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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
PubMed1999

Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast.

Germline mutations in PTEN, encoding a dual-specificity phosphatase on 10q23.3, cause Cowden syndrome (CS), which is characterized by a high risk of breast and thyroid cancers. Loss of heterozygosity of 10q22-24 markers and somatic PTEN mutations have been found to a greater or lesser extent in a variety of sporadic component and noncomponent cancers of CS. Among several series of sporadic breast carcinomas, the frequency of loss of flanking markers around PTEN is approximately 30 to 40%, and the somatic intragenic PTEN mutation frequency is <5%. In this study, we analyzed PTEN expression in 33 sporadic primary breast carcinoma samples using immunohistochemistry and correlated this to structural studies at the molecular level. Normal mammary tissue had a distinctive pattern of expression: myoepithelial cells uniformly showed strong PTEN expression. The PTEN protein level in mammary epithelial cells was variable. Ductal hyperplasia with and without atypia exhibited higher PTEN protein levels than normal mammary epithelial cells. Among the 33 carcinoma samples, 5 (15%) were immunohistochemically PTEN-negative; 6 (18%) had reduced staining, and the rest were PTEN-positive. In the PTEN-positive tumors as well as in normal epithelium, the protein was localized in the cytoplasm and in the nucleus (or nuclear membrane). Among the immunostain negative group, all had hemizygous PTEN deletion but no structural alteration of the remaining allele. Thus, in these cases, an epigenetic phenomenon such as hypermethylation, -ecreased protein synthesis or increased protein degradation may be involved. In the cases with reduced staining, 5 of 6 had hemizygous PTEN deletion and 1 did not have any structural abnormality. Finally, clinicopathological features were analyzed against PTEN protein expression. Three of the 5 PTEN immunostain-negative carcinomas were also both estrogen and progesterone receptor-negative, whereas only 5 of 22 of the PTEN-positive group were double receptor-negative. The significance of this last observation requires further study.

Antibodies, Monoclonal↗
PubMed1999

Allelic loss in human papillomavirus-positive and -negative vulvar squamous cell carcinomas.

Vulvar squamous cell carcinoma (VSCC) is a biologically and morphologically diverse disease, consisting of human papillomavirus (HPV)-positive and -negative tumors that differ in their morphological phenotypes and associated vulvar mucosal disorders. This study analyzed the frequencies of allelic loss (loss of heterozygosity (LOH)) in HPV-positive and -negative VSCCs to identify potential targets for the study of preinvasive diseases, to determine whether HPV status influenced patterns of LOH, and to determine whether these patterns differed from HPV-positive tumors of another genital site, cervical squamous cell carcinomas (CSCC). DNA extracted from microdissected archival sections of two index tumors, one each HPV negative and positive, was analyzed for LOH at 65 chromosomal loci. Loci scoring positive with either sample were included in an analysis of 14 additional cases that were also typed for HPV. Frequencies of LOH at loci were computed in a panel of HPV-positive and -negative VSCCs. Twenty-nine loci demonstrated LOH on the initial screen and were used to screen the remaining 14 tumors. High frequencies of LOH were identified, some of which were similar to a prior karyotypic study (3p, 5q, 8p, 10q, 15q, 18q, and 22q) and others of which had not previously been described in VSCC (1q, 2q, 8q, 10p, 11p, 11q, 17p, and 21q). With the exception of 5q and 10p, there were no significant associations between frequency of LOH and HPV status in VSCC. LOH at 3p and 11q were frequent in both VSCC and CSCC; however, allelic losses at several sites, including 5q, 8q, 17p, 21q, and 22q, were much more common in VSCC. VSCCs exhibit a broad range of allelic losses irrespective of HPV status, with high frequencies of LOH on certain chromosomal arms. This suggests that despite their differences in pathogenesis, both HPV-positive and -negative VSCCs share similarities in type and range of genetic losses during their evolution. Whether the different frequencies of LOH observed between VSCC and CSCC are real or reflect differences in stage and/or tumor size remains to be determined by further comparisons. The role of these altered genetic loci in the genesis of preinvasive vulvar mucosal lesions merits additional study.

Carcinoma, Squamous Cell↗
PubMed1999

hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis.

It has recently been suggested that silencing of the hMLH1 gene by promoter hypermethylation is the mechanism underlying the presence of the microsatellite instability (MSI) phenotype in sporadic colon and endometrial carcinomas. To determine whether hMLH1 promoter hypermethylation is a relatively early event in endometrial tumorigenesis we evaluated endometrial hyperplasia (EH) characterized as simple, complex, and atypical (the direct precursor of endometrial carcinoma) for hMLH1 aberrant methylation. In addition, we studied the hMLH1, hMSH2, hMSH3, and hMSH6 promoter methylation and MSI status of those endometrial carcinomas with synchronous hyperplasias and those without them. We found that 11 of 12 (91%) cases of endometrial carcinoma (EC) displaying MSI had hMLH1 promoter hypermethylation, whereas aberrant methylation of any of the other mismatch repair genes was not observed. All 15 cases of EC without MSI were unmethylated at hMLH1. Abnormal methylation of hMLH1 was also present in 8 of 116 (7%) cases of EH and was restricted primarily to the atypical endometrial hyperplasia (AEH) type with coexisting endometrial carcinoma. In this set, half of EH methylated at hMLH1 displayed MSI, whereas none of the unmethylated EH had MSI. Our data suggest that hypermethylation of hMLH1 can be an early event in the pathogenesis of EC, preceding the development of an apparent MSI phenotype in a subset of cases.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Mucinous endometrial epithelial proliferations: a morphologic spectrum of changes with diverse clinical significance.

BACKGROUND: Mucinous differentiation of the endometrium can occur in a spectrum of changes ranging from benign (metaplasia) to malignant (adenocarcinomas with mucinous differentiation). Mucinous proliferations with simple architecture are generally considered benign; however, more complex growth patterns have an uncertain biologic behavior, particularly when these changes are focal and/or are encountered in biopsy or curettage material. The disparity between the degree of cytologic atypia and the neoplastic potential makes their interpretation difficult in routine practice. We categorized and prospectively studied a series of these lesions based upon their degree of architectural complexity and correlated them with follow-up curettings and hysterectomies over a period of three years. METHODS: Mucinous proliferations of the endometrium were subdivided into three categories (A, B, or C) based upon increasing degrees of architectural complexity. Type A were mucin-containing epithelial cells, present singly or in small tufts, within architecturally benign glands or involving the endometrial surface. Type B proliferations were more complex, consisting of mucin-containing epithelial cells forming small pseudoglands with rigid, punched out spaces and no supporting stroma Conspicuous cytologic atypia or architectural features such as a filiform growth pattern characterized type C alterations. One hundred two curettings and 36 hysterectomies from 52 patients were reviewed. RESULTS: Patient's ages ranged from 39 to 71 years (median, 55 yr); 41 patients (80%) were over age 50. Twenty patients (40%) were receiving hormone replacement therapy. Nineteen type A, 17 type B, and 16 type C mucinous endometrial proliferations were analyzed. Excluding those cases in which a conventional coexisting precancerous lesion was also present in the initial endometrial sample, the percentages of endometrial carcinoma following a curettage diagnosis of types A to C, respectively, were 0, 64.7%, and 100%. Carcinomas following type B alterations were all well-differentiated and all were confined to the endometrium or inner third of the myometrium. CONCLUSION: Mucinous endometrial proliferations comprise a spectrum subdivisable into biologically meaningful subsets. A high percentage of type B alterations were found to have endometrial adenocarcinoma on follow-up; however, all were well-differentiated and showed either no or minimal invasion. This finding suggests that the absence of cytologic atypia in complex mucinous lesions identifies subsets of lesions at low concurrent risk for deeply invasive cancer. The presentation of type B lesions as predominantly microglandular surface lesions without co-existing atypical hyperplasias suggests that a subset of well-differentiated adenocarcinomas arise via neoplastic alterations in surface epithelium.

Adenocarcinoma, Mucinous↗
PubMed1998

Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: a possible mechanism of breast carcinogenesis.

