RESUMO
The BRCA1 gene on chromosome 17q21 is responsible for an autosomal dominant syndrome of increased susceptibility to breast and ovarian cancer but no somatic mutations in tumours have yet been described. To study the potential role of BRCA1 in sporadic carcinogenesis, we analysed the genomic DNA of tumour and normal fractions of 47 ovarian cancers for mutations in BRCA1 using the single-strand conformation polymorphism technique. We now describe somatic mutations in the DNA of four tumours which also had loss of heterozygosity (LOH) at a BRCA1 intragenic marker. Our data support a tumour suppressor mechanism for BRCA1; somatic mutations and LOH may result in inactivation of BRCA1 in at least a small number of ovarian cancers.
Assuntos
Mutação , Oncogenes , Neoplasias Ovarianas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 17 , DNA de Neoplasias/genética , Feminino , Genes Dominantes , Genes Supressores de Tumor , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Polimorfismo GenéticoRESUMO
BACKGROUND: In women with a family history of breast cancer, bilateral prophylactic mastectomy is associated with a decreased risk of subsequent breast cancer of approximately 90%. We examined the association between bilateral prophylactic mastectomy and breast cancer risk in women at high risk for breast cancer who also had mutations in BRCA1 and BRCA2 genes. METHODS: We obtained blood samples from 176 of the 214 high-risk women who participated in our previous retrospective cohort study of bilateral prophylactic mastectomy. We used conformation-sensitive gel electrophoresis and direct sequence analysis of the blood specimens to identify women with mutations in BRCA1 and BRCA2. The carriers' probabilities of developing breast cancer were estimated from two different penetrance models. RESULTS: We identified 26 women with an alteration in BRCA1 or BRCA2. Eighteen of the mutations were considered to be deleterious and eight to be of uncertain clinical significance. None of the 26 women has developed breast cancer after a median of 13.4 years of follow-up (range, 5.8-28.5 years). Three of the 214 women are known to have developed a breast cancer after prophylactic mastectomy. For two of these women, BRCA1 and BRCA2 screening was negative, and no blood specimen was available for the third. Estimations of the effectiveness of prophylactic mastectomy were performed, considering this woman as both a mutation carrier and a noncarrier. These calculations predicted that six to nine breast cancers should have developed among the mutation carriers, which translates into a risk reduction, after bilateral prophylactic mastectomy, of 89.5%-100% (95% confidence interval = 41.4% to 100%). CONCLUSIONS: Prophylactic mastectomy is associated with a substantial reduction in the incidence of subsequent breast cancer not only in women identified as being at high risk on the basis of a family history of breast cancer but also in known BRCA1 or BRCA2 mutation carriers.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Genes BRCA1 , Heterozigoto , Mastectomia , Mutação , Neoplasias da Mama/epidemiologia , Feminino , Genes BRCA2 , Humanos , IncidênciaRESUMO
The present studies were aimed at determining if the use of a cell culture medium that supports proliferation of human mammary epithelial cells of the luminal lineage would allow routine isolation of breast cancer cells from primary and metastatic tumor specimens. Results obtained with mammary epithelial cells derived from reduction mammoplasty specimens and primary breast carcinomas indicated that growth of cells on type I collagen-coated dishes in Ham's F-12 medium supplemented with insulin, hydrocortisone, epidermal growth factor, cholera toxin, and 5% fetal bovine serum resulted in the growth and serial passage of cells that stained positively for the luminal cell marker cytokeratin 19. By contrast, growth of mammary epithelial cells in a growth factor-supplemented serum-free medium resulted in the emergence of mammary epithelial cell colonies that were uniformly negative for keratin 19. Filter isolation methods were used to isolate individual keratin-19-positive colonies from primary cultures derived from breast cancer specimens. All of the luminal mammary epithelial cells isolated from breast cancer tissues expressed characteristics of normal cells. Keratin-19-positive colonies isolated from several different tumors all grew rapidly for 30 to 60 days in culture and then senesced. Cells were isolated from one tumor that was known to have undergone a loss of heterozygosity at a specific locus in the p53 gene. All colonies isolated from this specimen contained both p53 alleles, which was consistent with their origin from normal luminal cells. Cells were also isolated from one tumor in which the c-erbB2 protein was drastically overexpressed in the neoplastic cells. Once again, keratin-19-positive colonies isolated from this tumor did not overexpress the c-erbB-2 protein. Experiments were then performed with cells derived from pleural effusions and metastatic lymph nodes. Results obtained with these specimens indicated that the growth conditions that support the growth of normal luminal mammary epithelial cells do not support the growth of neoplastic cells. However, the omission of cholera toxin, epidermal growth factor, and type I collagen substratum resulted in the isolation of two long-term cell lines. Both cell lines have population doubling times of approximately 100 h, are hyperdiploid, and stain positively for cytokeratin 19. Thus, culture conditions that support the growth of normal luminal mammary epithelial cells do not, in general, support the growth of breast cancer cells.
