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4 edition of Analysis of genetic targets contributing to mutator phenotype of endometrial cancer found in the catalog.

Analysis of genetic targets contributing to mutator phenotype of endometrial cancer

Vessela Vassileva

Analysis of genetic targets contributing to mutator phenotype of endometrial cancer

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Published by National Library of Canada in Ottawa .
Written in English


Edition Notes

Thesis (M.Sc.) -- University of Toronto, 2002.

SeriesCanadian theses = -- Th`eses canadiennes
The Physical Object
FormatMicroform
Pagination2 microfiches : negative.
ID Numbers
Open LibraryOL21789809M
ISBN 10061268766X
OCLC/WorldCa54414957

  NYU Langone Medical Center / New York University School of Medicine. (, March 13). Genetic analysis better explains how uterine cancers resist treatment. ScienceDaily. Barnetson et al. () noted that the phenotype associated with biallelic MUTYH mutations may include extracolonic manifestations, including endometrial cancer and sebaceous carcinoma, as seen in other inherited colorectal cancer syndromes such as Muir-Torre syndrome () and .   Analysis of TCGA endometrial cancer exome sequencing data Though unpublished, whole exome somatic mutation data from The Cancer Genome Atlas (TCGA, available at ) analysis of EC have recently been made available to the research community, and we therefore sought to validate our findings in their cohort of by:   MSH6 knockout rats show a germ line mutator phenotype. To confirm loss of MSH6 function, we analyzed the presence of MSI in the germ line of msh6 −/− males. Two mononucleotide repeats, (G) 20 and (A) 30, and two dinucleotide repeats, (CA) 36 and (CA) 40, were analyzed in the outcrossed offspring of 9 msh6 −/− males and 19 msh6 +/+ by:


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Analysis of genetic targets contributing to mutator phenotype of endometrial cancer by Vessela Vassileva Download PDF EPUB FB2

Sincethe use of next generation sequencing to decode the mutational landscape of endometrial tumors has not only confirmed prior knowledge of established genetic targets for serous and endometrioid endometrial carcinomas, but has also uncovered novel significantly mutated genes, referred to herein as novel genetic targets, which represent candidate cancer genes in these by: 8.

PTEN mutations are the most frequent genetic lesions in endometrial adenocarcinomas of the endometrioid subtype. PTEN mutations are reported in 25%–83% of tumors, more frequently in endometrioid carcinomas and microsatellite unstable tumors, and are, thus, the most frequent genetic alteration reported in cancers [ 34 ].Cited by: The mutator phenotype hypothesis proposes that the intrinsic genetic instability of cancer cells drives tumorigenesis by producing a pool of mutations, some of which confer a selective advantage, allowing cells to proliferate under adverse by:   We have proposed that an early step in tumor progression is the expression of a mutator phenotype resulting from mutations in genes that normally function in the maintenance of genetic stability.

There is new and strong experimental evidence that supports the concept of a mutator phenotype in by: Schwartz S Jr, Yamamoto H, Navarro M, Maestro M, Reventes J, Perucho M.

Frameshift mutations at mononucleotide repeats in caspase-5 and other target genes in endometrial and gastrointestinal cancer of the microsatellite mutator phenotype. Cancer Res ; – PubMed Google ScholarCited by: 1. and strong experimental evidence that supports the concept of a mutator phenotype in cancer.

As technologies for chromosomal visualization and DNA advance, there are increasing data that human cancer cells contain large numbers of mutations. First, I will review the concept of a mutator phenotype.

Second, I will present the recent evidence that individualCited by: Genetics of endometrial cancer. Genetic analysis, which included the detection of chromosomal deletions and duplications, as well as k-ras and Her-2/neu mutations, was performed on endometrial.

TP53 (p53) The most frequently altered cancer gene in serous EC is the TP53 tumor suppressor gene. In early landmark studies, 80%–86% of serous tumors showed positive immunostaining for p53, and 53%–90% of tumors had somatic TP53 mutations.

TP53/p53 aberrations occur very early in the genesis of serous EC. Introduction. Endometrial cancer will aff women in the United States in and will result in 10, deaths with similar incidence and mortality rates world-wide [].Frequently, outcomes for adenocarcinoma of the endometrium are favorable because of the early symptoms of irregular/postmenopausal vaginal bleeding that trigger patients to seek care when the disease is at an Cited by: Genetics of Endometrial 10% of uterine cancer cases are genetic.

