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Biomedical subjects

G L Mutter

Publications and source records attributed to G L Mutter.

At least 19 recordsLinked to original sources
PubMed2005

Variability in organ-specific EGFR mutational spectra in tumour epithelium and stroma may be the biological basis for differential responses to tyrosine kinase inhibitors.

Organ-specific differences in epidermal growth factor receptor (EGFR) mutational spectra and frequencies were found in lung cancer and sporadic and BRCA1/2-related breast cancers. Additionally, we found a high frequency of EGFR mutations in the tumour stroma of these invasive breast carcinomas. Those organ-specific mutational spectra and potential targets in the cancer-associated stroma might influence the efficacy of TKI therapy.

Antineoplastic Agents↗
PubMed2005

EIN and WHO94.

Explore the source record for details and available documents.

Diagnosis, Differential↗
PubMed2002

Diagnosis of premalignant endometrial disease.

Modern molecular methods for precancer diagnosis have expanded the range of detectable disease to a preclinical level and provided material for histopathological correlation. The precancer scenario begins with sporadic acquisition of rare PTEN mutation bearing glands, which are morphologically unremarkable, and progresses to discrete foci of cytologically altered glands, readily visible on routinely stained sections. Clinical outcome studies of women with endometrial lesions have established threshold diagnostic features that confer increased cancer risk. This class of high risk lesions has been designated endometrial intraepithelial neoplasia (EIN). EIN is diagnosed by presence of cytological demarcation, crowded gland architecture, minimum size of 1mm, and careful exclusion of mimics. Most EIN lesions have been diagnosed as atypical endometrial hyperplasias in the World Health Organisation system. Specialised molecular and morphometric analyses have been extremely useful in redefining clinically relevant premalignant endometrial disease, but translation to improved patient care requires the informed participation of pathologists.

Endometrial Neoplasms↗
PubMed2001

A compendium of gene expression in normal human tissues.

This study creates a compendium of gene expression in normal human tissues suitable as a reference for defining basic organ systems biology. Using oligonucleotide microarrays, we analyze 59 samples representing 19 distinct tissue types. Of approximately 7,000 genes analyzed, 451 genes are expressed in all tissue types and designated as housekeeping genes. These genes display significant variation in expression levels among tissues and are sufficient for discerning tissue-specific expression signatures, indicative of fundamental differences in biochemical processes. In addition, subsets of tissue-selective genes are identified that define key biological processes characterizing each organ. This compendium highlights similarities and differences among organ systems and different individuals and also provides a publicly available resource (Human Gene Expression Index, the HuGE Index, http://www.hugeindex.org) for future studies of pathophysiology.

Cluster Analysis↗
PubMed2001

Molecular identification of latent precancers in histologically normal endometrium.

Discovery of somatically mutated cells in human tissues has been less frequent than would be predicted by in vitro mutational rates. We analyzed the PTEN tumor suppressor gene as an early marker for endometrial carcinogenesis, and we show that 43% of histologically normal premenopausal endometria contain rare glands that fail to express PTEN protein because of mutation and/or deletion. These persist between menstrual cycles. Histopathology of PTEN-null glands is initially unremarkable, but with progression, they form distinctive high-density clusters. These data are consistent with a progression model in which initial mutation is not rate limiting.

Adult↗
PubMed2001

Identification of a basal/reserve cell immunophenotype in benign and neoplastic endometrium: a study with the p53 homologue p63.

