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S Narod

Publications and source records attributed to S Narod.

At least 37 records · Page 2Linked to original sources
PubMed1999

Peritoneal serous papillary carcinoma, a phenotypic variant of familial ovarian cancer: implications for ovarian cancer screening.

OBJECTIVE: Our purpose was to report the cancers arising during a familial ovarian cancer screening program and investigate the tumor's clonality and association with BRCA1 and BRCA2 mutations. STUDY DESIGN: Program participants with a diagnosis of ovarian cancer or peritoneal serous papillary carcinoma were identified and their demographic characteristics, ultrasonographic findings, CA 125 results, operative reports, and pathology slides reviewed. Immunohistochemical analysis of p53, bcl-2, HER-2/neu, and nm23 H1 expression was performed on tumor tissues from multiple metastatic sites, and germline BRCA1 and BRCA2 mutations were identified. RESULTS: Three stage I ovarian cancers and 7 cases of peritoneal serous papillary carcinoma were diagnosed from among 1261 program participants. Ultrasonographic abnormalities triggered surgical exploration in all 3 cases of stage I disease. Elevated levels of CA 125 were the harbinger in 2 of 7 cases of peritoneal serous papillary carcinoma, abnormal ultrasonographic findings prompted diagnosis in 2 of 7 cases, and 3 of 7 women had abdominal symptoms 5, 6, and 16 months after screening. Results of immunohistochemical studies suggested multifocal disease in 5 of 7 patients with peritoneal serous papillary carcinoma. At least 3 of the patients with peritoneal serous papillary carcinoma carry BRCA1 185delAG mutations. CONCLUSION: Multifocal peritoneal serous papillary carcinoma may be a phenotypic variant of familial ovarian cancer, and screening strategies for these women cannot rely on ultrasonography and CA 125 testing to detect early disease.

Adult↗
PubMed1999

Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium.

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome caused by germline defects of mismatch repair (MMR) genes. Endometrial cancer is the most common extracolonic neoplasm in HNPCC and is the primary clinical manifestation of the syndrome in some families. The cumulative incidence of endometrial cancer among HNPCC mutation carriers is high, estimated to be from 22 to 43%. We hypothesized that women with double primary cancers of the colorectum and endometrium are likely to be members of HNPCC families. In order to determine how frequently HNPCC manifests in the context of double primary cancers, we examined alterations of two MMR genes, hMSH2 and hMLH1, in 40 unrelated women affected with double primary cancers. These cases were identified using hospital-based and population-based cancer registries in Ontario, Canada. MMR gene mutations were screened by single-strand conformation polymorphism analysis and confirmed by direct sequencing. Eighteen percent (seven of 40) were found to harbor mutations of one of the two MMR genes. Analysis of colorectal and/or endometrial tumors of mutation-negative probands found microsatellite instability in seven of 20 cases. Six of seven mutation-positive probands had strong family histories suggestive of HNPCC. First degree relatives of mutation-positive probands had a very high relative risk (RR) of colorectal cancer (RR = 8.1, CI 3. 5-15.9) and endometrial cancer (RR = 23.8, CI 6.4-61.0). The relative risk of mutation-negative cases was 2.8 (CI 1.7-4.5) for colorectal cancer and 5.4 (CI 2.0-11.7) for endometrial cancer. We recommend that all double primary patients with cancers at these sites should have a genetic evaluation, including molecular analysis for HNPCC where appropriate.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Immunohistochemistry for hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors.