Assuntos
Neoplasias da Mama/patologia , Mama/citologia , Sequência de Bases , Divisão Celular/fisiologia , Células Cultivadas , Meios de Cultura , Técnicas de Cultura , Células Epiteliais , Feminino , Humanos , Metástase Linfática , Dados de Sequência Molecular , Fenótipo , Derrame Pleural/citologia , Derrame Pleural/patologia , Células Tumorais CultivadasRESUMO
Chromosomal regions of allelic imbalance in tumors are predicted to define the general location of tumor suppressor genes. We previously localized a putative breast tumor suppressor gene to a 3 cM region on 17q25 by deletion mapping of microsatellite markers in breast tumors. To determine if the same 17q25 region of loss is important in the genesis of other tumor types, 32 ovarian tumors and 24 prostate tumors, as well as 33 additional breast tumors, were analysed with 17q25 polymorphic microsatellite markers. While no significant loss was observed in prostate tumors, greater than half of ovarian tumors exhibited loss coincident with the candidate region previously defined in breast tumors. These results suggest that one or more novel tumor suppressor genes exist on 17q25 within a concordant region of interstitial loss defined in both breast and ovarian neoplasms.
Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 17 , Deleção de Genes , Repetições de Microssatélites , Neoplasias Ovarianas/genética , Mapeamento Cromossômico , Feminino , Marcadores Genéticos , Humanos , Masculino , Polimorfismo Genético , Neoplasias da Próstata/genéticaRESUMO
PURPOSE: Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer. PATIENTS AND METHODS: A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy. RESULTS: Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005). CONCLUSION: Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1/genética , Neoplasias Ovarianas/genética , Adulto , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Modelos Logísticos , Anamnese , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
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.
Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 17 , Genes BRCA1 , Mutação em Linhagem Germinativa , Perda de Heterozigosidade , Neoplasias Ovarianas/genética , Idade de Início , Substituição de Aminoácidos , Proteína BRCA1/genética , Neoplasias da Mama/epidemiologia , Mapeamento Cromossômico , Família , Feminino , Marcadores Genéticos , Humanos , Escore Lod , Masculino , Neoplasias Ovarianas/epidemiologia , Linhagem , Reação em Cadeia da Polimerase , Medição de Risco , Fatores de Risco , Deleção de SequênciaRESUMO
Germline mutations in the BRCA1 tumor suppressor gene are thought to be the most common cause of hereditary ovarian cancer. The aim of this study was to explore further the role of BRCA1 alterations in the development of ovarian cancers. We sought to determine whether somatic BRCA1 mutations are ever present in ovarian cancers and whether mutation is always accompanied by loss of the wild-type allele. The entire coding region and intronic splice sites of BRCA1 were sequenced using genomic DNA samples from 103 unselected ovarian cancers. Thirteen clearly deleterious BRCA1 mutations and two variants of uncertain significance were found. Blood DNA was available in all but two cases and demonstrated that 4 of 13 mutations and both variants of uncertain significance were germline alterations, whereas in seven cases the mutation was a somatic change present only in the cancer. Using four microsatellite markers, loss of heterozygosity at the BRCA1 locus was found in all 15 ovarian cancers with BRCA1 sequence alterations, compared with only 58% of ovarian cancers that did not have BRCA1 mutations. BRCA1-associated ovarian cancers were characterized by serous histology and moderate histological grade. These data confirm prior reports suggesting that germline mutations in BRCA1 are present in about 5% of women with ovarian cancer. In addition, somatic mutations in BRCA1 occur in the development of some sporadic cases. The finding that both germline and somatic BRCA1 mutations are accompanied by loss of heterozygosity, suggests that loss of this tumor suppressor gene is a critical event in the development of these cancers.