BACKGROUND: Metaplastic differentiation, including squamous, mucinous, and tubal (ciliated), is common in both benign and neoplastic endometrium, and the cell of origin for this pathway is poorly understood. In this study, expression of a marker for basal and reserve cells in cervical squamous mucosa, designated p63, was investigated in a spectrum of endometrial alterations. METHODS: One hundred ninety different endometria from 132 patients were examined, including fetal (6), premenarchal (3), benign cyclic (29) and noncyclic (54), hyperplastic (14), and neoplastic (93) endometrial glandular epithelia. The latter included conventional endometrioid carcinomas with and without mucinous, ciliated, and squamous metaplasia, and uterine papillary serous carcinoma (UPSC). RESULTS: p63 expression was identified in basal/subcolumnar cells in the fetal endometrium in a distribution similar to that in basal/reserve cells of the cervix. Staining was confined to individual scattered basal and suprabasal cells in cycling endometrium. In polyps and postmenopausal endometria, focal clusters of p63-positive cells were identified in inactive glands or surface epithelium. Metaplastic (squamous or mucinous) epithelia, either alone or in conjunction with hyperplasias or carcinomas, exhibited the most intense staining, primarily in basal or subcolumnar cells. In some cases, immediately adjacent nonmetaplastic columnar epithelium also stained positive. UPSCs contained only rare scattered p63-positive cells. CONCLUSIONS: Cells with a basal or reserve cell phenotype exist in the endometrium during fetal life, are not conspicuous during the reproductive years, but may emerge during shifts in differentiation. Whether these cells signify specialized multipotential endometrial cells is not clear, but the similarity of these cells to basal/reserve cells of the cervix and their association with neoplasia merit further study.

Animals↗
PubMed2001

Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation.

OBJECTIVE: Endometrioid endometrial carcinoma is caused by a combination of mutational events and hormonal factors. We used large-scale messenger RNA expression analysis to discover genes that distinguish neoplastic transformation and examine the patterns of tumor expression of those genes which are normally regulated during the menstrual cycle. METHODS: Expression of approximately 6000 unique genes was quantified in 4 normal (2 proliferative, 2 secretory) and 10 malignant endometria using Affymetrix Hu6800 GeneChip probe arrays. Expression differences between normal and malignant tissue groups were measured by a test of statistical significance comparing the individual t statistic for each gene to the distribution of maximum t statistics among all genes following 1001 permutations of the tissue group assignments (Permax test). Hormonally responsive genes, selected by comparison of proliferative and secretory subsets of normal endometria using a combination of filters applied to the group means and t test rankings, were then examined in the tumors. RESULTS: Fifty genes with a Permax <0.50 provided excellent discrimination between normal and malignant groups and were predominantly characterized by diminished expression levels in the cancers. We found that 100 genes which are hormonally regulated in normal tissues are expressed in a disordered and heterogeneous fashion in cancers, with tumors resembling proliferative more than secretory endometrium. CONCLUSION: Neoplastic transformation is accompanied by predominant loss of activity of many genes constitutively expressed in normal source tissues and absence of expression profiles which characterize the antitumorigenic progestin response.

Adult↗
PubMed2001

Phytoestrogen supplementation and endometrial cancer.

BACKGROUND: Phytoestrogens are increasingly used by patients as "natural" alternatives to hormone replacement. Attention in scientific and lay literature has focused on their potential to prevent menopausal symptoms, bone loss, heart disease, or breast cancer. Less is known about effects on the endometrium, specifically, whether prolonged exposure to phytoestrogens could promote hyperplasia or neoplasia, as does unopposed estrogen. CASE: We report the case of a woman diagnosed with grade 1 endometrioid adenocarcinoma of the endometrium whose history was notable for extensive use of supplemental phytoestrogens. CONCLUSION: The effects of phytoestrogens on endometrial tissue are not known. Given their increasing popularity and availability in concentrated form as dietary supplements, additional research is warranted before we can counsel our patients regarding the safety of such supplements.

Adult↗
PubMed2001

A therapeutic target for hormone-independent estrogen receptor-positive breast cancers.

BACKGROUND: The action of the steroid hormone estradiol (E2) is mediated via interaction with a specific receptor (ER) that initiates a series of events downstream, leading to the modulation of hormone-responsive genes and cell proliferation. Antihormones also bind, but do not confer the active configuration to ER, thereby, blocking the transmission of E2-ER-initiated signals for cell proliferation. Although these compounds qualify for successful therapy of ER-positive [ER (+)] breast cancer patients, only a fraction of patients responds to antihormone treatment. In this study, the functional status of ER is determined to identify alternative targets for therapy of antihormone-resistant ER (+) breast cancers. METHOD: The interaction of ER with a specific DNA sequence, designated as E2 response element (ERE), was targeted to assess the functional state of ER. ER-ERE complex formation was measured by electrophoretic mobility shift assay (EMSA) and by a newly developed technique, based on the preferential binding of DNA-protein complex to a nitrocellulose membrane (NMBA) that measures both total and functional fraction of ER. RESULTS: The NMBA assay identified functional variants of ER among ER (+) breast cancer cell lines and breast tumor biopsy specimens. ER of (21PT) cells did not bind E2 and these cells were tamoxifen (TAM) resistant. However 21PT cells were sensitive to a calmodulin (CaM) antagonist, W7, that blocked ERE-ER complex formation. CONCLUSIONS: ER variants of the 21PT type were detected among breast cancer biopsy specimens, emphasizing the significance of an alternative therapeutic target for TAM-resistant ER (+) human breast cancers with compounds such as W7.

Adult↗
PubMed2000

Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers.

BACKGROUND: PTEN tumor suppressor gene mutations are the most frequent genetic lesions in endometrial adenocarcinomas of the endometrioid subtype. Testing the hypothesis that altered PTEN function precedes the appearance of endometrial adenocarcinoma has been difficult, however, partly because of uncertainties in precancer diagnosis. METHODS: Two series of endometrial cancer and precancer (endometrial intraepithelial neoplasia, as diagnosed by computerized morphometric analysis) tissue samples were studied, one for PTEN mutations by the use of denaturing gradient gel electrophoresis and another for PTEN protein expression by immunohistochemistry. Endometria altered by high estrogen levels that are unopposed by progestins-conditions known to increase cancer risk-were also studied by immunohistochemistry. Fisher's exact test was used for statistical analysis. RESULTS: The PTEN mutation rate was 83% (25 of 30) in endometrioid endometrial adenocarcinomas and 55% (16 of 29) in precancers, and the difference in number of mutations was statistically significant (two-sided P =.025). No normal endometria showed PTEN mutations. Although most precancers and cancers had a mutation in only one PTEN allele, endometrioid endometrial adenocarcinomas showed complete loss of PTEN protein expression in 61% (20 of 33) of cases, and 97% (32 of 33) showed at least some diminution in expression. Cancers and most precancers exhibited contiguous groups of PTEN-negative glands, while endometria altered by unopposed estrogens showed isolated PTEN-negative glands. CONCLUSIONS: Loss of PTEN function by mutational or other mechanisms is an early event in endometrial tumorigenesis that may occur in response to known endocrine risk factors and offers an informative immunohistochemical biomarker for premalignant disease. Individual PTEN-negative glands in estrogen-exposed endometria are the earliest recognizable stage of endometrial carcinogenesis. Proliferation into dense clusters that form discrete premalignant lesions follows.

Biomarkers, Tumor↗
PubMed2000

Linking gene expression patterns to therapeutic groups in breast cancer.

A major objective of current cancer research is to develop a detailed molecular characterization of tumor cells and tissues that is linked to clinical information. Toward this end, we have identified approximately one-quarter of all genes that were aberrantly expressed in a breast cancer cell line using differential display. The cancer cells lost the expression of many genes involved in cell adhesion, communication, and maintenance of cell shape, while they gained the expression of many synthetic and metabolic enzymes important for cell proliferation. High-density, membrane-based hybridization arrays were used to study mRNA expression patterns of these genes in cultured cells and archived tumor tissue. Cluster analysis was then used to identify groups of genes, the expression patterns of which correlated with clinical information. Two clusters of genes, represented by p53 and maspin, had expression patterns that strongly associated with estrogen receptor status. A third cluster that included HSP-90 tended to be associated with clinical tumor stage, whereas a forth cluster that included keratin 14 tended to be associated with tumor size. Expression levels of these clinically relevant gene clusters allowed breast tumors to be grouped into distinct categories. Gene expression fingerprints that include these four gene clusters have the potential to improve prognostic accuracy and therapeutic outcomes for breast cancer patients.

Adult↗
PubMed2000

Somatic mitochondrial DNA (mtDNA) mutations in papillary thyroid carcinomas and differential mtDNA sequence variants in cases with thyroid tumours.

