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O Serova

Publications and source records attributed to O Serova.

16 recordsLinked to original sources
PubMed1999

An update on DNA-based BRCA1/BRCA2 genetic counseling in hereditary breast cancer.

The identification of BRCA1 and BRCA2 mutations has enabled physicians to identify persons at high risk for carcinoma of the breast and ovary in hereditary breast-ovarian cancer (HBOC) families. Many physicians have limited knowledge about the effective translation of these new discoveries into clinical practice settings. This problem is further confounded by the limited number of genetic counselors who have experience with cancer genetics. Genetic counseling about DNA test results was provided to 420 patients from 37 HBC/HBOC families. Descriptive data were collected and recorded about their responses to questions posed immediately before and after test results were disclosed. Findings disclosed a significant tendency of patients to overestimate rather than underestimate their risk (P < .001) prior to receiving results. The chief reason for declining to receive results was fear of insurance discrimination. The primary reason that patients sought test results was for their children. Most women reported that, if testing identified them as mutation carriers, they would consider lifetime surveillance and prophylactic surgery. Responses to DNA test results were varied and often unpredictable. Counseling by an appropriately educated and skilled professional is essential to assist people in making decisions regarding testing and health management.

Adult↗
PubMed1998

Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study.

Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P<.001), although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. When the age at diagnosis of the breast cancer cases was examined by OCCR, cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than was seen in those outside this region (48 years vs. 42 years; P=.0005).

Adult↗
PubMed1997

A descriptive study of BRCA1 testing and reactions to disclosure of test results.

BACKGROUND: The identification of the BRCA1 gene is a powerful tool for predicting a patient's lifetime risk for carcinoma of the breast and ovary when she has hereditary breast/ovarian carcinoma (HBOC) syndrome. The process of BRCA1 testing and genetic counseling and participants' reactions to test results, are described. METHODS: Education about the natural history of HBOC syndrome and the pros and cons of genetic testing was provided to 14 HBOC families comprised of 2549 bloodline relatives. Of these, 388 underwent DNA testing. After informed consent was given by participants, formal linkage analysis and gene mutation studies were performed on the families. Qualitative data on intentions and emotional reactions were collected by physicians/counselors during the genetic counseling sessions. RESULTS: Of those tested, 181 received their results after further genetic counseling. Seventy-eight of them were positive and 100 were negative for BRCA1 gene mutation. Three had ambiguous findings. The most common reasons given for seeking DNA testing were concern about risk to children and concern about surveillance and prevention. Prophylactic mastectomy was considered by 35% of women who tested positive, whereas prophylactic oophorectomy was considered an important option by 76%. Twenty-five percent of both BRCA1 positive and negative individuals were concerned about discrimination by insurance companies. Eighty percent of those who tested negative reported emotional relief, whereas over one-third of those who tested positive reported sadness, anger, or guilt. CONCLUSIONS: DNA testing of patients with HBOC syndrome must be performed in the context of genetic counseling. The authors' results demonstrate the many complex clinical and nonclinical issues that are important in this process.

Adult↗
PubMed1996

Identification of seven new BRCA1 germline mutations in Italian breast and breast/ovarian cancer families.

We analyzed 16 Italian breast and breast/ovarian cancer families for BRCA1 germline mutations using a combination of the protein truncation test (PTT) and the single-strand conformation polymorphism techniques. Genomic DNA from the affected proband of each family was analyzed by applying the PTT to exon 11 of the BRCA1 gene. This initial screening led to the identification of truncated protein products in three families that were shown to carry three different frameshift mutations. In the families that scored negative in the PTT, single-strand conformation polymorphism analysis of the entire coding sequence of the gene revealed four additional mutations consisting of one nonsense, one in-frame deletion, one frameshift, and one missense mutation (in a family with a case of male breast cancer). The four frameshift mutations resulted in a decreased expression of the mutant allele, whereas no loss of transcript was associated with the other three mutations. All mutant alleles were shown to cosegregate with the cancer phenotype within the families, and none have previously been reported.

Adult↗
PubMed1996

Localization of the human phosphotyrosine phosphatase-related genes (h-PRL-1) to chromosome bands 1p35-p34, 17q12-q21, 11q24-q25 and 12q24.

The h-PRL-1 gene codes for a new phosphotyrosine phosphatase that may play an important role in the control of basic cellular processes such as cell growth and proliferation. Using the cDNA of the h-PRL-1 gene as a probe, we examined a somatic mouse and hamster x human hybrid panel and found that chromosomes 1, 17 and 11 harbor sequences homologous to h-PRL-1. By in situ hybridization of metaphase spreads, subchromosomal localizations were determined at bands 1p35-p34, 17q12-q21 and 11q24-q25; in addition, a faint signal was detected at 12q24. The chromosomal assignment of the genes homologous to h-PRL-1 will help the investigation of its possible involvement in human diseases involving genetic alteration at these chromosomal regions.

Animals↗
PubMed1996

A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families.

We have analyzed 20 breast-ovarian cancer families, the majority of which show positive evidence of linkage to chromosome 17q12 for germ-line mutations in the BRCA1 gene. BRCA1 mutations cosegregating with breast and ovarian cancer susceptibility were identified in 16 families, including 1 family with a case of male breast cancer. Nine of these mutations have not been reported previously. The majority of mutations were found to generate a premature stop codon leading to the formation of a truncated BRCA1 protein of 2%-88% of the expected normal length. Two mutations altered the RING finger domain. Sequencing of genomic DNA led to the identification of a mutation in the coding region of BRCA1 in 12 families, and cDNA analysis revealed an abnormal or missing BRCA1 transcript in 4 of the 8 remaining families. A total of eight mutations were associated with a reduced quantity of BRCA1 transcript. We were unable to detect BRCA1 mutations in 4 of the 20 families, but only 1 of these was clearly linked to BRCA1. It is expected that the majority of clear examples of the breast-ovarian syndrome will be associated with germ-line mutations in the coding region of BRCA1.

Alternative Splicing↗
PubMed1996

Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.

Several BRCA1 mutations have now been found to occur in geographically diverse breast and ovarian cancer families. To investigate mutation origin and mutation-specific phenotypes due to BRCA1, we constructed a haplotype of nine polymorphic markers within or immediately flanking the BRCA1 locus in a set of 61 breast/ovarian cancer families selected for having one of six recurrent BRCA1 mutations. Tests of both mutations and family-specific differences in age at diagnosis were not significant. A comparison of the six mutations in the relative proportions of cases of breast and ovarian cancer was suggestive of an effect (P = .069), with 57% of women presumed affected because of the 1294 del 40 BRCA1 mutation having ovarian cancer, compared with 14% of affected women with the splice-site mutation in intron 5 of BRCA1. For the BRCA1 mutations studied here, the individual mutations are estimated to have arisen 9-170 generations ago. In general, a high degree of haplotype conservation across the region was observed, with haplotype differences most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. For several of the instances, there was evidence for multiple, independent, BRCA1 mutational events.

Alleles↗
PubMed1995

The human plakoglobin gene localizes on chromosome 17q21 and is subjected to loss of heterozygosity in breast and ovarian cancers.

The gene encoding human plakoglobin was mapped to chromosome 17q12-q22. An intragenic restriction fragment length polymorphism was used to localize the plakoglobin gene distal to locus KRT10 and proximal to the marker D17S858. The plakoglobin gene colocalizes with the polymorphic 17q21 marker UM8 on the same cosmid insert. This subregion of chromosome 17 is known to be particularly subjected to genetic alterations in sporadic breast and ovarian tumors. We show loss of heterozygosity of the plakoglobin gene in breast and ovarian tumors. We have identified a low-frequency polymorphism in the plakoglobin coding sequence which results in an arginine to histidine substitution at amino acid position 142 of the protein, as well as a silent mutation at nucleotide position 332 of the coding sequence. This polymorphism allowed us to demonstrate an allelic association of plakoglobin with predisposition to familial breast and ovarian cancers. Our results, together with the present knowledge about the biological function of plakoglobin, suggest that plakoglobin might represent a putative tumor suppressor gene for breast and ovarian cancers.

Amino Acid Sequence↗
PubMed1995

A 100-kb physical and transcriptional map around the EDH17B2 gene: identification of three novel genes and a pseudogene of a human homologue of the rat PRL-1 tyrosine phosphatase.

In this paper, we describe the physical map and transcriptional organisation of a 100-kb region with the BRCA1 locus at 17q12-21. Using the cDNA of the EDH17B2 gene as a probe, we screened a human genomic cosmid library. Positive cosmid clones were aligned and a contig around the EDH17B2 gene was established, expanding the previously reported map. In order to identify genes located in this region, we used the cosmid inserts to select cDNAs from a human ovarian cDNA library. Among the clones identified, cDNA OV-1 corresponds to a human homologue of a rat PRL-1 tyrosine phosphatase gene that shows enhanced expression during hepatic regeneration and in some tumour cell lines. Neither the OV-1 nor the PRL-1 protein shares strong homology with any previously characterised phosphotyrosine phosphatase, suggesting that they probably belong to a new phosphatase family. In an attempt to characterise the OV-1 gene, we found that the genomic sequence present on chromosome 17 probably corresponds to a nonfunctional copy of the gene, as it contains several sequence changes that disrupt the potential coding information of the gene. Three other cDNAs, corresponding to unrelated genes, were also identified and characterised. They did not reveal striking homologies in database sequence comparison and therefore represent new genes localised on chromosome 17q, in a region that frequently shows loss of heterozigosity in sporadic breast and ovarian cancers.

Amino Acid Sequence↗
PubMed1994

Epidermolytic palmoplantar keratoderma cosegregates with a keratin 9 mutation in a pedigree with breast and ovarian cancer.

Epidermolytic palmoplantar keratosis (EPPK) cosegregates with breast and ovarian cancers in a large French pedigree, raising the possibility that a single genetic mutation might cause these conditions and offering a potential lead to the identification of a hereditary breast/ovarian cancer gene. We have performed linkage analysis and show that the EPPK locus lies on the long arm of chromosome 17 near the type I keratin gene cluster and the proposed breast cancer gene (BRCA1). The type I keratin 9 gene has been partially sequenced in four affected individuals. A single base mutation within the rod domain of the protein cosegregates with EPPK in all affected individuals tested. Although inheritance of this mutation is likely responsible for EPPK, it is unlikely to be the cause of the breast and ovarian cancer.

Adolescent↗
PubMed1994

The gene for hereditary breast-ovarian cancer, BRCA1, maps distal to EDH17B2 in chromosome region 17q12-q21.

A gene for hereditary breast and ovarian cancer, BRCA1, has been mapped to chromosome 17q12-q21. This gene is responsible for cancer susceptibility in the majority of families with multiple cases of ovarian cancer and early-onset breast cancer. We report linkage results of a family with 10 cases of breast cancer and a single case of ovarian cancer. A recombinant event in this family places BRCA1 distal (telomeric) to the locus EDH17B2, which codes for the enzyme estradiol 17 beta-dehydrogenase II. This recombinant is based on the appearance of breast cancer in a 45 year old woman. Under our genetic model, we estimate the probability that this woman carries a BRCA1 mutation to be 94%. These data further reduce the region of assignment of BRCA1 on chromosome 17q12-q21 and should expedite positional cloning of this important gene.

Adult↗