Inactivation of deoxyribonucleic acid (DNA) mismatch repair genes, most commonly human mutL homologue 1 (hMLH1) or human mutS homologue 2 (hMSH2), is a recently described alternate pathway in cancer development and progression. The resulting genetic instability is characterized by widespread somatic mutations in tumor DNA, and is termed high-frequency microsatellite instability (MSI-H). Although described in a variety of tumors, mismatch repair deficiency has been studied predominantly in colorectal carcinoma. Most MSI-H colorectal carcinomas are sporadic, but some occur in patients with hereditary nonpolyposis colorectal cancer (HNPCC), and are associated with germline mutations in mismatch repair genes. Until now, the identification of MSI-H cancers has required molecular testing. To evaluate the role of immunohistochemistry as a new screening tool for mismatch repair-deficient neoplasms, the authors studied the expression of hMLH1 and hMSH2, using commercially available monoclonal antibodies, in 72 formalin-fixed, paraffin-embedded tumors that had been tested previously for microsatellite instability. They compared immunohistochemical patterns of 38 MSI-H neoplasms, including 16 cases from HNPCC patients with known germline mutations in hMLH1 or hMSH2, with 34 neoplasms that did not show microsatellite instability. Thirty-seven of 38 MSI-H neoplasms were predicted to have a mismatch repair gene defect, as demonstrated by the absence of hMLH1 and/or hMSH2 expression. This included correspondence with all 16 cases with germline mutations. All 34 microsatellite-stable cancers had intact staining with both antibodies. These findings clearly demonstrate that immunohistochemistry can discriminate accurately between MSI-H and microsatellite-stable tumors, providing a practical new technique with important clinical and research applications.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.

The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

Adult↗
PubMed1998

What you don't know can hurt you: adverse psychologic effects in members of BRCA1-linked and BRCA2-linked families who decline genetic testing.

PURPOSE: To identify members of hereditary breast and ovarian cancer families who are at risk for adverse psychologic effects of genetic testing. PATIENTS AND METHODS: A prospective cohort study with baseline (preeducation) assessments of predictor variables (ie, sociodemographic factors, cancer history, and cancer-related stress symptoms) was performed. The primary outcome variable (presence of depressive symptoms) was assessed at baseline and at 1- and 6-month follow-up evaluations. Participants were 327 adult male and female members of BRCA1- and BRCA2-linked hereditary breast and ovarian cancer families, who were identified as carriers, noncarriers, or decliners of genetic testing. RESULTS: The presence of cancer-related stress symptoms at baseline was strongly predictive of the onset of depressive symptoms in family members who were invited but declined testing. Among persons who reported high baseline levels of stress, depression rates in decliners increased from 26% at baseline to 47% at 1-month follow-up; depression rates in noncarriers decreased and in carriers showed no change (odds ratio [OR] for decliners v noncarriers=8.0; 95% confidence interval [CI], 1.9 to 33.5; P=.0004). These significant differences in depression rates were still evident at the 6-month follow-up evaluation (P=.04). CONCLUSION: In BRCA1/2-linked families, persons with high levels of cancer-related stress who decline genetic testing may be at risk for depression. These family members may benefit from education and counseling, even if they ultimately elect not to be tested, and should be monitored for potential adverse effects.

Adolescent↗
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↗
PubMed1997

The influence of psychological distress on use of genetic testing for cancer risk.

The recent identification of BRCA1, a breast cancer susceptibility gene, offers an unprecedented opportunity for high-risk individuals to learn whether they are genetically predisposed to develop breast or ovarian cancer. This study examined the relationships between psychological distress and use of BRCA1 testing by 149 high-risk individuals from hereditary cancer families. After a baseline assessment of demographics, objective risk, cancer-specific distress, and global distress (depressive symptoms), study participants were offered the opportunity to receive genetic counseling and to learn whether they carry a mutation in the BRCA1 gene. Overall, 58% of study participants requested BRCA1 test results, and 42% declined to learn their genetic status. After controlling for demographic factors and risk status, cancer-specific distress was significantly and positively related to BRCA1 test use, whereas global distress was unrelated to test use.

Adult↗
PubMed1996

BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes.

OBJECTIVES: To identify predictors of utilization of breast-ovarian cancer susceptibility (BRCA1 gene) testing and to evaluate outcomes of participation in a testing program. DESIGN: Prospective cohort study with baseline interview assessment of predictor variables (eg, sociodemographic factors, knowledge about hereditary cancer and genetic testing, perceptions of testing benefits, limitations, and risks). BRCA1 test results were offered after an education and counseling session in a research setting. Outcome variables (including depression, functional health status, and prophylactic surgery plans [follow-up only]) were assessed at baseline and 1-month follow-up interviews. PARTICIPANTS: Adult male and female members (n=279) of families with BRCA1-linked hereditary breast-ovarian cancer (HBOC). RESULTS: Of subjects who completed a baseline interview (n=192), 60% requested BRCA1 test results (43% of all study subjects requested results). Requests for results were more frequent for persons with health insurance (odds ration [OR], 3.74; 95% confidence interval [CI], 2.06-6.80); more first-degree relatives affected with breast cancer (OR, 1.59; 95% CI, 1.16-2.16); more knowledge about BRCA1 testing (OR, 1.85; 95% CI, 1.36-2.50); and indicating that test benefits are important (OR, 1.45; 95% CI, 1.13-1.86). At follow-up, noncarriers of BRCA1 mutations showed statistically significant reductions in depressive symptoms and functional impairment compared with carriers and nontested individuals. Individuals identified as mutation carriers did not exhibit increases in depression and functional impairment. Among unaffected women with no prior prophylactic surgery, 17% of carriers (2/12) intended to have mastectomies and 33% (4/12) to have oophorectomies. CONCLUSIONS: Only a subset of HBOC family members are likely to request BRCA1 testing when available. Rates of test use may be higher in persons of a higher socioeconomic status and those with more relatives affected with breast cancer. For some high-risk individuals who receive test results in a research setting that includes counseling, there may be psychological benefits. More research is needed to assess the generalizability of these results and evaluate the long-term consequences of BRCA1 testing.

Adult↗
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

Generation of a transcription map at the HSD17B locus centromeric to BRCA1 at 17q21.

A detailed transcription map of the 320-kb region containing the HSD17B locus on chromosome 17 was generated. Thirty unique cDNA fragments, retrieved following the hybridization of immobilized YACs to primary pools of cDNAs prepared from RNA of mammary gland, ovary, placenta, and the Caco-2 cell line, were aligned into 10 transcription units by physical mapping and hybridization to RNAs of a series of tissues. The cDNAs were then further characterized by sequencing and used to screen mammary gland cDNA libraries. Fragments corresponding to the broadly expressed gamma-tubulin and Ki antigen genes were identified. A full-length cDNA clone encoding a 117-amino-acid protein homologous to the rat ribosomal protein L34 was isolated. Portions of genes with restricted patterns of expression were also obtained, including the previously characterized HSD17B1. One new gene, for which a full-length cDNA was isolated, was found to have an interesting tissue-specific pattern of expression with abundant mRNA in both the colon and the testis and in the mammary carcinoma cell line BT-474. This contrasted with the barely detectable level observed in several tissues including normal mammary gland. Of the five additional transcription units identified, one showed no similarity, two showed identity to human expressed sequences, and two displayed similarity to genes of animal species by amino acid alignment. These latter cDNA clones include potential homologues of a rat nuclear tyrosine phosphatase and of a factor of Drosophila that is known to be involved in the negative regulation of transcription of segment identity genes.

Amino Acid Sequence↗
PubMed1995

Tumor suppressor activity of the gene encoding mammary-derived growth inhibitor.

The gene encoding mammary-derived growth inhibitor (MDGI), a protein previously purified from bovine mammary gland and shown to have modest antiproliferative activity for human breast cancer cells in vitro, is demonstrated to function as a potent tumor suppressor gene. Human breast cancer cells transfected with a MDGI expression construct exhibited differentiated morphology, reduced proliferation rate, reduced clonogenicity in soft agar, and reduced tumorgenicity in nude mice relative to mock-transfected or untransfected controls. We mapped the human homologue of this gene to chromosome 1p33-35, a locus previously shown to exhibit frequent loss of heterozygosity in human breast cancer. MDGI immunoreactivity was detected in epithelial cells of human breast tissue, but not on ductal carcinoma cells on the same sections. Our results suggest that MDGI is a strong candidate for the distal 1p breast tumor suppressor gene. Furthermore, as prior reports have demonstrated that MDGI is hormonally regulated in breast epithelial cells and maximally expressed at the time of maximal differentiated function (just prior to lactation), MDGI is a candidate mediator of the differentiating effect of pregnancy on breast epithelial cells, which may be involved in the protective effect of early parity on subsequent breast cancer incidence.