Somatic mutations in mtDNA have recently been identified in colorectal tumours. Studies of oncocytic tumours have led to hypotheses which propose that defects in oxidative phosphorylation may result in a compensatory increase in mitochondrial replication and/or gene expression. Mutational analysis of mtDNA in thyroid neoplasia, which is characterised by increased numbers of mitochondria and is also one of the most common sites of oncocytic tumours. has been limited to date. Using the recently developed technique of two-dimensional gene scanning, we have successfully examined 21 cases of thyroid tumours, six cases of non-neoplastic thyroid pathology, 30 population controls, nine foetal thyroid tissues and nine foetal tissues of non-thyroid origin, either kidney or liver. We have identified three different somatic mutations (23%) in papillary thyroid carcinomas. In addition, we have found significant differential distributions of mtDNA sequence variants between thyroid carcinomas and controls. Interestingly, these variants appear to be more frequent in the genes which encode complex I of the mitochondrial electron transport chain compared to normal population controls. These findings suggest first, that somatic mtDNA mutations may be involved in thyroid tumorigenesis and second, that the accumulation of certain non-somatic variants may be related to tumour progression in the thyroid.

Adenoma↗
PubMed2000

Endometrial precancer diagnosis by histopathology, clonal analysis, and computerized morphometry.

Management of endometrial precancers is compromised by longstanding debate over the natural history of endometrial hyperplasias and inconsistencies in their diagnosis. The recent demonstration that some hyperplasias, like cancers, are phenotypically monoclonal is useful in recognizing biological precancers. A clonal analysis has been undertaken of a series of 93 endometrial tissues and their morphology has been evaluated by subjective diagnostic classification and computerized morphometric analysis. A pathologist's diagnosis of atypical endometrial hyperplasia was highly associated with monoclonal growth. Both microsatellite-stable and microsatellite-unstable precancers were classified as atypical hyperplasias, indicating overlapping morphologies for these two groups. Diagnosis of non-atypical endometrial hyperplasias was not reproducible and identified a group of lesions equally likely to be monoclonal as polyclonal. Computerized morphometry resolved these lesions into monoclonal and polyclonal subgroups with a high degree of accuracy and reproducibility. The predictive value of morphometry was dominated by that fraction of the sample which consisted of stroma (volume percentage stroma). This can be measured manually and used to predict monoclonality when below the threshold value of 55%. This study shows that morphometric analysis reproducibly and precisely identifies monoclonal endometrial precancers from histological sections. It may serve, furthermore, to classify accurately lesions judged by pathologists as indeterminate (non-atypical hyperplasias). The material from this study (available at www.endometrium.org from March 1, 2000) and precisely defined architectural diagnostic criteria provide new tools for diagnostic standardization of endometrial precancers.

Cell Lineage↗
PubMed2000

Endometrial intraepithelial neoplasia (EIN): will it bring order to chaos? The Endometrial Collaborative Group.

The diagnosis of precancerous lesions of the endometrium remains unstandardized because existing World Health Organization classification categories do not correspond to distinctive biologic groups and are inadequately supported by reproducible histopathologic criteria. A group of gynecologic pathologists was convened to consider revised diagnostic classification and criteria based on newly available information. We propose the terms endometrial hyperplasia (EH), endometrial intraepithelial neoplasia (EIN), and adenocarcinoma to define distinctive subgroups that are functionally relevant to clinical management of patients with endometrial disease. Endometrial precancers are collectively designated EIN in recognition of their monoclonal growth. At present there is no effective strategy for constructive subdivision of EIN lesions into grades or subgroups. EIN is to be distinguished from adenocarcinoma and the diffuse hormonal changes of EH seen in anovulation. An archive of genetically and morphologically classified endometrial precancers at www.endometrium.org provides a resource for centralized review of the histopathology of EIN lesions. A new architectural criterion for EIN diagnosis, diminution of stromal volume to less than approximately half of the total sample volume, will also assist in discriminating between EH and EIN. Implementation of this proposal will bring diagnostic terminology into agreement with current concepts of premalignant endometrial disease and facilitate more uniform patient management.

Adenocarcinoma↗
PubMed2000

Intratumoral genetic heterogeneity and progression of endometrioid type endometrial adenocarcinomas.