We focused our analysis on WNT pathway target genes since it is one of the main regulators of endometrial. The presence of the positive replication errors (RER) phenotype in familial and multiple primary malignancies of endometrial cancer, and its association with a poor prognosis was examined.

We analyzed 40 endometrial cancers for RER. Eight endometrial cancers with the RER(+) phenotype at multiple microsatellite loci were : K. Kobayashi, S. Sagae, T. Takeda, M. Sugimura, Y. Nishioka, R. Kudo. According to the mutator phenotype theory in cancer, the rate of random mutations cannot explain the frequency of mutations in cancer, and the mutations in the genes that are essential for the.

CANCER is the result of an accumulation of somatic events, including mutations, which affect gene function. Somatic mutations occur spontaneously at a low rate due to the inherent inaccuracy of genomic processing or exposure to endogenous and exogenous mutagens (for a review, see B ertram ).According to the mutator hypothesis (N owell ; L oeb et al.

), an elevated rate of Cited by:   Cancer is a genetic disease. Most cancer-causing mutations are somatic, occurring in the affected tissue during the course of carcinogenesis; however, most cancers also have a hereditary component that is caused by predisposing mutations that affect the germline, are heritable and contribute to the initiation of by: Lynch syndrome, also called Hereditary Non-polyposis Colorectal Cancer (HNPCC) syndrome, is a hereditary cancer syndrome that increases a person’s risk of developing several different types of cancer, including endometrial (uterine) and colorectal syndrome is linked to mutations in the MLH1, MSH2, EPCAM, MSH6 or PMS2 genes.

In addition to endometrial and colon cancer. At the practical level of improving cancer survival rates, possibly the most important new concept is that of Loeb,59– 61 who formulated the concept of the “mutator phenotype”.

This idea. Endometrial carcinoma is the most common malignant tumor of the female genital tract and the fourth most common cancer in women in the Western world. 1 The annual incidence has been estimated at 10–20 perwomen. For the last 25 years, endometrial carcinoma has been subdivided into two major types (types I and II) based on epidemiology, clinical features, and conventional Cited by: a connection between a mutator phenotype and cancer development.

The role of a mutator phenotype in cancer development is also integral to Nowell's model [21] on tumor progression. On average, we identify 43 mutations per tumour, excluding four cases with a mutator phenotype that harboured inactivating mutations in mismatch repair by:   The impact of mutators on cancer therapy.

The expression of a mutator phenotype in human cancers and in particular the accumulation of subclonal and random mutations has important implications. From the data so far presented, I estimate that each cancer cell within most tumours contains >10, by:   The mutator phenotype hypothesis has been controversial for many years.

There is the extreme technical challenge of accurately quantifying very rare mutations. Also, it is argued that the number of stem cell divisions is adequate to generate the large number of mutations found in human tumors without invoking an increase in mutation rates (9).Cited by:   Endometrial cancer will aff women in the United States in and will result in 10, deaths with similar incidence and mortality rates world-wide [1].

Frequently, outcomes for adenocarcinoma of the endometrium are favorable because of the early symptoms of irregular/postmenopausal vaginal bleeding that trigger patients to seek care when the disease is at an Cited by:   MLH3 is a recently described member of the DNA mismatch repair gene family.

Based on its interaction with the MutL homologue MLH1, it was postulated that MLH3 might play a role in tumorigenesis. Germ line and somatic mutations in MLH3 have been identified in a small fraction of colorectal cancers, but the role of MLH3 in colorectal cancer tumorigenesis remains by:   A mutational analysis of three DNA mismatch repair (MMR) genes (hMLH1, hMSH2 and hMSH6) in patients with endometrial cancer who meet our criteria for familial predisposition to HNPCC‐associated endometrial cancers was performed.

Mutations were detected in 18 of the patients (%).Cited by: MSI or mutator phenotype (3, 4). MMR-deficient tumor cells are susceptible to progressive accumulation of somatic mutations at re-peated sequences in the coding regions of key target genes, such as DNA repair.

A model has been proposed for the tumor mutator pathway, in which the Cited by:   Qiao, L. & Feng, Y. Genetic variations of prostate stem cell antigen (PSCA) contribute to the risk of gastric cancer for Eastern Asians: a meta-analysis based Cited by: MOLECULAR GENETICS. The most common genes in which germline mutations may cause this disease are MSH2 on chromosome 2p16, MLH1 on chromosome 3p21 which account for approximately 90 % of cases of Lynch syndrome, MSH6 on 2p15, and much less commonly, PMS2 on chromosome 7p22, which can be a rare cause of childhood brain cancer, when biallelic mutations are present (De Vos et al.