Assuntos
Genes BRCA1 , Mutação em Linhagem Germinativa , Mutação , Neoplasias Ovarianas/genética , Adulto , Idoso , Feminino , Humanos , Perda de Heterozigosidade , Pessoa de Meia-IdadeRESUMO
While sequence analysis is considered by many to be the most sensitive method of detecting unknown mutations in large genes such as BRCA1, most published estimates of the prevalence of mutations in this gene have been derived from studies that have used other methods of gene analysis. In order to determine the relative sensitivity of techniques that are widely used in research on BRCA1, a set of blinded samples containing 58 distinct mutations were analysed by four separate laboratories. Each used one of the following methods: single strand conformational polymorphism analysis (SSCP), conformation sensitive gel electrophoresis (CSGE), two dimensional gene scanning (TDGS), and denaturing high performance liquid chromatography (DHPLC). Only the laboratory using DHPLC correctly identified each of the mutations. The laboratory using TDGS correctly identified 91% of the mutations but produced three apparent false positive results. The laboratories using SSCP and CSGE detected abnormal migration for 72% and 76% of the mutations, respectively, but subsequently confirmed and reported only 65% and 60% of mutations, respectively. False negatives therefore resulted not only from failure of the techniques to distinguish wild type from mutant, but also from failure to confirm the mutation by sequence analysis as well as from human errors leading to misreporting of results. These findings characterise sources of error in commonly used methods of mutation detection that should be addressed by laboratories using these methods. Based upon sources of error identified in this comparison, it is likely that mutations in BRCA1 and BRCA2 are more prevalent than some studies have previously reported. The findings of this comparison provide a basis for interpreting studies of mutations in susceptibility genes across many inherited cancer syndromes.
Assuntos
Frequência do Gene/genética , Genes BRCA1 , Testes Genéticos/métodos , Mutação/genética , Cromatografia Líquida de Alta Pressão , Análise Mutacional de DNA/economia , Análise Mutacional de DNA/métodos , Éxons/genética , Genes BRCA2 , Predisposição Genética para Doença/genética , Testes Genéticos/economia , Humanos , Desnaturação de Ácido Nucleico , Polimorfismo Conformacional de Fita Simples , Reprodutibilidade dos Testes , Projetos de Pesquisa , Sensibilidade e Especificidade , Método Simples-Cego , TemperaturaRESUMO
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.
Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 17 , Genes Supressores de Tumor , Ligação Genética , Neoplasias Ovarianas/genética , Adulto , Idade de Início , Feminino , Marcadores Genéticos , Haplótipos , Humanos , Escore Lod , Pessoa de Meia-Idade , Mutação , Linhagem , Polimorfismo Conformacional de Fita Simples , Valor Preditivo dos Testes , Fatores de RiscoRESUMO
It is unknown what proportion of women at high risk for breast cancer, entering phase II chemoprevention trials, have BRCA1/2 alterations, and whether their initial biomarker patterns or response to preventive interventions will differ between carriers and non-carriers. As part of a 6-month phase II chemoprevention trial of diflouromethlyornithine (DFMO), high-risk subjects (family history, prior precancerous breast disease or prior breast cancer), who had random peri-areolar fine needle evidence of epithelial hyperplasia with or without atypia, were offered genetic counselling and testing at the completion of their study participation. 97% of the 119 women eligible for testing underwent BRCA1/2 gene sequencing, 3 declined. 26 (22%) of the 116 women had an alteration in BRCA1/2. Known deleterious mutations were present in 3 (3%), uncertain significance mutations in 19 (16%), and probable polymorphisms in 6 (5%). There does not appear to be a difference in initial biomarker distribution between participants with and without germ line alterations.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Eflornitina/uso terapêutico , Genes BRCA1/genética , Mutação em Linhagem Germinativa/genética , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Adulto , Proteína BRCA2 , Neoplasias da Mama/prevenção & controle , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Linhagem , Fatores de RiscoRESUMO
This report describes the case of a 32-year-old female with chronic pelvic pain who was otherwise in good health. Endocervical curettings contained rare cells with intranuclear and cytoplasmic inclusions characteristic of cytomegalovirus (CMV) infection. Endometrial curettings demonstrated a stromal lymphocytic and plasmacytic infiltrate as well as numerous small, non-necrotizing granulomas, but no CMV by microscopic examination. However, CMV was identified by the polymerase chain reaction in DNA extracted from a paraffin section of the endometrial tissue. In conjunction with previous reports, the clinical and pathologic features of this case suggest that CMV can cause chronic endometritis in nonimmunocompromised patients. Furthermore, CMV infection should be considered in the differential diagnosis of granulomatous endometritis. This case demonstrates the usefulness of using the polymerase chain reaction to detect CMV in paraffin-embedded material.
Assuntos
Infecções por Citomegalovirus/complicações , Citomegalovirus/isolamento & purificação , Endometrite/etiologia , Adulto , Curetagem , Infecções por Citomegalovirus/patologia , Eletroforese em Gel de Ágar , Endometrite/patologia , Endométrio/microbiologia , Feminino , Granuloma/patologia , Humanos , Reação em Cadeia da PolimeraseRESUMO
In areas of the world where hepatitis B and aflatoxin ingestion are common, alterations of the p53 tumor suppressor gene have frequently been reported in hepatocellular carcinoma (HCC). In particular, G-to-T transversions at codon 249 of the p53 gene have been consistently observed in hepatocellular carcinomas in China and sub-Saharan Africa. The goal of this study was to determine the frequency and relationship of p53 gene alterations and hepatitis B in formalin-fixed, paraffin-embedded HCCs resected in the United States. Since immunoreactivity for p53 correlates closely with the presence of missense mutations in the p53 gene, we performed immunohistochemical staining with the monoclonal antibody PAb1801. Only seven of 37 cases (19%) demonstrated nuclear accumulation of p53 gene product, in contrast to 10 of 20 cases (50%) of colon carcinoma metastatic to the liver. Staining was not observed in seven liver cell adenomas, 10 cases of focal nodular hyperplasia, or eight cases of cirrhosis. DNA was extracted from formalin-fixed paraffin sections for additional analysis with use of the polymerase chain reaction (PCR). G-to-T transversions of the third nucleotide of codon 249 were demonstrated in only four of 37 cases (11%), three of which had stained with PAb1801. Of 13 patients for whom there was information about a restriction fragment length polymorphism (RFLP) for BstUI within the fourth exon of the p53 gene, allelic loss of p53 was demonstrated in only two cases (15%), both of which stained with PAb1801. Because of previous reports specifically associating hepatitis B with p53 mutations in HCC, we performed nested PCR for hepatitis B virus DNA. Five of 37 cases (14%) contained hepatitis B virus DNA, two of which stained diffusely for p53 and three of which had codon 249 mutations. Our findings indicate that alterations in the p53 gene, particularly at codon 249, are uncommon in HCCs in the United States, and when present are associated with hepatitis B. Since hepatitis B is infrequently associated with HCC in our patient population, the role of p53 alterations in hepatocellular carcinogenesis may not be as significant as in other parts of the world where hepatitis B and aflatoxin are more prevalent.
Assuntos
Carcinoma Hepatocelular/genética , DNA Viral/genética , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Criança , Pré-Escolar , Códon , DNA Viral/análise , Feminino , Amplificação de Genes , Genes Virais/genética , Triagem de Portadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Reação em Cadeia da PolimeraseRESUMO
The incidence and severity of recurrent hepatitis C virus (HCV) infection in liver transplant recipients vary widely, and the long-term sequelae of recurrent infection are not known. To better define the biology of recurrent HCV in liver transplant patients, we reviewed the histology of recurrent HCV in serial biopsies of 19 patients with pretransplant polymerase chain reaction (PCR) evidence of HCV infection. All posttransplant (post-TX) biopsies (n = 81) were reviewed, and RNA was extracted from at least one paraffin-embedded biopsy from each patient. RNA was analyzed for HCV by nested, reverse transcription-PCR (RT-PCR) using primers for the 5' non-coding region of HCV as well as for albumin (as an internal control). All post-TX biopsies tested (12-1,677 days post-TX) were positive for HCV RNA by RT-PCR, while normal control biopsies were negative. Fifteen of 19 patients developed recurrent chronic hepatitis typical of HCV. Many of these patients showed a progression from early biopsies with acute lobular hepatitis to later biopsies with chronic hepatitis with portal lymphoid aggregates. An acute lobular hepatitis typified by sinusoidal lymphocytosis, acidophil bodies, and lobular disarray was seen an average of 135 days post-TX, with a range of 39-279 days. The time post-TX between this and earlier non-hepatitis biopsies was significantly different (p < 0.0004, Student's t test). Chronic hepatitis with portal lymphoid aggregates was seen an average of 356 days post-TX, with a range of 89-1,365 days. The time post-TX was significantly longer than for acute lobular hepatitis (p < 0.03, Student's t test). Fifty-three percent of HCV TX patients progressed from acute lobular hepatitis to chronic hepatitis with lymphoid aggregates within 1 year of TX, and 79% showed these changes within 4 years. Six patients had progressive fibrosis; one die of liver failure and two became cirrhotic. Recurrent HCV appears to progress from an acute lobular hepatitis to chronic hepatitis with lymphoid aggregates in the majority of patients. Significant scarring occurred in 32% of patients and 16% developed end-stage liver disease from recurrent HCV. These later findings suggest that the long-term course of recurrent HCV in liver allografts may not be as indolent as first thought.
Assuntos
Hepacivirus/isolamento & purificação , Hepatite C/patologia , Hepatite C/cirurgia , Hepatite Crônica/patologia , Transplante de Fígado/patologia , RNA Viral/isolamento & purificação , Sequência de Bases , Estudos de Coortes , Eletroforese em Gel de Ágar , Hepatite C/virologia , Hepatite Crônica/cirurgia , Hepatite Crônica/virologia , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , DNA Polimerase Dirigida por RNA , Recidiva , Estudos Retrospectivos , Transplante HomólogoRESUMO
Ovarian tumors of low malignant potential ("borderline tumors") have been proposed variably to represent a distinctive type of malignancy, precursors of frank ovarian malignancy, or a nonmalignant process. We analyzed 81 malignant and 39 borderline ovarian tumors for p53 immunoreactivity and alterations in codon 12 of Ki-RAS in order to correlate these alterations with tumor and cell type. Diffuse p53 immunoreactivity was significantly more prevalent among malignant (36 of 81, 44%) than among borderline (3 of 39, 8%) tumors and was particularly prevalent among serous invasive carcinomas (16 of 26, 62%). Conversely, mutations in codon 12 of Ki-RAS were significantly more prevalent in borderline (16 of 39, 41%) than in malignant (9 of 81, 11%) ovarian tumors and were most prevalent among mucinous tumors. This preliminary molecular analysis suggests that serous borderline tumors have some molecular features usually associated with malignancy but are unlikely to represent a precursor of invasive serous carcinoma. In contrast, mucinous borderline tumors may represent a precursor or variant of mucinous carcinoma of the ovary.
