sachs L; Taube A; Tishelman C
TI - Risk in numbers--difficulties in the transformation of genetic knowledge from research to people--the case of hereditary cancer.
SO - Acta Oncol 2001;40(4):445-53
AD - Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
Difficulties in communicating diagnostic information are exacerbated when the 'diagnosis' is a 'genetic risk' for cancer. The risk estimation demanded in this situation differs from other types of probability estimations. Observations of participants in 45 consultation sessions between physicians and potential patients were conducted at a clinic for hereditary cancer to explore the communication of genetic information. Thirty-three sessions were audiotaped, transcribed verbatim and analyzed, along with notes from the other sessions. A dominant theme was found to be numerical discussion of risk. Further analysis resulted in the description of problems for practitioners in the process of translating scientific knowledge into clinical management. Problems in providing information include unclear aims of the consultation sessions, mixing various types of background information and probabilities, recognizing how low the predictive values are, and difficulties in communicating the relationship between probability and conclusions. Problems in communicating information about the genetic risk for cancer are of at least two types: dilemmas arising from uncertainties implicit in the nature of the information itself and difficulties in communicating information in a manner that those concerned can interpret. These issues need clarification, so that information with far-reaching consequences can be made as clear and comprehensible as possible for those involved.

8
UI - 21255254
AU - Jass JR; Talbot IC
TI - Molecular and cellular biology of pre-malignancy in the gastrointestinal tract.
SO - Best Pract Res Clin Gastroenterol 2001 Apr;15(2):175-89
AD - Department of Pathology, University of Queensland Mayne Medical School, Herston Road, Herston, Queensland, 4006, Australia.
Important pathogenic alterations within established cancers are acquired during the pre-malignant stage. These genetic alterations can be grouped into specific neoplastic pathways that differ within and between anatomical sites. By understanding the mechanisms that determine the initiation and progression of each pathway, it will be possible to develop novel approaches to the diagnosis, prevention and treatment of cancer. This chapter outlines the principles underlying the molecular characterization of pre-malignant lesions, taking colorectal neoplasia as the main model. Copyright 2001 Harcourt Publishers Ltd.

9
UI - 21319740
AU - Lodder L; Frets PG; Trijsburg RW; Meijers-Heijboer EJ; Klijn JG; Duivenvoorden HJ; Tibben A; Wagner A; van der Meer CA; van den Ouweland AM; Niermeijer MF
TI - Psychological impact of receiving a BRCA1/BRCA2 test result.
SO - Am J Med Genet 2001 Jan 1;98(1):15-24
AD - Department of Medical Psychology and Psychotherapy, Erasmus University Rotterdam/Netherlands Institute for Health Sciences.
Mutation analysis for autosomal dominant hereditary breast/ovarian cancer genes (BRCA1/BRCA2) became an important technique for women at risk of carrying these mutations. Healthy female mutation carriers have a high lifetime risk for breast and/or ovarian cancer and may opt for frequent breast and ovary surveillance or prophylactic surgery (mastectomy and/or oophorectomy). Psychological distress was assessed in 78 healthy women at risk of having inherited a BRCA1/BRCA2 mutation opting for genetic testing and 56 partners several weeks prior to ("pre-test") and after ("post-test") learning about their DNA test result. Twenty-five women were found to be mutation carriers, and 53 were non-mutation carriers. One goal of the study was to identify individuals at risk for high distress in the weeks following disclosure of the test result. Interview transcripts were used to give a fuller picture of pre- and post-test distress. High post-test anxiety was reported by 20% of the mutation carrier women and by 35% of their partners. Eleven percent of women without the mutation and 13% of their partners reported high post-test anxiety levels. High post-test anxiety in women was significantly related to 1) a high level of pre-test anxiety and 2) being a mutation carrier. Women without a mutation who had a sister identified as a mutation carrier recently had higher post-test levels of depression than the other non-mutation carriers. It is suggested to consider seriously the need for psychological support in mutation carriers who had been anxious at pre-test already. For most non-mutation carriers, psychological follow-up might be of lesser importance, but those having a sister receiving an unfavorable test result should be informed about the possibility that they might not feel relief.

10
UI - 21392351
AU - Addar MH
TI - New trends in prenatal screening for chromosomal abnormalities.
SO - Saudi Med J 2000 May;21(5):429-32
AD - Ob/Gyn Department, King Khalid University Hospital, PO Box 7805, Riyadh 11472, Kingdom of Saudi Arabia.
In the recent years, the scope of prenatal genetic diagnosis has expanded greatly with the development of a number of new methods, such as maternal serum screening and ultrasound screening for detection of fetal abnormalities. These methods have the advantage of providing earlier diagnosis in addition to being non-invasive and of less psychological traumas. Pre-implantation genetic diagnosis is another new growing field offering the genetic diagnosis prior to implantation. The most promising of all is the first trimester biochemical screening in conjunction with ultrasound nuchal translucency screening.

11
UI - 21199889
AU - Peng S; Lu XM; Luo HR; Xiang-Yu JG; Zhang YP
TI - Melanocortin-1 receptor gene variants in four Chinese ethnic populations.
SO - Cell Res 2001 Mar;11(1):81-4
AD - Laboratory of Cellular and Molecular Evolution, Kunming Institute of Zoology, the Chinese Academy of Sciences.
There is strong relationship between melanocortin-1 receptor (MC1R) gene variants and human hair color and skin type. Based on a sequencing study of MC1R gene in 50 individuals from the Uygur, Tibetan, Wa and Dai ethnic populations, we discuss the occurrence of 7 mc1r variants consisting of 5 nonsynonymous sites (Val60Leu, Arg67Gln, Val92Met, Arg163Gln and Ala299Val) and 2 synonymous sites (C414T and A942G), among which C414T and Ala299Val were reported for the first time. Confirmation and analysis were also made of 122 individuals at three common point mutations (Val92Met, Arg163Gln, A942G) using PCR-SSCP. The frequency of Arg163Gln variant varies in the four ethnic populations, with percentage of 40%, 85.0%, 66.2% and 72.7%, respectively, while those of Val92Met and A942G are roughly similar in these four populations. The different environments, migration and admixture of various ethnic groups in China might have impact on the observed frequency of Arg163Gln.

12
UI - 21249992
AU - Sparks AB; Peterson SN; Bell C; Loftus BJ; Hocking L; Cahill DP; Frassica FJ; Streeten EA; Levine MA; Fraser CM; Adams MD; Broder S; Venter JC; Kinzler KW; Vogelstein B; Ralston SH
TI - Mutation screening of the TNFRSF11A gene encoding receptor activator of NF kappa B (RANK) in familial and sporadic Paget's disease of bone and osteosarcoma.
SO - Calcif Tissue Int 2001 Mar;68(3):151-5
AD - Molecular Genetics Laboratory, Johns Hopkins Oncology Center, Baltimore, MD, USA.
Paget's disease of bone (PDB) is a common disorder characterized by focal areas of increased and disorganized osteoclastic bone resorption, leading to bone pain, deformity, pathological fracture, and an increased risk of osteosarcoma. Genetic factors play an important role in the pathogenesis of Paget's disease. In some families, the disease has been found to be linked to a susceptibility locus on chromosome 18q21-22, which also contains the gene responsible for familial expansile osteolysis (FEO)--a rare bone dysplasia with many similarities to Paget's disease. Insertion mutations of the TNFRSF11A gene encoding Receptor Activator of NF kappa B (RANK) have recently been found to be responsible for FEO and rare cases of early onset familial Paget's disease. Loss of heterozygosity (LOH) affecting the PDB/FEO critical region has also been described in osteosarcomas suggesting that TNFRSF11A might also be involved in the development of osteosarcoma. In order to investigate the possible role of TNFRSF11A in the pathogenesis of Paget's disease and osteosarcoma, we conducted mutation screening of the TNFRSF11A gene in patients with familial and sporadic Paget's disease as well as DNA extracted from Pagetic bone lesions, an osteosarcoma arising in Pagetic bone and six osteosarcoma cell lines. No specific abnormalities of the TNFRSF11A gene were identified in a Pagetic osteosarcoma, the osteosarcoma cell lines, DNA extracted from Pagetic bone lesions, or DNA extracted from peripheral blood in patients with familial or sporadic Paget's disease including several individuals with early onset Paget's disease. These data indicate that TNFRSF11A mutations contribute neither to the vast majority of cases of sporadic or familial PDB, nor to the development of osteosarcoma.

13
UI - 21301480
AU - Johnston LB; Chew SL; Lowe D; Reznek R; Monson JP; Savage MO
TI - Investigating familial endocrine neoplasia syndromes in children.
SO - Horm Res 2001;55 Suppl 1():31-5
AD - St Bartholomew's Hospital, London, UK. l.b.johnston@mds.qmw.ac.uk
Familial endocrine neoplasia syndromes multiple endocrine neoplasia (MEN) type 1, MEN type 2 and von Hippel Lindau (VHL) can now be diagnosed genetically in childhood. Paediatric endocrinologists must therefore be prepared to investigate and manage these children. This paper provides an overview of the major features of these syndromes and suggests protocols for regular screening of children known to be at risk of developing these disorders. Copyright 2001 S. Karger AG, Basel.

14
UI - 21332237
AU - Spencer K
TI - Between pregnancy biological variability of first trimester markers of Down syndrome: implications for screening in subsequent pregnancies.
SO - Prenat Diagn 2001 Jun;21(6):445-7
AD - Endocrine Unit, Clinical Biochemistry Department, Harold Wood Hospital, Gubbins Lane, Romford, Essex RM3 0BE, UK. kevinSpencer1@cs.com
In a group of 149 women who had undergone routine first trimester screening using fetal nuchal translucency thickness (NT) and maternal serum free beta-hCG and pregnancy associated plasma protein-A (PAPP-A) in two consecutive pregnancies the within person between pregnancy biological variability of these markers has been assessed. For fetal NT there was no correlation between NT MoM in the first and second pregnancy (r=0.0800). For maternal serum free beta-hCG MoM a significant correlation was observed (r=0.4174) as was also found for PAPP-A MoM (r=0.3270). The implications for such between pregnancy marker association is that women who have an increased risk of Down syndrome in their first pregnancy are 1.5-2 times more likely to repeat this event in their next pregnancy. This observation may be useful in counselling women in the first trimester screening of a subsequent pregnancy. Copyright 2001 John Wiley & Sons, Ltd.

15
UI - 21339007
AU - Wang J; Liu ZL; Chen B
TI - Dopamine D5 receptor gene polymorphism and the risk of levodopa-induced motor fluctuations in patients with Parkinson's disease.
SO - Neurosci Lett 2001 Jul 27;308(1):21-4
AD - Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University of Medical Sciences, 510080, Guangzhou, China. jianwang@fudan.edu
Motor fluctuations are the most common complication of levodopa therapy for Parkinson's disease (PD). Genetic factors could play a role in determining the occurrence of motor fluctuations. To investigate whether dopamine receptor D5 (DRD5) T978C polymorphism is associated with the risk of developing motor fluctuations in PD, we studied this polymorphism in a case-control study of 120 subjects with sporadic PD and 110 control subjects. We found that the overall allelic and genotypic frequencies did not differ significantly between patients with PD and control subjects (all P>0.7), and between motor fluctuators (n=50) and non-motor fluctuators (n=50) (all P>0.8). It suggests that DRD5 T978C polymorphism is not associated with the susceptibility to PD, nor with the risk of developing motor fluctuations in PD. Therefore, other polymorphisms that alter the expression of the dopamine receptors should be further studied.

16
UI - 21369414
AU - Lalloo F; Evans G
TI - Molecular genetics and endometrial cancer.
SO - Best Pract Res Clin Obstet Gynaecol 2001 Jun;15(3):355-63
AD - Department of Clinical Genetics, St Mary's Hospital, Hathersage Rd, Manchester, M13 0JH, UK.
Endometrial cancer is the ninth most common malignancy in females. Inherited forms of this malignancy exist. Mutations in mismatch repair genes result in hereditary non-polyposis colorectal cancer, which confers a lifetime risk of bowel cancer between 60-80% and an endometrial cancer risk of up to 60%. Current screening involves the use of transvaginal ultrasound and hysteroscopy. Genetic testing for mutations in the mismatch repair genes is available, and if a pathogenic change is found within a family, predictive testing becomes available for unaffected family members. If blood samples from family members are unavailable, tumour blocks may be studied to assess microsatellite instability, a feature of mismatch repair gene mutations.While mutations in the mismatch repair genes are found in inherited endometrial cancer they are rarely seen in sporadic cancers. However, there are a range of somatic gene mutations that are currently being studied in order to provide insight into the pathogenesis of endometrial cancer. Copyright 2001 Harcourt Publishers Ltd.

17
UI - 21371428
AU - Hull SC; Prasad K
TI - Reading between the lines: direct-to-consumer advertising of genetic testing.
SO - Hastings Cent Rep 2001 May-Jun;31(3):33-5

18
UI - 21377737
AU - Maassen JA; Lemkes HH; Losekoot M
TI - [From gene to disease; 'maturity-onset diabetes of the young' (MODY), monogenetic inheritable forms of diabetes mellitus]
SO - Ned Tijdschr Geneeskd 2001 Jul 14;145(28):1352-3
AD - Afd. Moleculaire Celbiologie, Leids Universitair Medisch Centrum, Postbus 9503, 2300 RA Leiden. j.a.maassen@lumc.nl
Maturity-onset diabetes of the young (MODY) exhibits an autosomal dominant pattern of inheritance and can be divided in at least five subtypes (MODY 1 to 5), each subtype being caused by mutations in a specific gene. The unambiguous molecular diagnosis of the specific MODY subtype facilitates an early diagnosis of diabetes and can help to reduce the development of diabetic complications. Furthermore, MODY2 patients generally have a milder clinical course and fewer complications than MODY3 patients, who consequently require a more aggressive therapeutic approach.

19
UI - 21365244
AU - Mihai R
TI - Molecular influences in thyroid and parathyroid surgery.
SO - Best Pract Res Clin Endocrinol Metab 2001 Jun;15(2):177-88
AD - University Department of Surgery, Bristol Royal Infirmary, Bristol, UK.
Recent progress in molecular biology and genetics has made a major impact on the management of patients with multiple endocrine neoplasia syndromes MEN-1 and MEN-2. The understanding of the mechanisms involved in inherited thyroid and parathyroid tumours also offered valuable answers for other models of neoplasia. In addition, parathyroid surgery has witnessed rapid progress, from the cloning of the calcium receptor to the development of calcimimetics, a new class of drugs that could shift the management of hyperparathyroidism from surgical intervention to medical treatment. Laboratory techniques initially designed for research are more and more being used for clinical diagnosis. For example, the use of the polymerase chain reaction is currently being evaluated in the early diagnosis of metastatic thyroid carcinoma by identifying specific gene products in the local lymph nodes. This chapter attempts to convince the reader that molecular biology is no longer restricted to the laboratory but has an increasing impact on clinical decisions to which an endocrine surgeon is exposed. Copyright 2001 Harcourt Publishers Ltd.

20
UI - 97195534
AU - Serova OM; Mazoyer S; Puget N; Dubois V; Tonin P; Shugart YY; Goldgar D; Narod SA; Lynch HT; Lenoir GM
TI - Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes?
SO - Am J Hum Genet 1997 Mar;60(3):486-95
AD - International Agency for Research on Cancer, Lyon, France.
To estimate the proportion of breast cancer families due to BRCA1 or BRCA2, we performed mutation screening of the entire coding regions of both genes supplemented with linkage analysis of 31 families, 8 containing male breast cancers and 23 site-specific female breast cancer. A combination of protein-truncation test and SSCP or heteroduplex analyses was used for mutation screening complemented, where possible, by the analysis of expression level of BRCA1 and BRCA2 alleles. Six of the eight families with male breast cancer revealed frameshift mutations, two in BRCA1 and four in BRCA2. Although most families with female site-specific breast cancers were thought to be due to mutations in either BRCA1 or BRCA2, we identified only eight mutations in our series of 23 site-specific female breast cancer families (34%), four in BRCA1 and four in BRCA2. According to the posterior probabilities calculated for mutation-negative families, based on linkage data and mutation screening results, we would expect 8-10 site-specific female breast cancer families of our series to be due to neither BRCA1 nor BRCA2. Thus, our results suggest the existence of at least one more major breast cancer-susceptibility gene.

21
UI - 21060593
AU - Gorski B; Byrski T; Huzarski T; Jakubowska A; Menkiszak J; Gronwald J; Pluzanska A; Bebenek M; Fischer-Maliszewska L; Grzybowska E; Narod SA; Lubinski J
TI - Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.
SO - Am J Hum Genet 2000 Jun;66(6):1963-8
AD - Department of Genetics and Pathology, Hereditary Cancer Center, 70-115 Szczecin, Poland.
We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age <50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities-5382insC, C61G, and 4153delA-accounted for 51%, 20%, and 11% of the identified mutations, respectively.

22
UI - 21249655
AU - Newman LA; Kuerer HM; Hunt KK; Vlastos G; Ames FC; Ross MI; Singletary SE
TI - Educational review: role of the surgeon in hereditary breast cancer.
SO - Ann Surg Oncol 2001 May;8(4):368-78
AD - Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Up to 10% of the breast cancers detected in the United States are related to an inherited germline mutation, usually in the BRCA1 or BRCA2 genes, and the majority of these patients will at some point require surgical evaluation and/or treatment. Women who harbor a genetic predisposition for breast cancer face an increased risk for early onset disease, bilateral tumors, and other non-breast malignancies, such as ovarian cancer. These issues raise questions regarding the appropriate surveillance regimen, and the potential efficacy of risk reduction strategies that should be considered. Once a breast cancer diagnosis has been established, the prognosis appears to be similar to stage-controlled sporadic breast cancer, despite an increased prevalence of adverse primary tumor features. However, the role of breast conservation therapy for these patients and the optimal means of addressing the substantially increased risk for contralateral tumors is not yet defined. The reported literature in this area, including a discussion of the value of genetic counseling and genetic testing, is reviewed.

23
UI - 21303198
AU - Chang J; Hilsenbeck SG; Sng JH; Wong J; Ragu GC
TI - Pathological features and BRCA1 mutation screening in premenopausal breast cancer patients.
SO - Clin Cancer Res 2001 Jun;7(6):1739-42
AD - Breast Center, Baylor College of Medicine, Houston Texas 77030, and Departments of Medical Oncology and Pathology, National University of Singapore, Singapore 0511. jcchang@breastcenter.tmc.edu
PURPOSE: Risk calculations for carrying BRCA1/BRCA2 mutations are based on family history and the age of onset of cancers. However, women may carry these deleterious mutations without a strong family history. Additional criteria for risk estimation would be of value. It has been recently established that BRCA1-associated breast cancers are associated with poor tumor differentiation (TD3) and estrogen receptor (ER) negativity. The aim of this study is to determine whether morphological features of breast cancers in premenopausal patients (age < 45 years) could determine additional women who may benefit from BRCA1 screening. EXPERIMENTAL DESIGN: In a prospective, systematic study of 76 consecutive breast cancer patients (age < 45 years), genomic DNA was obtained from peripheral blood, and eight mutations in BRCA1 (10.5%) were found. Archival paraffin-embedded breast cancer specimens were then analyzed for tumor differentiation and ER status. RESULTS: In patients < 45 years of age, 25% (6 of 24) of ER-negative and TD3 breast cancers were found to harbor mutations in BRCA1. Only 5.6% (2 of 36) of BRCA1-associated breast cancers did not have this morphological profile, compared with 94.4% (34 of 36) patients without BRCA1 mutations, giving an odds ratio of 5.67 (95% confidence interval, 1.04-32; P = 0.05). Finally, only one patient with BRCA1 mutations had a significant family history. CONCLUSIONS: In patients with early-onset breast cancer, the use of morphological criteria provides an additional strategy to determine those patients who might benefit from genetic testing.

24
UI - 21416114
AU - Becker KF; Keller G; Hoefler H
TI - The use of molecular biology in diagnosis and prognosis of gastric cancer.
SO - Surg Oncol 2000 Jul;9(1):5-11
AD - Technische Universitaet Muenchen, Klinikum rechts der Isar, Institut fuer Pathologie, Munich, Germany. kf.becker@lrz.tum.de
The investigation of molecular and genetic changes in gastric cancer has brought new insights into the pathogenesis of the disease. Knowledge of the genetic abnormalities and altered molecules could be used for differential diagnosis in case of an unknown primary tumor, allows their evaluation as prognostic factors, and could open novel avenues for more specific clinical interventions. Clinically relevant molecules whose expression or structure is altered include the plasminogen activator and its inhibitor plasminogen activator inhibitor type 1, the cell cycle regulator cyclin E, epidermal growth factor, the apoptosis inhibitor bcl-2, the cell adhesion molecule E-cadherin, and the multifunctional protein beta-Catenin. In addition, genetic instability is commonly seen. Gene amplification and protein overexpression of the growth factor receptors c-erbB2 and K-sam may be prognostic factors for intestinal- and diffuse-type gastric cancer, respectively. There has long been evidence for a genetic predisposition to gastric cancer by epidemiological studies and case reports. Very recently, germ line mutations of E-cadherin have been identified that are responsible for a dominantly inherited from of diffuse-type gastric cancer and could be used to identify individuals that are at high risk. The clinical implications of the recent findings for diagnosis, prognosis, therapy, and risk assessment are discussed.

25
UI - 21414911
AU - Welch MA
TI - What genetic testing can tell you about breast cancer risk.
SO - JAAPA 2001 Mar;14(3):50-2, 57-8, 61
AD - M.D. Anderson Cancer Center, Houston, Tex., USA.

26
UI - 21414907
AU - Mayes JR
TI - Hard choices when breast cancer threatens.
SO - JAAPA 2001 Mar;14(3):6, 9

27
UI - 21351425
AU - The EUROCJD Group
TI - Genetic epidemiology of Creutzfeldt-Jakob disease in Europe.
SO - Rev Neurol (Paris) 2001 Jul;157(6-7):633-7
The prion protein gene was studied in patients with definite or probable Creutzfeldt-Jakob disease (CJD) registered by national CJD units of 6 European countries. The role of genetic factors in CJD was also investigated by comparing the frequencies of a family history of dementia and Parkinson's disease in CJD cases and matched controls. Codon 129 genotype was examined in 337 CJD cases of whom 73.2 p. 100 were homozygous for methionine, 10.9 p. 100 were homozygous for valine and 15.7 p. 100 were heterozygous. The genotype frequencies were not statistically different across countries. Future differences, if any, would constitute a meaningful signal for the surveillance of CJD in Europe. A prion protein gene mutation was found in 14.5 p. 100 of CJD cases; only 40 p. 100 of them had a known family history of CJD. The case-control study showed that positive family histories of dementia and Parkinson's disease were both associated with CJD. Although recall bias is the most likely explanation for this finding, the hypothesis that neurodegenerative diseases might share unknown genetic risk factors can also be considered.

28
UI - 21387552
AU - Tomkins J; Banner SJ; McDermott CJ; Shaw PJ
TI - Mutation screening of manganese superoxide dismutase in amyotrophic lateral sclerosis.
SO - Neuroreport 2001 Aug 8;12(11):2319-22
AD - Department of Neurology, University of Sheffield, E Floor, Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
Seventy-seven cases of ALS were screened for mutations in the manganese superoxide dismutase gene (SOD2). DNA was extracted from CNS tissue and screened using single stranded conformation polymorphism and heteroduplex analysis. No mutations were identified in the entire coding region of the SOD2 gene. The known polymorphism in the mitochondrial targeting sequence was identified. No association was found between this polymorphism and ALS. A further polymorphism was detected in the intronic sequence upstream of exon 4, though no association with ALS was demonstrated. We therefore conclude that mutations in SOD2 do not appear to cause ALS.

29
UI - 21387607
AU - Venken K; Meuleman J; Irobi J; Ceuterick C; Martini R; De Jonghe P; Timmerman V
TI - Caspr1/Paranodin/Neurexin IV is most likely not a common disease-causing gene for inherited peripheral neuropathies.
SO - Neuroreport 2001 Aug 8;12(11):2609-14
AD - Peripheral Neuropathy Group, Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology (VIB), B-2610 Antwerpen, Belgium.
Contactin associated protein 1 (Caspr1/Paranodin/Neurexin IV) is an axonal transmembrane molecule mainly localised at the paranodal junction. Since molecular alterations in septate-like junctions at the paranodes might have important consequences for the function of the nerve fiber, we considered that Caspr1 could be involved in the pathogenesis of inherited peripheral neuropathies. In this study, we physically mapped the Caspr1 gene on chromosome 17q21.1 and determined its genomic structure. We performed a mutation analysis of the Caspr1 gene in a cohort of 64 unrelated patients afflicted with distinct inherited peripheral neuropathies. Since no disease causing mutations were found, we suggest that Caspr1 is probably not a common cause of inherited peripheral neuropathies.

30
UI - 21400201
AU - Fonesca R; Oken MM; Greipp PR; Eastern Cooperative Oncology Group Myeloma Group
TI - The t(4;14)(p16.3;q32) is strongly associated with chromosome 13 abnormalities in both multiple myeloma and monoclonal gammopathy of undetermined significance.
SO - Blood 2001 Aug 15;98(4):1271-2

31
UI - 21396251
AU - Berry DA
TI - Role of population-based studies in assessing genetic cancer risk.
SO - J Natl Cancer Inst 2001 Aug 15;93(16):1188-9

32
UI - 21396264
AU - Loman N; Johannsson O; Kristoffersson U; Olsson H; Borg A
TI - Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer.
SO - J Natl Cancer Inst 2001 Aug 15;93(16):1215-23
AD - Department of Oncology, Lund University Hospital, Sweden. Niklas.Loman@onk.lu.se
BACKGROUND: BRCA1 and BRCA2 are the two major susceptibility genes involved in hereditary breast cancer. This study was undertaken to provide reliable population-based estimates of genetic influence and to characterize the nature and prevalence of BRCA1 and BRCA2 germline mutations in early-onset breast cancer. METHODS: In a series comprising all women diagnosed with breast cancer under the age of 41 years in southern Sweden during 1990 through 1995 (n = 262), family history of cancer was evaluated in 95% (n = 250) of the case subjects and germline mutations in BRCA1 and BRCA2 were analyzed in 89% (n = 234). All statistical tests were two-sided. RESULTS: A total of 97 case subjects had at least one first- or second-degree relative with breast or ovarian cancer; 34 (14%; 95% confidence interval [CI] = 9.6% to 18%) cases had at least two first- or second-degree relatives, 22 (8.8%; 95%CI = 5.3% to 12%) had one first-degree relative, and 41 (16%; 95% CI = 12% to 21%) had one second-degree relative with either cancer. If two females affected with breast or ovarian cancer who were related through an unaffected male were also defined as first-degree relatives, then a higher number of case subjects, 120 (48%; 95% CI = 42% to 54%), had at least one first-degree or second-degree relative with breast or ovarian cancer. Sixteen (6.8%; 95% CI = 4.0% to 11%) BRCA1 mutation carriers and five (2.1%; 95% CI = 0.70% to 4.9%) BRCA2 mutation carriers were identified. Among case subjects with one first- or more than one first- or second-degree relative with breast or ovarian cancer, BRCA mutations were more frequent (P<.001) than among the case subjects without this degree of family history. BRCA mutations were also statistically significantly more common among women with bilateral breast cancer than among women with unilateral breast cancer (P =.002). BRCA mutations were more common among younger case subjects than among older ones (P =.0027). CONCLUSIONS: Almost half (48%) of women in southern Sweden with early-onset breast cancer have some family history of breast or ovarian cancer, and 9.0% of early-onset breast cancer cases are associated with a germline mutation in BRCA1 or BRCA2. Mutation carriers were more prevalent among young women, women with at least one first- or second-degree relative with breast or ovarian cancer, and women with bilateral breast cancer.

33
UI - 21413768
AU - Takayama T; Ohi M; Hayashi T; Miyanishi K; Nobuoka A; Nakajima T; Satoh T; Takimoto R; Kato J; Sakamaki S; Niitsu Y
TI - Analysis of K-ras, APC, and beta-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis.
SO - Gastroenterology 2001 Sep;121(3):599-611
AD - Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
BACKGROUND & AIMS: We have previously shown that aberrant crypt foci (ACF) are the putative precursor lesions of colorectal adenomas and subsequent cancer in humans using magnifying endoscopy. The present study was designed to investigate these genetic alterations in ACF biopsy specimens from normal subjects, familial adenomatous polyposis (FAP) or sporadic patients. METHODS: The non-FAP cases included 34 normal subjects, 35 colorectal adenoma patients, and 19 colorectal cancer patients; there were 4 FAP patients. Biopsies were performed on ACF by magnifying endoscopy. K-ras mutations were analyzed by 2-step polymerase chain reaction and restriction fragment length polymorphism, APC mutations by in vitro-synthesized protein assay, and beta-catenin mutations by direct sequencing. Full-length APC and beta-catenin were detected by immunofluorescence. RESULTS: In non-FAP cases, K-ras mutations were detected in 82% (89/106) of nondysplastic ACF and 63% (17/27) of dysplastic ACF. APC mutation and beta-catenin accumulation were not detected in non-FAP ACF, whereas in adenoma of these patients, positivity of APC mutation and beta-catenin accumulation were 78% (24/31), and that of K-ras mutation was 65% (20/31). FAP patients showed K-ras mutations in only 13% (1/8) of dysplastic ACF, which is the predominant form of ACF found in FAP. In FAP patients, somatic APC mutations were found in 100% of dysplastic ACF, as they are in adenoma. The frequency of K-ras mutations was 73% (8 of 11) in FAP adenoma. CONCLUSIONS: The data suggest that in sporadic colorectal carcinogenesis, assuming the biological implication of ACF as a precursor of adenomas, there is a route where K-ras mutation mainly occurs during the formation of ACF, which then become adenomas wherein APC mutation occurs. In FAP, however, somatic mutation of APC predominantly occurs during ACF formation, followed by K-ras mutation.

34
UI - 21433656
AU - Schwartz MD; Benkendorf J; Lerman C; Isaacs C; Ryan-Robertson A; Johnson L
TI - Impact of educational print materials on knowledge, attitudes, and interest in BRCA1/BRCA2: testing among Ashkenazi Jewish women.
SO - Cancer 2001 Aug 15;92(4):932-40
AD - Department of Oncology, Georgetown University, 2233 Wisconsin Avenue NW, Washington, DC 20007, USA. schwartm@georgetown.edu
BACKGROUND: The recent identification of several BRCA1/BRCA2 founder mutations among Ashkenazi Jewish individuals has led to increased salience of BRCA1/BRCA2 testing for Jewish individuals. Little is known about interest in BRCA1/BRCA2 testing among Ashkenazi Jews from the general population. Furthermore, previous research has not generally evaluated the impact of education on interest in testing among individuals from the general population. The goal of the current study was to examine whether a brief educational booklet regarding BRCA1/BRCA2 testing would influence knowledge, attitudes, and interest in testing among Ashkenazi Jewish women from the general population. METHODS: After a baseline telephone interview, participants were randomized to receive either genetic testing educational print materials (n = 195 women) or general breast cancer education control materials (n = 196 women). One month after receiving these materials, the authors reassessed knowledge, attitudes, and interest in BRCA1/BRCA2 gene testing. RESULTS: Relative to the breast cancer education control materials, the genetic testing education materials led to increased knowledge, increased perception of the risks and limitations of testing, and decreased interest in obtaining a BRCA1/BRCA2 mutation test. CONCLUSIONS: These data indicate that preliminary print education can be used to educate low-risk individuals about BRCA1/BRCA2 genetic testing. This approach may be used to educate low-risk individuals about the benefits and risks/limitations of BRCA1/BRCA2 testing, so that they can make informed decisions about whether to pursue genetic counseling. Copyright 2001 American Cancer Society.

35
UI - 21422437
AU - Feith GW
TI - [From gene to disease; from polycystines to polycystic kidney disease]
SO - Ned Tijdschr Geneeskd 2001 Apr 7;145(14):708

36
UI - 21239095
AU - Pigullo S; Maria ED; Marchese R; Assini A; Bellone E; Scaglione C; Vitale C; Bonuccelli U; Barone P; Ajmar F; Martinelli P; Abbruzzese G; Mandich P
TI - No evidence of association between CAG expansions and essential tremor in a large cohort of Italian patients.
SO - J Neural Transm 2001;108(3):297-304
AD - Department of Oncology, Biology and Genetics, University of Genova, Italy.
Essential tremor (ET) is one of the most common movement disorders. However the pathogenesis is as yet unknown, although a genetic cause has long been recognised. Clinical and molecular evidences suggested that the ET gene might contain a CAG expanded region. In a cohort of Italian ET patients Repeat Expansion Detection (RED) approach did not demonstrate large CAG expansions. We extended the study towards specific targets: the channel proteins hSKCa3 and CACNL1A4. Direct assessment of CAG stretches within these two genes did not demonstrate any CAG expansion in affected subjects. Also a case-control analysis failed to reveal any evidence of association, thus excluding these genes as a cause of ET.

37
UI - 21239096
AU - Nishimura AL; Oliveira JR; Otto PA; Matioli SR; Brito-Marques PR; Bahia VS; Nitrini R; Zatz M
TI - No evidence of association between the D10S1423 locus and Alzheimer disease in Brazilian patients.
SO - J Neural Transm 2001;108(3):305-10
AD - Center of the Study of the Human Genome, Department of Biology, Institute of Biosciences, University of Sao Paulo, Brazil.
In a genome survey for Alzheimer's disease (AD), Zubenko et al. (1998) reported that the 234bp allele of the D10S1423 locus was more frequent among AD cases than in controls. We have analyzed this polymorphic locus in patients and healthy controls and observed that the 226bp allele is the most frequent allele in the D10S1423 locus in Brazilian AD patients. However, no statistically significant association between any D10S1423 allele was observed in AD patients as well as in controls.

38
UI - 21408466
AU - Molero AE; Pino-Ramirez G; Maestre GE
TI - Modulation by age and gender of risk for Alzheimer's disease and vascular dementia associated with the apolipoprotein E-varepsilon4 allele in Latin Americans: findings from the Maracaibo Aging Study.
SO - Neurosci Lett 2001 Jul 6;307(1):5-8
AD - Institute for Biological Research and Cardiovascular Center, Faculty of Medicine, University of Zulia, Apdo. Postal 10.636, Maracaibo 4002-a, Venezuela.
An ongoing longitudinal study in Maracaibo, Venezuela, examined the interaction between apolipoprotein E (APOE) genotypes and Alzheimer's disease (AD) and vascular dementia (VD), evaluating age and gender as potential modifiers of risk. Overall, carriers of at least one varepsilon4 allele were at higher risk for AD, not for VD; however, the risk was significant only for subjects older than 65, and it increased 10-fold in subjects older than 85. The risk of AD conferred by APOE-varepsilon4, adjusted for age and stratified by gender, was significant only for women. No association was found between the varepsilon-2 allele and AD or VD. The results support the notions that APOE-varepsilon4 is relevant for late-onset, not early onset AD, and that age and gender act as modulators of this association.

39
UI - 21419036
AU - Gui GP; Hogben RK; Walsh G; A'Hern R; Eeles R
TI - The incidence of breast cancer from screening women according to predicted family history risk: Does annual clinical examination add to mammography?
SO - Eur J Cancer 2001 Sep;37(13):1668-73
AD - Department of Academic Surgery, Royal Marsden NHS Trust and Institute of Cancer Research, London, UK. gerald.gui@rhm.nthames.nhs.uk
In breast cancer, mutations of predisposition genes such as BRCA-1/2 and other genes as yet uncharacterised are manifest in up to 10% of cases. Although the prior probability of the presence of a breast cancer predisposing gene can be calculated for individual women, there is no published evidence to justify predicted risk as a selection criteria for screening. This study aims to define which patient groups with a significant family history should be screened, and whether clinical examination is necessary in addition to mammography. The Claus model was used to predict breast cancer risk in women with a family history. Women were divided into two groups according to their predicted risk: group I consisted of women at standard risk (lifetime risk less than 1:6) and group II with moderate/high risk (lifetime risk greater than or equal to 1:6). Women were cancer-free at the point of entry, and screening consisted of annual clinical examination and mammography from the age of 35 years. This study consisted of 1500 women in group I and 1078 in group II. The period of observation was 5902.0 and 4327.8 women years, respectively. A total of 31 cancers were detected, 12 in group I and 19 in group II. The median age at diagnosis in group II was 45 years (range 26-66 years) compared with 54.5 years (range 38-63 years) in group I (P=0.03). The relative risk of developing breast cancer in group II was 2.6 (95% confidence interval (CI) 1.2-5.8). When compared with breast cancer incidence in the normal population, the standardised incidence ratio in group II was significantly higher at 2.8 (95% CI: 1.7-4.2). The standardised incidence ratio of women in group I was similar to that of the general population (1.1 (95% CI: 0.6-1.8)). A total of 26/31 (84%) cancers detected were palpable, of which 14 (54%) were not visible on mammography. Approximately one-third of all palpable cancers were detected at ro

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