The genetic alterations in colorectal cancer progression are determined by one of two separate and distinct underlying pathways of genomic instability.

The. NIH researchers identify novel genes that may drive rare, aggressive form of uterine cancer Serous endometrial tumors account for some of the most difficult to treat cancers of the uterine lining. Researchers have identified several genes that are linked to one of the most lethal forms of uterine cancer, serous endometrial cancer.

A FORWARD GENETIC APPROACH starts with the Phenotype. A screen (often or P-element) is set up to RECOVER mutants that exhibit the PARTICULAR PHENOTYPE of INTEREST. To define the genes that correspond with the newly generated mutations, further GENETIC MAPPING, COMPLEMENTATION CROSSES and eventually SEQUENCING will be undertaken.

Cancer Genetics Overview discusses hereditary cancers and the role of genetic variants (mutations). Get information about genetic counseling, familial cancer syndromes, genomic sequencing, germline and somatic testing, ethical and legal issues and more in this summary for clinicians.

The Cancer Genome Atlas (TCGA) targets more than 30 different cancer types, collecting hundreds of samples for each type. Each disease is studied individually by multiple groups across TCGA. Our Center is analyzing data collected for many of these diseases in order to understand each cancer more deeply.

A form of hereditary colon cancer, we now call Lynch syndrome (LS), was first identified more than years ago, but it was not until that rapid progress in unraveling the underlying genetic cause of this disease really began with the serendipitous discovery of a “mutator phenotype” in colon by: 1.

Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body.

The first sign is most often vaginal bleeding not associated with a menstrual period. Other symptoms include pain with urination, pain during sexual intercourse, or pelvic lty: Oncology, gynecology. When a woman has high circulating levels of estrogen and low levels of progesterone over long periods of time, the risk for uterine (endometrial) cancer rises.

The cells in fatty tissue also make estrogen, which helps explain why obesity (50 pounds or more overweight) is the biggest risk factor for developing this cancer. This was referred to as the “mutator phenotype.” It suggests that early mutation in stability genes (i.e.

DNA repair, mismatch repair, DNA replication, or chromosome maintenance) will lead to the mutator phenotype and further mutations contribute to the subsequent invasive and metastatic properties of the neoplastic growth.

About 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we investigated the presence and phenotypic features of Circulating Tumor Cells (CTC) in high-risk EC patients.

CTC isolation was carried out in peripheral blood samples from 34 patients, Cited by:   Genetic defects in DNA polymerase accuracy, proofreading, or mismatch repair (MMR) induce mutator phenotypes that accelerate adaptation of microbes and tumor cells.

Certain combinations of mutator alleles synergistically increase mutation rates to levels that drive extinction of haploid cells. The maximum tolerated mutation rate of diploid cells is by: acquisition of mutator phenotype in cancer genomes. The enzymatic activity of APOBEC cytidine deaminase, which is responsible for the generation of Sig2 mutations, can be variable often leading to hypermutations.

A recent study demonstrated that APOBEC activity may be associated with episodic mutation bursts in cancer cell lines [22]. An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the activation (turning on) of proto-oncogenes, but tumor suppressor genes cause cancer when they are inactivated (turned off).

Inherited abnormalities of tumor suppressor genes have been found in some family cancer syndromes. Endometrial carcinoma is the most common gynecologic cancer, ranking fourth in incidence among invasive tumors in women, after breast, lung and colon cancer.1 There are clear indications that inheritance plays a major role in certain cases of human endometrial cancer.

It has been shown that, particularly for early-onset endometrial cancer, the risk for a woman is increased nearly 3-fold if a.Genomic instability leading to a mutator phenotype is an essential feature of Only XRCC2 exon 3 was sequenced in the endometrial cancer cell lines.

XRCC2 (Ensembl #ENSG) has three coding exonis with a short 5′ untranslated region (UTR) and a long 3′ UTR.

Loss of XRCC2 function appears to contribute to the cancer phenotype Cited by: Endometrial cancers exhibit a different mechanism of tumorigenesis and progression depending on histopathological and clinical types. The most frequently altered gene in estrogen-dependent endometrioid endometrial carcinoma tumors is PTEN.

Microsatellite instability is another important genetic event in this type of tumor. In contrast, >p53 mutations or Her2/neu overexpression are Cited by: