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S D Merajver

Publications and source records attributed to S D Merajver.

26 records · Page 2Linked to original sources
PubMed1995

Genetic analysis of eight breast-ovarian cancer families with suspected BRCA1 mutations.

BRCA1 is a breast cancer-related tumor suppressor gene located on human chromosome 17q21. Inherited mutations in BRCA1 are thought to be responsible for approximately half of all inherited breast cancer and to confer increased risk for ovarian, colon, or prostate cancer. Studies of affected families and population-based studies have provided some information on the prevalence of BRCA1 mutations in Caucasian U.S. and European populations as well as on the penetrance of these mutations. We review the available data on the epidemiology of breast cancer with specific reference to BRCA1. In addition, we describe the genetic analysis of one large family with multiple affected individuals now known to harbor a BRCA1 germline mutation but initially identified by genetic linkage analysis. This family is presented as a model of the challenges that can be encountered in genetic analysis of familial forms of cancer. To this end, we compare the outcome of analysis before and after the identification of a mutation that predisposes family members to early-onset breast and ovarian cancers. We describe seven additional families with evidence of linkage between breast cancer and genetic markers in the BRCA1 region. Each of these families generated a 2-point LOD (i.e., logarithm of the odds) score greater than 1.18 for at least one polymorphic marker flanking BRCA1. These families have formed the basis of our efforts to characterize BRCA1 mutations. First-pass mutation analysis using the single-strand conformation polymorphism approach failed to identify any mutations in the seven families. We consider the possible reasons for the apparent low mutation-detection efficiency.

Adult↗
PubMed1995

Germline BRCA1 mutations and loss of the wild-type allele in tumors from families with early onset breast and ovarian cancer.

The BRCA1 gene on human chromosome 17q21 is responsible for an autosomal dominant syndrome of inherited early onset breast/ovarian cancer. It is estimated that women harboring a germline BRCA1 mutation incur an 85% lifetime risk of breast cancer and a greatly elevated risk of ovarian cancer. The BRCA1 gene has recently been isolated and mutations have been found in the germline of affected individuals in linked families. Previous studies of loss of heterozygosity (LOH) in breast tumors have been carried out on sporadic tumors derived from individuals without known linkage to BRCA1 and on tumors from linked families. Loss of large regions of chromosome 17 has been observed, but these LOH events could not be unequivocally ascribed to BRCA1. We have studied 28 breast and 6 ovarian tumors from families with strong evidence for linkage between breast cancer and genetic markers flanking BRCA1. These tumors were examined for LOH using genetic markers flanking and within BRCA1, including THRA1, D17S856, EDH17B1, EDH17B2, and D17S183. Forty-six percent (16/34) of tumors exhibit LOH which includes BRCA1. In 8 of 16 tumors the parental origin of the deleted allele could be determined by evaluation of haplotypes of associated family members; in 100% of these cases, the wild-type allele was lost. In some of these families germline mutations in BRCA1 have been determined; analyses of tumors with LOH at BRCA1 have revealed that only the disease-related allele of BRCA1 was present. These data strongly support the hypothesis that BRCA1 is a tumor suppressor gene.

Age of Onset↗
PubMed1994

Familial breast cancer. Approaching the isolation of a susceptibility gene.

Family history is recognized widely as a significant risk factor for the development of breast cancer. A gene (BRCA1), mutations in which confer susceptibility to early-onset breast and ovarian cancer, has been mapped to chromosome 17q12-21. An intensive search for this gene is currently underway in a number of laboratories. Recent data support the hypothesis that BRCA1 is a tumor suppressor gene that may be important in the development of both inherited and sporadic breast and ovarian cancers. Genetic and physical maps of the BRCA1 candidate region largely have been completed and efforts are being directed at identification of candidate genes from within this region. A small number of families recently have received results of genetic-linkage testing, indicating which family members likely are to be carriers of a germline BRCA1 mutation, and, therefore, have a lifetime risk of developing breast cancer of approximately 85%. The imminent isolation of BRCA1 will make predictive testing for breast cancer a reality for many women and likely will pave the way for novel diagnostic and therapeutic strategies in the future.

Breast Neoplasms↗
PubMed1994

Progress toward isolation of a breast cancer susceptibility gene, BRCA1.

The high incidence of breast cancer and/or ovarian cancer in some families appears to be due to germ-line mutations in BRCA1. Genetic analysis of such families suggests that the BRCA1 candidate region lies between D17S857 and D17S78 on chromosome 17q21 (Kelsell et al. 1993; Simard et al. 1993). To identify and isolate BRCA1, we have used linkage and meiotic recombination analysis, characterized regions displaying LOH in tumor DNA from BRCA1-linked families, performed YAC and cosmid clone isolation and ordering, and used three complementary transcript-searching strategies. We have identified as many as 28 genes from the BRCA1 candidate region, and we are searching for constitutive mutations in these candidate genes by several methods in an attempt to identify BRCA1.

BRCA1 Protein↗
PubMed1987

Purification and structural characterization of herpes simplex virus glycoprotein C.

Purification of herpes simplex virus glycoprotein C (gC) in microgram amounts yielded sufficient material for an analysis of its secondary structure. Purification was facilitated by using the mutant virus gC-3, which bears a point mutation that interrupts the putative hydrophobic membrane anchor sequence, causing the secretion of gC-3 protein into the cell culture medium. gC-3 protein was purified by size fractionation of concentrated culture medium from infected cells on a gel filtration column of Sephacryl S-200, followed by immunoaffinity chromatography on a column constructed of gC-specific monoclonal antibodies cross-linked to a protein A-Sepharose CL-4B matrix. Purified gC-3 had a molecular weight of 130,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the size expected for gC, was reactive with gC-specific monoclonal antibodies in protein immunoblots, and contained amino acid sequences characteristic of gC as determined by radiochemical amino acid microsequence analyses. Polyclonal antisera obtained from a rabbit immunized with gC-3 reacted with wild-type gC in immunoprecipitation, enzyme immunoassay, and immunoelectroblot (western blot) assays. Deglycosylation by treatment with trifluoromethanesulfonic acid reduced the molecular weight of gC-3 by approximately 35%. Analyses of both native and deglycosylated gC-3 by Raman spectroscopy showed that the native molecule consists of about 17% alpha-helix, 24% beta-sheet, and 60% disordered secondary structures, whereas deglycosylated gC-3 consists of about 8% alpha-helix, 10% beta-sheet, and 81% disordered structures. These data were in good agreement with the 11% alpha-helix, 18% beta-sheet, 61% beta-turn, and 9% disordered structures calculated from Chou-Fasman analysis of the primary sequence of gC-3.

Amino Acid Sequence↗
PubMedDate not supplied

Cancer-specific worry interference in women attending a breast and ovarian cancer risk evaluation program: impact on emotional distress and health functioning.

Intrusive thoughts about cancer, often identified as 'cancer-specific worries' or 'cancer-specific distress', have been postulated to be associated with dysfunction in women at increased risk of developing breast or ovarian cancer. The current study discusses the development and validation of a measure designed to assess women's perceptions of the interference such worries create in their daily functioning. Analyses revealed that approximately two-thirds of a high-risk breast cancer clinic sample perceived worries about breast cancer as interfering with their functioning across a variety of life domains. Multiple regression analyses indicated that worry interference scores predicted Profile of Mood States (POMS) Anxiety and Confusion, and Short Form-36 (SF-36) Role-Emotional and Mental Health scores after the effects of other variables such as frequency of worry about breast cancer, and having a family history of cancer had been considered. Women who perceived their worries as interfering with their functioning reported higher levels of anxiety and confusion, and diminished mental health and role functioning. The results add to the expanding area of anxiety/distress in at-risk populations by providing (1) a direct measure of the perceived interference associated with breast cancer-specific thoughts, (2) a validation of the measure via its associations with standard measures of emotional distress and health functioning, and (3) evidence of the measure's incremental predictive value in explaining distress and quality of life, after consideration of background variables, such as having a family history of cancer.

Activities of Daily Living↗
PubMedDate not supplied

RhoC GTPase overexpression modulates induction of angiogenic factors in breast cells.

Inflammatory breast cancer (IBC) is a distinct and aggressive form of locally advanced breast cancer. IBC is highly angiogenic, invasive, and metastatic at its inception. Previously, we identified specific genetic alterations of IBC that contribute to this highly invasive phenotype. RhoC GTPase was overexpressed in 90% of archival IBC tumor samples, but not in stage-matched, non-IBC tumors. To study the role of RhoC GTPase in contributing to an IBC-like phenotype, we generated stable transfectants of human mammary epithelial cells overexpressing the RhoC gene, and studied the effect of RhoC GTPase overexpression on the modulation of angiogenesis in IBC. Levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-6 (IL-6), and interleukin-8 (IL-8) were significantly higher in the conditioned media of the HME-RhoC transfectants than in the untransfected HME and HME-beta-galactosidase control media, similar to the SUM149 IBC cell line. Inhibition of RhoC function by introduction of C3 exotransferase decreased production of angiogenic factors by the HME-RhoC transfectants and the SUM149 IBC cell line, but did not affect the control cells. These data support the conclusion that overexpression of RhoC GTPase is specifically and directly implicated in the control of the production of angiogenic factors by IBC cells.

ADP Ribose Transferases↗