Assuntos
Adenocarcinoma Mucinoso/patologia , Carcinoma Papilar/patologia , Genes p53/genética , Genes ras/genética , Mutação , Neoplasias Ovarianas/genética , Códon , Feminino , Humanos , Estadiamento de NeoplasiasRESUMO
We compared molecular alterations in histologically homologous ovarian and uterine carcinomas, including the prevalence of allelic loss of markers on 17q (within and distal to the familial breast-ovarian cancer gene BRCA1), mutations of codon 12 of Ki-ras and immunohistochemical expression of the p53 and c-erbB2 gene products in endometrioid and papillary serous carcinomas occurring in the uterus and ovary. A total of 86 uterine and 28 ovarian endometrioid carcinomas, as well as 8 uterine and 26 ovarian papillary serous carcinomas, were evaluated. The prevalence of p53 gene product immunoreactivity was similar in papillary serous carcinomas occurring in the uterus (6 of 8, 75%) and ovary (16 of 26, 62%). Allelic loss on 17q also was seen in similarly high proportions of uterine (3 of 7, 43%) and ovarian (16 of 25, 64%) papillary serous carcinomas. In contrast, expression of the p53 gene product was seen in significantly more endometrioid tumors of the ovary (14 of 28, 50%) than in those occurring in the uterus (4 of 86, 5%) (p < 0.0001). Allelic loss on 17q also was present in significantly more ovarian (19 or 27, 70% than in uterine (2 of 72, 3%) endometrioid carcinomas (p < 0.0001). Immunohistochemical expression of c-erbB2 and mutations of codon 12 of Ki-ras were present in a minority of carcinomas. Endometrioid tumors of the ovary and endometrium, although histologically similar, may arise from different genetic events, whereas uterine papillary serous carcinoma shares with its ovarian counterpart several molecular alterations that may account for its aggressive clinical behavior.
Assuntos
Carcinoma/genética , Carcinoma/patologia , Cromossomos Humanos Par 17 , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Perda de Heterozigosidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Feminino , Humanos , Receptor ErbB-2/genética , Proteína Supressora de Tumor p53/genética , Proteínas ras/genéticaRESUMO
OBJECTIVE: To correlate mutations in BRCA1 and BRCA2 with family history of breast cancer in a first-degree relative for women diagnosed with breast cancer before age 45 who do not have a personal or family history of ovarian cancer. METHODS: Family history for women with breast cancer diagnosed before age 45 was provided by ordering physicians via a test requisition form designed for this purpose. Gene analysis was performed by dye primer sequencing for the entire coding regions of BRCA1 and BRCA2. Because a personal and family history of ovarian cancer are known to be significantly associated with mutations, women with either were excluded from analysis. RESULTS: Overall, deleterious mutations in BRCA1 or BRCA2 were identified in 85 of 440 women (19%) with breast cancer under 45. Mutations were identified in 73 of 276 women (26%) with a first degree family history of breast cancer compared to 12 of 164 without (7%) (P < .0001). When results were analyzed by the age of diagnosis in first degree relatives, mutations were identified in 56 of 185 women (30%) with at least one first degree relative with breast cancer diagnosed before age 50 compared with 17 of 91 women (19%), where the first degree family history of breast cancer was at or over age 50 (P = .042). CONCLUSION: Among women with breast cancer diagnosed before age 45, a first-degree relative diagnosed with the disease under age 50 is an indicator of a mutation in BRCA1 or BRCA2 even in the absence of a family history of ovarian cancer. Therefore, women diagnosed with early-onset breast cancer should be asked about the age of onset in any first-degree relative diagnosed with the disease, as well as about any family history of ovarian cancer. Mutations in BRCA2 account for a substantial proportion of hereditary breast cancer. Therefore, studies that are limited to BRCA1 or that do not analyze by age of onset of breast cancer in relatives may underestimate the contribution of mutations in BRCA1 and BRCA2 to women with early onset breast cancer.
Assuntos
Neoplasias da Mama/genética , Análise Mutacional de DNA , Testes Genéticos , Síndromes Neoplásicas Hereditárias/genética , Oncogenes , Deleção de Sequência , Adulto , Idade de Início , Proteína BRCA2 , Neoplasias da Mama/epidemiologia , DNA de Neoplasias/genética , Feminino , Genes BRCA1 , Predisposição Genética para Doença , Humanos , Proteínas de Neoplasias/genética , Síndromes Neoplásicas Hereditárias/epidemiologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Reação em Cadeia da Polimerase , Fatores de Transcrição/genética , Utah/epidemiologiaRESUMO
We present a case of a 25-year-old patient at term pregnancy who presented with a bilateral ovarian neoplasm that was histologically and immunohistochemically indistinguishable from ependymoma of the central nervous system. Progesterone receptors were detected in primary and recurrent neoplasms by immunohistochemistry. This is the first case of this rare neoplasm to present during pregnancy as well as with bilateral ovarian involvement. Together with a previously reported case of recurrent ovarian ependymoma with estrogen and progesterone receptors, this case suggests that hormonal responsiveness of this rare neoplasm may be pathogenically significant.
Assuntos
Ependimoma/ultraestrutura , Neoplasias Ovarianas/ultraestrutura , Complicações Neoplásicas na Gravidez/diagnóstico , Receptores de Progesterona/análise , Adulto , Ependimoma/química , Ependimoma/complicações , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Ovarianas/química , Neoplasias Ovarianas/complicações , Ovário/química , Ovário/patologia , Ovário/ultraestrutura , Gravidez , Complicações Neoplásicas na Gravidez/patologiaRESUMO
Chronic endometritis is characterized histologically by plasma cells infiltrating endometrial stroma. Although it has been speculated that many instances of chronic endometritis are infectious, the origin of most cases is not apparent by routine histopathologic evaluation. Chlamydia trachomatis, an obligate intracellular bacterium, is known to cause chronic endometritis in the setting of pelvic inflammatory disease. The authors analyzed 43 specimens of histopathologically diagnosed chronic endometritis from 38 patients for C trachomatis by PCR using primers for the single-copy major outer membrane protein (MOMP) gene. C trachomatis was detected in only one such case in which dense plasma cell infiltrates were present and concurrent C trachomatis infection of the cervix was documented. Using serially diluted DNA from formalin-fixed, paraffin-embedded McCoy cells, the sensitivity of this method was shown to be equivalent to a single infected cell in a paraffin section. In conjunction with the results of other studies, these data indicate a limited role, if any, of C trachomatis in the origin of mild or moderate chronic endometritis.
Assuntos
Chlamydia trachomatis/genética , Chlamydia trachomatis/isolamento & purificação , DNA Bacteriano/análise , Endometrite/microbiologia , Adolescente , Adulto , Idoso , Doença Crônica , Endometrite/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Plasmócitos/patologia , Reação em Cadeia da PolimeraseRESUMO
Cytomegalovirus lung infection may produce perivascular lymphocytic infiltrates indistinguishable from those found in lung biopsy samples obtained from lung transplant recipients with acute rejection. With the polymerase chain reaction used to detect cytomegalovirus DNA, 43 transbronchial samples from 26 lung or combined heart-lung transplant recipients were analyzed, as were lung biopsy samples (devoid of characteristic cytomegalic cells) obtained from 18 non-lung transplant recipients who were not immunosuppressed. Of 25 samples manifesting acute rejection, nine contained cytomegalovirus DNA. Eight samples negative for rejection also contained cytomegalovirus DNA. Cytomegalovirus DNA was detected in 2 of 18 samples from the patients not undergoing transplantation. A significant correlation was noted between cytomegalovirus culture and polymerase chain reaction results (p = 0.01). There was no association between the presence of cytomegalovirus DNA sequences and patient antibody titer status or histologic evidence of rejection (p > 0.5). Cytomegalovirus sequences were found in 44% of transplant lung samples that did not manifest perivascular infiltrates or other evidence of rejection and 36% of transplant samples manifesting perivascular infiltrates. From these results it would seem that cytomegalovirus infection is just as likely not to be accompanied by perivascular infiltrates as to be associated with them. It may be appropriate to regard perivascular lymphoid infiltrates as more likely a sign of acute rejection.