While conducting a search for cell cycle-regulated genes in human mammary carcinoma cells, we identified HSIX1, a recently discovered member of a new homeobox gene subfamily. HSIX1 expression was absent at the onset of and increased toward the end of S phase. Since its expression pattern is suggestive of a role after S phase, we investigated the effect of HSIX1 in the G2 cell cycle checkpoint. Overexpression of HSIX1 in MCF7 cells abrogated the G2 cell cycle checkpoint in response to x-ray irradiation. HSIX1 expression was absent or very low in normal mammary tissue, but was high in 44% of primary breast cancers and 90% of metastatic lesions. In addition, HSIX1 was expressed in a variety of cancer cell lines, suggesting an important function in multiple tumor types. These data support the role for homeobox genes in tumorigenesis/tumor progression, possibly through a cell cycle function.

Base Sequence↗
PubMed1998

Patterns of allelic loss (LOH) in vulvar squamous carcinomas and adjacent noninvasive epithelia.

The pathogenesis of carcinoma of the vulva is diverse and includes both human papilloma virus (HPV)-positive and HPV-negative pathways. The objective of this study was to correlate the morphology with patterns of loss of heterozygosity (LOH) within four vulvar carcinomas and in adjacent vulvar epithelia. Tumors were categorized as HPV positive or negative by polymerase chain reaction (PCR) analysis. Forty-one different sites of normal squamous mucosa, hyperplasia, vulvar intraepithelial neoplasia (VIN), and carcinoma were microdissected in duplicate, and each extracted DNA was analyzed in duplicate for LOH at 10 chromosomal loci by PCR and polyacrylamide gel electrophoresis. Patterns of LOH were compared within different sites of tumors and between the tumor and the noninvasive epithelia. Of three tumors with multiple invasive foci analyzed, divergent patterns of LOH were identified in two, correlating in one with differences in tumor grade. In one HPV-16-positive case, multiple sites of VIN displayed heterogeneity for LOH consistent with divergent clonal or subclonal populations, some of which were not shared by the tumor. In one HPV-negative case, LOH was found in foci of hyperplasia and differentiated VIN (atypical hyperplasia), the latter sharing LOH with the invasive carcinoma at some but not all chromosomal loci. This study suggests that a genetic relationship exists between VIN and carcinoma, irrespective of HPV involvement. It also suggests that in HPV-negative tumors, allelic loss may predate the onset of invasive carcinoma and, in some cases, cellular atypia (VIN). However, the divergent patterns of LOH observed imply that many genetic alterations in the adjacent vulvar epithelium are not directly related to the invasive carcinoma.

Carcinoma in Situ↗
PubMed1997

Role of imprinting in abnormal human development.

Parental-specific differences in the expression of certain genes (imprinting), may be implicated in the pathogenesis of anomalous gestations, but only a minority manifest themselves as malformation syndromes. Delayed or lost gestations are much more frequent sequelae, as are those disorganized to such an extent that they are usually classified as neoplastic rather than developmental processes. Expression levels from imprinted loci are dependent not only on the number of genomic alleles present and their structural integrity, but also on their specific parental origin. Anomalous expression of imprinted genes during development is sometimes caused by imbalanced representation of maternal and paternal contributions, 'uniparental disomy'. Uniparental parthenogenetic or androgenetic gestations form ovarian teratomas or complete hydatidiform moles, respectively--examples of an arrested developmental program. Uniparental disomy of individual chromosomes or portions thereof has been associated with developmental delay or gestational loss. The phenotype of hemizygous mutation or deletion of imprinted genes is modified by the parental origin of the mutant copy, with dichotomous syndromes defined by parental inheritance, as in the Prader-Willi and Angelman syndromes. Lastly, failure of the imprinting process itself, 'loss of imprinting', may quantitatively alter expression levels of normally imprinted transforming or tumor-suppressing genes, thereby increasing risk for developmental tumors such as Wilms' tumor or choriocarcinoma.

Abortion, Spontaneous↗
PubMed1997

Monoclonal origin of vulvar intraepithelial neoplasia and some vulvar hyperplasias.

Squamous neoplasms of the female genital tract, including vulvar intraepithelial neoplasia, presumably are derived from a single cell. This study addressed this hypothesis and determined the clonal status of other squamous epithelial alterations associated with vulvar carcinoma, including hyperplasia and lichen sclerosis. X chromosome inactivation patterns of 22 epithelial lesions and matched normal epithelium were determined using a polymerase chain reaction (PCR)-based assay targeting the X-linked human androgen receptor gene (HUMARA). Clonality was inferred by comparing matched lesional and control tissues as follows: 1) monoclonal, if intensity of either PCR product was skewed relative to normal reference epithelium (control), 2) polyclonal, if both lesional and control were unskewed, and 3) unknown, if both lesion and control tissues were skewed toward the same allele. Two cases were excluded because of noninformative homozygous HUMARA alleles. Of 8 vulvar intraepithelial neoplasias analyzed, 7 were scored monoclonal and 1 polyclonal. Of 12 hyperplasias, 6 were monoclonal, including one with lichen sclerosis, 2 were polyclonal, and in 4, the clonal status could not be determined. The PCR-based clonal assay supports a monoclonal derivation for vulvar intraepithelial neoplasia and, in some cases, vulvar hyperplasia, and lichen sclerosis. The finding of monoclonal hyperplasia and lichen sclerosis suggests that clonal expansion may evolve before the development of morphological atypia in these epithelia.

Carcinoma in Situ↗
PubMed1997

Pathobiology of vulvar squamous neoplasia.

Vulvar squamous carcinoma is an uncommon neoplasm that afflicts a spectrum of women and has been associated with granulomatous vulvar diseases, papillomaviruses, and chronic inflammatory disorders of the vulva. Histopathological, molecular, and epidemiological studies have revealed two subsets of vulvar squamous neoplasia, which are distinguished by their association with human papillomaviruses and patient demographics. This review summarizes the evidence both supporting the diverse pathogenesis of these tumors and the existence of factors that may be common to both groups. Ultimately, the pathway to both human papillomavirus positive and negative vulvar cancers may involve not only obvious precancerous changes but also biological events in the vulvar mucosa that precede the onset of morphological atypia.

Carcinoma, Squamous Cell↗
PubMed1997

Disseminated peritoneal leiomyomatosis. Clonality analysis by X chromosome inactivation and cytogenetics of a clinically benign smooth muscle proliferation.

Disseminated peritoneal leiomyomatosis (DPL, leiomyomatosis peritonealis disseminata) is a rare condition in which multiple histologically benign smooth muscle tumorlets diffusely stud peritoneal and omental surfaces in females, predominantly of reproductive age. Although the distribution of these lesions suggests a metastatic process, DPL generally has a benign clinical course and has been regarded as a metaplastic process. We assessed clonality of 42 tumorlets and 15 normal tissues from four females with DPL by analyzing X chromosome inactivation as indicated by the methylation status of the androgen receptor gene (HUMARA). In each of the four patients, the same parental X chromosome was nonrandomly inactivated in all tumorlets, consistent with a metastatic unicentric neoplasm, or alternatively, selection for an X-linked allele in clonal multicentric lesions. Anomalous demethylation of the marker for X inactivation (HUMARA) was associated with loss of heterozygosity for markers spanning the X chromosome, or monosomy X, in part of one leiomyomatous lesion. Biallelic demethylation of the HUMARA microsatellite polymorphism was also found in one intramural leiomyoma. Two of six DPL lesions karyotyped had cytogenetic abnormalities involving chromosomes 7, 12, and 18, suggesting a pathogenesis in common with uterine leiomyomas.

Adult↗
PubMed1996

Allelotype mapping of unstable microsatellites establishes direct lineage continuity between endometrial precancers and cancer.

Progressive microsatellite changes in replication error positive (RER+) endometrium were used to reconstruct evolutionary stages of nonfamilial adenocarcinoma. RER+ putative endometrial precancers (atypical endometrial hyperplasias) progress to RER+ carcinomas, which retain some of the altered microsatellites acquired in earlier precursor stages. The RER+ phenotype may provide a specific marker for early-stage endometrial neoplasms that cannot be resolved by routine histopathology and may be a useful tool to stratify stages in the evolution of RER+ tumors.

Adenocarcinoma↗
PubMed1996

Uteri of women with endometrial carcinoma contain a histopathological spectrum of monoclonal putative precancers, some with microsatellite instability.