OBJECTIVES: Development of genetic heterogeneity is one mechanism whereby tumors may acquire increasing aggressiveness during neoplastic progression. In this study we relate development of intratumoral genetic heterogeneity to invasion and metastatic spread of sporadic endometrioid (type I) endometrial adenocarcinomas. METHODS: Microsatellite unstable adenocarcinomas underwent detailed microsatellite allelotype mapping with reconstruction of neoplastic lineages using maximum parsimony analysis. RESULTS: Within individual patients, tumor allelotypes sometimes varied between regions of histologically identical tumor, indicating that genotypic variation may reflect differences inapparent by histology. Comparison of noninvasive (surface/luminal) with invasive (myometrial invasion or metastasis) carcinoma showed highly related genotypes in 3/8 cases in which the invasive component can be recognized as evolved from the superficial tumor lineage by progressive clonal selection. In 3/8 cases superficial and invasive genotypes independently evolved different sets of altered microsatellites, indicating either divergence at an early stage in tumor evolution or independent selection events. A total of 2/8 cases had random patterns of marker distribution between sampled areas that were not informative in delineating systematic relationships between surface and invasive tumor. CONCLUSIONS: We conclude from these results that endometrial tumor progression may occur through physical extension of existing clones or through creation of new subclones with altered growth properties. The latter occurs in about half of cases, where myometrial invasion may select for particular clones that are poorly represented on the luminal surface.

Alleles↗
PubMed2000

Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors.

Germline mutations in PTEN (MMAC1/TEP1) are found in patients with Cowden syndrome, a familial cancer syndrome which is characterized by a high risk of breast and thyroid neoplasia. Although somatic intragenic PTEN mutations have rarely been found in benign and malignant sporadic thyroid tumors, loss of heterozygosity (LOH) has been reported in up to one fourth of follicular thyroid adenomas (FAs) and carcinomas. In this study, we examined PTEN expression in 139 sporadic nonmedullary thyroid tumors (55 FA, 27 follicular thyroid carcinomas, 35 papillary thyroid carcinomas, and 22 undifferentiated thyroid carcinomas) using immunohistochemistry and correlated this to the results of LOH studies. Normal follicular thyroid cells showed a strong to moderate nuclear or nuclear membrane signal although the cytoplasmic staining was less strong. In FAs the neoplastic nuclei had less intense PTEN staining, although the cytoplasmic PTEN-staining intensity did not differ significantly from that observed in normal follicular cells. In thyroid carcinomas as a group, nuclear PTEN immunostaining was mostly weak in comparison with normal thyroid follicular cells and FAs. The cytoplasmic staining was more intense than the nuclear staining in 35 to 49% of carcinomas, depending on the histological type. Among 81 informative tumors assessed for LOH, there seemed to be an associative trend between decreased nuclear and cytoplasmic staining and 10q23 LOH (P = 0.003, P = 0.008, respectively). These data support a role for PTEN in the pathogenesis of follicular thyroid tumors.

Cell Nucleus↗
PubMed2000

Histopathology of genetically defined endometrial precancers.

Endometrial precancers are monoclonal, benign neoplasms prone to malignant transformation. A type collection (deposited at www.endometrium.org) of confirmed precancers has been identified by their monoclonal growth and continuity of acquired genetic markers that occur between premalignant and malignant phases of tumorigenesis. Computerized morphometry of these premalignant lesions, designated endometrial intraepithelial neoplasia (EIN), has disclosed new architectural criteria and revised cytologic criteria for their diagnosis. EIN lesions originate focally and expand in size over time, in keeping with a proliferative monoclonal origin. They are characterized by closely packed glands (volume percentage stroma < 55%) with cytology that is clearly demarcated from that of the adjacent field. A minimum homogeneous field of cytologically demarcated glands is required to accurately assess the architecture diagnostic of EIN, and morphometry-diagnosed lesions with a largest diameter of at least 1 to 2 mm have previously been shown to predict the relevant clinical outcome of concurrent or future endometrial adenocarcinoma. Nonphysiologic loss of the PTEN protein, a tumor suppressor gene mutated in many endometrioid adenocarcinomas, is seen in individual glands of endometrium exposed to unopposed estrogens and in packed clusters of EIN glands. The isolated PTEN-free glands in anovulatory endometria may be the earliest stage of endometrial tumorigenesis, but they are not readily distinguishable by routine histology, nor do they have a defined natural history.

Biomarkers, Tumor↗