Animals↗
PubMed1995

A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening.

OBJECTIVES: To report the initial experience of an international group of investigators in identifying mutations in the BRCA1 breast and ovarian cancer susceptibility gene, to assess the spectrum of such mutations in samples from patients with different family histories of cancer, and to determine the frequency of recurrent mutations. DESIGN: Nine laboratories in North America and the United Kingdom tested for BRCA1 mutations in DNA samples obtained from a total of 372 unrelated patients with breast or ovarian cancer largely chosen from high-risk families. Three of these laboratories also analyzed a total of 714 additional samples from breast or ovarian cancer cases, including 557 unselected for family history, for two specific mutations that had been found to recur in familial samples. PARTICIPANTS: A total of 1086 women with either breast or ovarian cancer. MAIN OUTCOME MEASURE: The detection of sequence variation in patients' DNA samples that is not found in sets of control samples. RESULTS: BRCA1 mutations have now been identified in a total of 80 patient samples. Thirty-eight distinct mutations were found among 63 mutations identified through a complete screen of the BRCA1 gene. Three specific mutations appeared relatively common, occurring eight, seven, and five times, respectively. When specific tests for the two most common mutations were performed in larger sets of samples, they were found in 17 additional patients. Mutations predicted to result in a truncated protein accounted for 86% of the mutations detected by complete screening. CONCLUSIONS: The high frequency of protein-terminating mutations and the observation of many recurrent mutations found in a diverse set of samples could lead to a relatively simple diagnostic test for BRCA1 mutations. More data must be accumulated to address specifically the sensitivity and specificity of such a diagnostic testing procedure and to better estimate the age-specific risk for breast and ovarian cancer associated with such mutations.

Adult↗
PubMed1995

Clinicopathological relevance of the association between gastrointestinal and sebaceous neoplasms: the Muir-Torre syndrome.

The association between sebaceous neoplasms of the skin and visceral cancers, known as Muir-Torre syndrome, is described in three patients, including one with an extensive history of cancer in his family. The first patient, a 54-year-old man, developed multiple sebaceous adenomas, epitheliomas, and carcinomas in association with a colonic carcinoma 6 years after cardiac transplantation. Family history in this patient disclosed colon cancer in 17 relatives. The second patient was a 51-year-old man who had recurrent adenocarcinoma of the sigmoid colon, adenocarcinoma arising in Barrett's esophagus, and sebaceous epithelioma during a period of 15 years. The third patient was a 90-year-old man with a sebaceous adenoma followed 5 months later by adenocarcinoma of the sigmoid colon with liver metastases. Muir-Torre syndrome in 129 other patients published in the literature is reviewed. Although it is a rare disease, Muir-Torre syndrome requires recognition because skin lesions may be the first sign of the syndrome and this may lead to early diagnosis of associated visceral cancers. Moreover, because this syndrome appears to be inherited, family members should be screened for visceral cancer, especially colorectal adenocarcinoma.

Adenocarcinoma, Sebaceous↗
PubMed1995

Family history and the risk of prostatic carcinoma in a high risk group of urological patients.

PURPOSE: We examine the association of family history and prostatic carcinoma. MATERIALS AND METHODS: A total of 2,968 consecutive patients referred for prostate cancer detection responded to a questionnaire and underwent transrectal ultrasound examination with or without biopsy. RESULTS: Of the men 329 (11.1%) had a family history of prostate cancer. No differences were observed between groups with and without a family history with respect to mean patient age, serum prostate specific antigen level or biopsy rate. Prostate cancer was detected in 133 of 329 patients (40.4%) with a family history and 769 of 2,639 (29.1) with no family history (p < 0.001, odds ratio 1.7). No significant differences were observed between cancer patients with or without a family history with respect to mean Gleason score (6.0 versus 6.2), patient age at diagnosis (65.8 versus 66.7) and prostate specific antigen level (16.8 versus 17.1). CONCLUSIONS: Patients with a family history of prostate cancer have a greater risk of the disease. In this select group of patients a positive family history was not associated with an earlier age at cancer diagnosis or a different histological grade of tumor.

Aged↗