We have tested the hypothesis that endometrial precancers persist in uteri of patients with endometrial carcinoma and are monoclonal. Twenty-two hysterectomies with both well-differentiated endometrial adenocarcinoma and adjacent (normal or abnormal) noncancerous endometrium underwent successful clonal analysis using a PCR assay for nonrandom X chromosome inactivation. Monoclonal lesions included endometrial carcinoma, endometrial polyps, and atypical endometrial hyperplasias, whereas normal and anovulatory endometrium were polyclonal. Comparison of the specific X chromosome copy preferentially inactivated by the matched monoclonal cancers and associated monoclonal lesions allowed us to exclude polyps, but not endometrial hyperplasias, as potential precancers. The repetitive genetic marker (HUMARA) for X inactivation was altered in some cancers, permitting identification of microsatellite instability (RER+). Two patients with RER+ cancers also had adjacent RER+ hyperplasias. The seven monoclonal and two RER+ hyperplasias had focal or diffuse cytological atypia, a feature previously associated with risk for endometrial cancer. We conclude that: (a) putative endometrial precancers and cancers share a monoclonal growth pattern; (b) cancers with microsatellite instability may acquire this feature as precancers; and (c) monoclonal endometrial precancers have the morphology of hyperplasias, which vary in the extent of cytological atypia and degree of architectural complexity.

Adenocarcinoma↗
PubMed1995

X chromosome inactivation in the normal female genital tract: implications for identification of neoplasia.

Monoclonal proliferative lesions may be identified by X chromosome inactivation skewing relative to normal polyclonal tissues. We have quantitatively analyzed X-inactivation patterns throughout polyclonal uterine tissues to develop interpretive criteria for recognition of monoclonal neoplasms. Six fresh tissue samples (two samples each of cervix, endometrium, and myometrium) were collected from hysterectomy specimens, and the percentage of androgen receptor (HUMARA) marker allele present on inactive X chromosomes was calculated from a PCR assay. Exact balancing yields 50% of the marker on the inactive X, whereas complete skewing shows either 0 or 100%. X inactivation was similar throughout the tissues of each uterus but was significantly different among the 11 women studied. Comparison of differences in X inactivation between pairs of polyclonal tissue samples within each uterus (Xi spread) permitted delineation of cumulative experimental and biological variation of this parameter. Polyclonal-polyclonal Xi spread averaged 10.7 and was independent of the tissue type, sampling site, or the individual studied. Severe baseline skewing of reference polyclonal tissues or contamination of monoclonal tissue by polyclonal cells may reduce the polyclonal-monoclonal Xi spread. The extent of X-inactivation skewing necessary to infer a monoclonal process should exceed the 20 or 27 point spread seen, respectively, between 85 and 95% of polyclonal samples.

Base Sequence↗
PubMed1995

PCR bias in amplification of androgen receptor alleles, a trinucleotide repeat marker used in clonality studies.

Trinucleotide CAG repeats in the X-linked human androgen receptor gene (HUMARA) have proved a useful means of determining X chromosome haplotypes, and when combined with methylation analysis of nearby cytosine residues permits identification of non-random X inactivation in tumors of women. Co-amplification of two alleles in a heterozygote generates PCR products which differ in the number of CAG units, and thus their melting and secondary structure characteristics. We have shown that under optimal conditions amplification efficiency of two HUMARA alleles is near-equivalent, generating PCR products in a ratio proportional to that of the genomic template. In contrast, reduction of template quantity, damage of template by ultraviolet irradiation or addition of monovalent salts (sodium chloride, sodium acetate or ammonium acetate) produces highly variable imbalances of allelic PCR products, with a strong tendency to preferentially amplify lower molecular weight alleles. Variability and biasing was diminished by substitution of 7-deaza-2'-dGTP for dGTP during amplification, an intervention which reduces stability of intramolecular and intermolecular GC base pairing. We conclude that DNA which is scanty, damaged or salt contaminated may display amplification bias of GC-rich PCR targets, potentially confounding accurate interpretation or reproducibility of assays which require co-amplification of alleles.

Alleles↗
PubMed1995

A polymerase chain reaction assay for non-random X chromosome inactivation identifies monoclonal endometrial cancers and precancers.

We hypothesize that endometrial carcinoma and their precursors share a monoclonal growth pattern and tested this thesis with archival paraffin-embedded tissues using a polymerase chain reaction-based assay for non-random X chromosome inactivation. Of the 10 well-differentiated endometrial adenocarcinoma cases with heterozygous markers (HUMARA, X-linked androgen receptor gene), 9 had skewed X inactivation consistent with a monoclonal process, and one contained a structurally altered HUMARA gene. X inactivation skewing similar to that of the tumor was seen in matched control polyclonal tissues of 4 (of 9) cases, caused by the small number of endometrial stem cells at the time of embryonic X inactivation. When the polymerase chain reaction assay was applied to four potential endometrial precancers (atypical endometrial hyperplasia) and matched control tissues, two were inconclusive, and two were found to be monoclonal. We conclude that 1) it is essential to include polyclonal control tissues in X inactivation analyses to determine whether skewing is a specific indicator of monoclonality; and 2) endometrial adenocarcinomas and some putative precancers, atypical endometrial hyperplasia, are monoclonal.

Adenocarcinoma↗
PubMed1994

Analysis of HPV-positive and -negative vulvar carcinomas for alterations in c-myc, Ha-, Ki-, and N-ras genes.

Mutation or overexpression of certain host genes, including c-myc, Ha-ras, and Ki-ras, have been associated with genital squamous neoplasia, specifically in the cervix, and have been implicated in the natural history of these tumors. The relationship of these host gene alterations to vulvar squamous cell carcinomas has not been previously studied. We analyzed archival material from 13 human papillomavirus-positive and -negative vulvar squamous cell carcinomas for mutations in Ha-, Ki-, and N-ras genes, and a smaller number of fresh samples for c-myc amplification, using PCR-based assays. For comparison, eight cervical squamous cell carcinomas (three fixed and five fresh) were also analyzed. Analysis for ras mutations revealed a previously reported silent allelic variant at nucleotide 1744 in the Ha-ras gene, but no mutations in codons 12, 13, or 61. Similarly, genomic amplification of c-myc beyond a maximum of three haploid copies was not identified in the cases. These findings indicate that alterations in myc or ras sequences are not linked to vulvar squamous cell carcinomas or to the presence or absence of HPV nucleic acids. Moreover, they apparently will not distinguish vulvar from cervical carcinomas, both groups appearing to be unlikely to harbor these sequence alterations.

Base Sequence↗
PubMed1994

Multinucleated atypia of the vulva. Report of a distinct entity not associated with human papillomavirus.

The vulvar mucosa often demonstrates epithelial nuclear atypia in association with reactive and inflammatory conditions. These nuclear changes are usually mild and can be readily distinguished from vulvar intraepithelial neoplasia (VIN) and human papillomavirus (HPV)-related lesions. In a recent survey of vulvar biopsies in reproductive-aged women, we identified 12 cases of an unusual pattern of atypia associated with multinucleated epithelial cells but lacking the usual stigmata of reactive changes, condyloma, or VIN. The average age of the patients with multinucleated atypia of the vulva (MAV) was 37 years. The multinucleated cells were commonly in the lower to middle epithelial layers and contained between two and 10 nuclei, often with prominent nucleoli. In contrast to condyloma and VIN, there was no surface atypia, and the multinucleated cells lacked hyperchromasia, irregularity, or variation in nuclear size. No significant inflammation or identifiable infectious process was present, and none of the patients had received any topical treatment other than mild corticosteroids. Two of the patients had a history of VIN at a noncontiguous site. None of the 12 cases contained HPV DNA by either in situ hybridization or polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) analysis. This is in contrast to 49 of 65 women with VIN and 21 of 26 with condyloma who had HPV demonstrable by the PCR method (p < 0.00001). Immunoperoxidase stains for herpes types I and II were also negative in all the cases. Thus, MAV appears to be a distinct entity occurring in relatively young women; when it is not associated with condyloma or VIN, MAV is not related to HPV. As the morphologic features may overlap with both condyloma and VIN, it is important that MAV not be confused with these lesions or vice versa. It is not known whether MAV is a risk factor for VIN, represents an exaggerated reactive response, or is an entity with a distinct origin.

Adult↗