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J N Weitzel

Publications and source records attributed to J N Weitzel.

At least 19 recordsLinked to original sources
PubMed2004

Genetic discrimination: the clinician perspective.

Clinicians attending continuing education sessions in California were surveyed about their beliefs and attitudes regarding genetic discrimination and their knowledge of protective legislation. Two hundred seventy-one surveys were collected from physicians (n = 191) and nurses (n = 80). Most respondents lacked information or were misinformed about the existence of protective legislation (58.3%) or published cases of insurance discrimination (85.2%); 52.4% believed that mutation carriers have difficulty obtaining health insurance; 13% would not encourage genetic testing, despite a family history of cancer. Clinician concerns about potential genetic discrimination, and lack of information regarding protective legislation, may influence access to care.

Genetic Counseling↗
PubMed2004

Effects of a cancer genetics education programme on clinician knowledge and practice.

BACKGROUND: Many clinicians lack adequate knowledge about emerging standards of care related to genetic cancer risk assessment and the features of hereditary cancer needed to identify patients at risk. OBJECTIVE: To determine how a clinical cancer genetics education programme for community based clinicians affected participant knowledge and changed clinical practice. METHODS: The effects of the programme on participant knowledge and changes in clinical practice were measured through pre and post session knowledge questionnaires completed by 710 participants and practice impact surveys completed after one year by 69 out of 114 eligible annual conference participants sampled. RESULTS: Respondents showed a 40% average increase in specific cancer genetics knowledge. Respondents to the post course survey reported that they used course information and materials to counsel and refer patients for hereditary cancer risk assessment (77%), shared course information with other clinicians (83%), and wanted additional cancer genetics education (80%). CONCLUSIONS: There was a significant immediate gain in cancer genetics knowledge among participants in a targeted outreach programme, and subset analysis indicated a positive long term effect on clinical practice. Clinician education that incorporates evidence based content and case based learning should lead to better identification and care of individuals with increased cancer risk.

Curriculum↗
PubMed2002

The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population.

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906G-->C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P=.042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P=.033). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria.

Alanine↗
PubMed2000

The HRAS1 minisatellite locus and risk of ovarian cancer.

Approximately 10% of ovarian cancers are due to mutations in highly penetrant inherited cancer susceptibility genes. The highly polymorphic HRAS1 minisatellite locus, located just downstream from the proto-oncogene H-ras-1 on chromosome 11p, consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. Mutant alleles of this locus represent a major risk factor for cancers of the breast, colorectum, and bladder, and it was found that BRCAI mutation carriers with at least one rare HRAS1 allele have a greater risk of ovarian cancer than BRCA1 carriers with only common HRAS1 alleles. There are no conclusive studies of HRAS1 alleles in sporadic epithelial ovarian cancer. A case-control study of HRAS1 alleles was performed on DNA from 136 Caucasian patients with ovarian cancer and 108 cancer-free controls using conventional (Southern blot) and PCR-based methods to determine the frequency of rare HRAS1 alleles. Odds ratios (ORs) were estimated using unconditional logistic regression methods. A single degree of freedom test was used to assess the significance of linear trend across categories of increasing exposure. A statistically significant association between rare HRAS1 alleles and risk of ovarian cancer was observed [OR, 1.70; 95% confidence interval (CI), 1.03-2.80; P = 0.04]. Having only one rare allele was associated with a relative risk of 1.66 (95% CI, 0.91-3.01), whereas having two rare alleles increased the relative risk to 2.86 (95% CI, 0.75-10.94; trend P = 0.03). Analysis of HRAS1 allele types by the age of the case at diagnosis revealed that younger cases (<45 years) had a borderline statistically significant increased association with rare HRAS1 alleles compared to older cases (> or = 0 years; OR, 1.89; 95% CI, 0.90-3.98; P = 0.09). Rare HRAS1 alleles contribute to ovarian cancer predisposition in the general population. Thus, the HRAS1-variable number of tandem repeats locus may function as a modifier of ovarian cancer risk in both sporadic and hereditary ovarian cancer.

Alleles↗
PubMed1999

Genetic cancer risk assessment. Putting it all together.

Dramatic advances in our understanding of the genetic basis for cancer have led to the development of new technologies and tools for genetic cancer risk assessment. Yet, cancer is a complex disorder, and risk assessment, counseling, and management strategies need to consider several important domains: state of cancer genetics knowledge, state of mind (previous cancer experience within the family), state of technology, and state of the art in terms of management. There are several barriers to the efficient identification and counseling of patients and families at high risk for cancer because of inherited susceptibility mutations. Chief among these concerns is the lack of access to competent counseling and education services that are equipped to handle the complex and rapidly evolving medical, technological, and ethical issues. Cancer risk assessment is developing into a distinct discipline in which established empiric risk models are recast along with rapidly evolving genetic technologies for estimation of individual cancer risk. Cancer genetics consultants are an important resource for primary care physicians, gynecologists, surgeons, and oncologists. However, no formal qualification criteria exist for either physicians or allied health care professionals who subspecialize in this new field. This article covers the unique domains of cancer genetics in health care and surveys models for delivery of cancer genetics services and tools for risk assessment. Coupled with innovative cancer diagnostic and preventive services and research, we have the potential to make great strides in cancer prevention and control.

Education, Medical, Continuing↗
PubMed1999

The current social, political, and medical role of genetic testing in familial breast and ovarian carcinomas.

Few advances in medical science have yielded as much publicity and controversy as discoveries in genetics. Moving quickly from the bench to the bedside, genetic testing for inherited susceptibility to breast and ovarian cancer has had a significant impact on our paradigms for decisions about the treatment and prevention of disease. Assessment of cancer risk is developing into a distinct discipline, with rapidly evolving genetic technologies and models for estimating an individual's risk of cancer. Exciting developments in chemoprevention of breast cancer demonstrate the potential to offer a broader range of options for decreasing cancer risk. This article will consider recent advances in the understanding of cancer genetics, and describe the state-of-the-art in terms of management of individuals with inherited susceptibility to breast and ovarian cancer.

Breast Neoplasms↗
PubMed1998

Folate depletion impairs DNA excision repair in the colon of the rat.

BACKGROUND/AIMS: Diminished folate status appears to promote colonic carcinogenesis by, as of yet, undefined mechanisms. Impaired DNA repair plays a significant role in the evolution of many colon cancers. Since folate is essential for the de novo synthesis of nucleotides and since folate depletion has previously been associated with excessive DNA strand breaks, it was hypothesised that folate depletion may impair DNA repair. Studies were therefore performed to examine whether folate depletion affects the two major categories of DNA repair. METHODS: Study 1: eight weanling male Sprague-Dawley rats were fed on diets containing either 0 or 8 mg folate/kg diet with 1% succinylsulphathiazole for four weeks. After viable colonocytes had been harvested, DNA excision repair was evaluated by a single cell gel electrophoresis assay. Study 2: eighteen animals were fed on similar diets for five weeks. Also in study 2, 18 additional rats were fed on the same defined diet without succinylsulphathiazole for 15 weeks. Weekly injections with the procarcinogen, 1,2-dimethylhydrazine (20 mg base/kg), were administered to the latter group of animals. Five microsatellite loci from different chromosomes were investigated for instability in hepatic and colonic DNA. RESULTS: In study 1, a significantly retarded rate of DNA excision repair was observed in the folate deficient colonocytes compared with controls (p < 0.05). In study 2, there was no evidence of instability at the five microsatellite loci associated with either short or long term folate depletion. CONCLUSIONS: Folate deficiency impairs DNA excision repair in rat colonic mucosa; a similar degree of deficiency, even when administered in conjunction with a colonic carcinogen, did not produce evidence of a widespread defect in mismatch repair.

1,2-Dimethylhydrazine↗
PubMed1997

A novel 4-cM minimally deleted region on chromosome 11p15.1 associated with high grade nonmucinous epithelial ovarian carcinomas.

Prior cytogenetic and restriction fragment length polymorphism studies have demonstrated that allelic deletion of chromosome 11p is common in human invasive epithelial ovarian tumors. To construct a highly detailed deletion map of chromosome 11p, we used 13 polymorphic microsatellite CA repeat primers to identify regions harboring potential tumor suppressor genes. Twenty-three of 48 samples (48%) of invasive epithelial ovarian cancer showed LOH involving at least one locus, consistent with prior studies. None of the five mucinous tumors showed allelic deletion at any of the 13 primers, suggesting that loss of heterozygosity at chromosome 11p may not be involved in the pathogenesis of mucinous ovarian cancer. Two separate minimally deleted regions were identified in nonmucinous ovarian cancer. The first is an 11-cM region on chromosome 11pl5.5-15.3 that extends from D11S2071 to D11S988 and includes the HRAS locus. The second is a novel 4-cM region on 11p15.1, defined by marker D11S1310. Deletion of both regions at 11p15.5-15.3 and 11p15.1 is strongly associated with high grade nonmucinous epithelial ovarian cancer.

Chromosome Deletion↗
PubMed1996

Genetic counseling for familial cancer risk.

Public interest in genetic screening is greater than ever. Guided by clues in the pedigree, clinicians can refer selected patients for an intensive genetic workup. Despite the limited number of DNA-based tests and the dearth of effective preventive strategies, patients can benefit from existing risk assessment, surveillance, prevention, and counseling.

Base Sequence↗
PubMed1995

Allelic loss at 7q31.1 in human primary ovarian carcinomas suggests the existence of a tumor suppressor gene.

We studied loss of heterozygosity (LOH) in chromosome 7q in order to determine the location of a putative tumor suppressor gene (TSG) in human epithelial ovarian carcinomas. Samples were obtained from 26 primary ovarian carcinomas at the time of staging laparotomy. Paired normal and tumoral DNAs were used as templates for polymerase chain reaction amplification of a set of 14 (C-A)n microsatellite repeats on 7q21-qter. All the cases studied presented LOH at one or more loci on 7q. Seventy-three percent LOH (in 14 of 19 informative cases) were detected in D7S522 at 7q31.1. The percentages of LOH were normally distributed around microsatellite D7S522 determining a smallest common deleted region of 1 cM. The high incidence of LOH in primary ovarian carcinomas suggests that a TSG relevant to the development of ovarian cancers is present at 7q31.1, confirming our previous functional evidence for a TSG in this region.

Adult↗
PubMed1994

Molecular genetic changes associated with ovarian cancer.

Multiple specific chromosomal deletions can be found in human epithelial ovarian cancer by cytogenetic analysis or molecular techniques. Somatic allelic deletion or loss of heterozygosity (LOH) in a tumor is considered circumstantial evidence for the location of tumor suppressor genes. We have examined 27 primary epithelial ovarian tumors for the presence of LOH at 19 polymorphic markers on chromosomes 1, 5, 6, 9, 11, 13, and 17. Markers near the adenomatous polyposis coli (APC) gene at 5q21 showed LOH in 50% (10/20) of informative cases. LOH was seen in 53% (8/15) at the IFNA locus on 9p, another region implicated in other tumors, but not previously associated with ovarian cancer. We observed LOH for markers on 11p15 in 50% (12/24) of ovarian cancer DNAs from informative cases, while only 25% (4/16) at 11q13 and 29% (5/17) at 11q24 showed LOH. Only a portion of distal 11p was deleted in six cases. The incidence of LOH (50%) at HGH (17q22-q24) was greater than that at D17S579 (39%; 17q21), a locus tightly linked to BRCA1. Sixty-four percent (7/11) showed allelic loss at 17p11. LOH was infrequently observed at markers on chromosomes 1, 6, and 13q. Most cases showing LOH were stage III or IV, and most showed LOH at more than one locus. These studies support the concept that multiple genetic loci are involved in ovarian tumorigenesis. Two additional regions thought to harbor genes important in other cancers, 5q21 and 9p21, can now be added to the growing spectrum of molecular alterations seen in ovarian cancer.

Adult↗
PubMed1994

A single P1 clone bearing three genes from human chromosome 11p15.5: HRC1, HRAS1, and RNH.

Molecular genetic alterations of chromosome 11p15.5 are a common finding in human cancer. We previously reported the characterization of two cosmids representing a 55-kilobase (kb) region of DNA surrounding the protooncogene HRAS1. A cluster of genes was identified adjacent to this locus, and one of these genes, HRC1, was divergently transcribed 30 kb upstream from HRAS1. A recent report placed the gene for placental ribonuclease inhibitor (RNH, ribonuclease-angiogenin inhibitor) within 90 kb of HRAS1 by pulsed-field gel electrophoresis (PFGE) mapping. We used recombinant P1 bacteriophage clones for physical mapping to determine the position of RNH relative to the HRAS1 transcription unit and HRC1 on chromosome 11p15.5. PFGE and Southern analysis of genomic DNA suggested the order of the genes (HRC1-HRAS1-RNH). P1 clones confirmed this assignment, and placed RNH within 30-50 kb of the 3' end of HRAS1. Furthermore, a single 80-kb P1 clone that bears all three genes was isolated and clarified the Not I restriction map for the HRAS1-RNH interval. Their close physical association was predicted by simple screening of an arrayed P1 library; the clone containing all three genes was selected from multiple positive signals obtained for each HRC1 and RNH because it mapped to the same library-well address.

Bacteriophage P1↗
PubMed1992

The HRAS1 gene cluster: two upstream regions recognizing transcripts and a third encoding a gene with a leucine zipper domain.

We have cloned and characterized a 55-kb region of DNA surrounding HRAS1. It contains a cluster of two, and possibly three, genes associated with CpG islands within the 32 kb immediately upstream of HRAS1. We have sequenced cDNAs representing one of these genes, provisionally designated HRC1. The locus, which is located 29 kb upstream of HRAS1, is divergently transcribed. HRC1 cDNA probe recognizes fragments on Southern blots of DNA from other vertebrate species. In human DNA, multiple homologous fragments are detected in addition to the predicted ones containing HRC1. Therefore, this locus may represent a member of an evolutionarily conserved gene family. HRC1 expression is upregulated with HRAS1 in the EJ bladder carcinoma cell line, suggesting the possibility of coordinate regulation. The deduced translational product of the longest open reading frame (1119 nucleotides, 373 amino acids) predicts a protein with regions rich in glutamine and proline and a region similar to the helix-loop-helix motif adjacent to a carboxy-terminal leucine zipper dimerization motif with four heptad repeats. Alternate splicing of terminal exons occurs, resulting in the truncation of one proline-rich domain and preservation of the leucine zipper. Thus, a biologically important region of chromosome 11p consists of a gene cluster. At least one of these genes, in addition to HRAS1, may be involved in regulation of cell growth or differentiation.

Amino Acid Sequence↗
PubMed1990

Surreptitious ingestion of a long-acting vitamin K antagonist/rodenticide, brodifacoum: clinical and metabolic studies of three cases.

The vitamin K metabolism of three patients with factitious purpura due to brodifacoum ingestion was studied. These patients, who presented with bleeding disorders due to deficiency of the vitamin K-dependent blood clotting proteins, were refractory to vitamin K1 at standard doses and required fresh frozen plasma to control bleeding until large doses of vitamin K1 were used. Metabolic studies demonstrated a blockade in vitamin K utilization, consistent with the presence of a vitamin K antagonist, but the patients denied use of anticoagulants. Warfarin assays were negative. We show that the factitious purpura in each patient was due to the surreptitious ingestion of brodifacoum, a potent second generation long-acting vitamin K antagonist used as a rodenticide. The coagulopathies responded to long-term therapy with large doses of vitamin K1. The serum elimination half-time for brodifacoum ranged from 16 to 36 days in these patients. The anticoagulant effect is of long duration, requiring chronic vitamin K treatment. With increasing availability of new rodenticides, factitious purpura due to surreptitious ingestion of these potent vitamin K antagonists is emerging as a new problem, previously associated with warfarin, with important implications for diagnosis and treatment.

4-Hydroxycoumarins↗
PubMed1988

A unique case of breast carcinoma producing pancreatic-type isoamylase.

A 71-yr-old woman with a widely metastatic lipid-rich variant of breast cancer was found to have striking hyperamylasemia (85-fold normal). By isoelectric focusing, agarose gel electrophoresis, and a wheat protein inhibitor assay, the predominant serum amylase appeared to be identical to pancreatic isoamylase. Serum trypsin, serum lipase, and an abdominal computed tomography scan were normal, excluding the possibility of pancreatitis. Furthermore, both the primary breast tumor and skin metastases that developed 10 yr later stained immunohistochemically for amylase. Thus, breast carcinoma must be added to the list of tumors causing ectopic hyperamylasemia, and this case shows that nonpancreatic malignancies may produce pancreatic-type hyperamylasemia.

Aged↗