Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endometrial cancer is the most common cancer in women with Lynch syndrome. The identification of individuals with Lynch syndrome is desirable because they can benefit from increased cancer surveillance. The purpose of this study was to determine the feasibility and desirability of molecular screening for Lynch syndrome in all endometrial cancer patients. Unselected endometrial cancer patients (N = 543) were studied. All tumors underwent microsatellite instability (MSI) testing. Patients with MSI-positive tumors underwent testing for germ line mutations in MLH1, MSH2, MSH6, and PMS2. Of 543 tumors studied, 118 (21.7%) were MSI positive (98 of 118 MSI high and 20 of 118 MSI low). All 118 patients with MSI-positive tumors had mutation testing, and nine of them had deleterious germ line mutations (one MLH1, three MSH2, and five MSH6). In addition, one case with an MSI-negative tumor had abnormal MSH6 immunohistochemical staining and was subsequently found to have a mutation in MSH6. Immunohistochemical staining was consistent with the mutation result in all seven truncating mutation-positive cases but was not consistent in two of the three missense mutation cases. We conclude that in central Ohio, at least 1.8% (95% confidence interval, 0.9-3.5%) of newly diagnosed endometrial cancer patients had Lynch syndrome. Seven of the 10 Lynch syndrome patients did not meet any published criteria for hereditary nonpolyposis colorectal cancer, and six of them were diagnosed at age >50. Studying all endometrial cancer patients for Lynch syndrome using a combination of MSI and immunohistochemistry for molecular prescreening followed by gene sequencing and deletion analysis is feasible and may be desirable.
 ...
PMID:Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. 1790 73

Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.
 ...
PMID:Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). 1732 85

In 1983, Bokhman proposed a dualistic model of endometrial tumorigenesis based on the clinical observations and clinicopathologic correlations. The majority of endometrial cancers (approximately 70-80%), designated as type I carcinomas, follow the estrogen-related pathway. Histologically, most of the type I tumors seem to arise in the background of hyperplastic endometrium, show an endometrioid differentiation, and are of low grade. Clinically, they are overall characterized by a favorable behavior. Another 10-20% of endometrial cancers, designated as type II carcinomas, follow the estrogen-unrelated pathway and arise in the background of atrophic endometrium. Type II tumors usually occur at an older age, approximately 5-10 years later than type I tumors. They are typically high-grade carcinomas of nonendometrioid differentiation, most frequently serous, less frequently clear cell. Type II carcinomas behave as an aggressive clinical course and poor prognosis. This dualistic model was subsequently supported by the molecular studies, approximately a decade later. At present, endometrioid and serous carcinoma, which represent the major phenotypes of types I and II endometrial carcinomas, respectively, are characterized by distinctive types of genetic instability and molecular alterations. In endometrioid (type I) carcinoma, four major genetic changes are responsible for the tumorigenesis, i.e. silencing of PTEN tumor suppressor gene, presence of microsatellite instability due to alterations of the mismatch repair genes, mutation of K-ras protooncogene, and alteration of beta-catenin gene. On the other hand, p53 mutation and overexpression of Her2/neu oncogene are two major genetic alterations in serous and clear cell (type II) carcinomas. However, like in any model, there is evidence for exceptions. Many endometrial carcinomas are in the gray zone with overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II endometrial cancers. Finally, a small group of endometrial carcinoma is noted to be hereditary. It is known as the most common extracolonic malignancy in hereditary nonpolyposis colorectal cancer (Lynch syndrome), an autosomal dominantly inherited disorder of cancer susceptibility. Inactivation of the mismatch repair genes MSH2 and MSH6 seems to play a central role in the tumorigenesis.
 ...
PMID:Molecular carcinogenesis of endometrial cancer. 1738 85

Identification of the microsatellite instability (MSI) phenotype in endometrial carcinoma is important given that such tumors are the most common noncolorectal tumors to occur in hereditary nonpolyposis colorectal cancer syndrome, and may bear prognostic relevance. The objective of this study was to assess the utility of immunohistochemistry (IHC), a simple and fast technique, in detecting MSI in endometrial carcinoma. The study subjects consisted of 90 endometrial carcinoma patients with equal representation of MSI-high (MSI-H) and non-MSI-H tumors. MSI was tested using the standard polymerase chain reaction-based method and the 5 NCI-recommended markers. Overall, IHC with MLH1 and MSH2 antibodies detected 69% of MSI-H tumors with a specificity of 100%. Adding PMS2 and MSH6 to the antibody panel increased the sensitivity to 91% but decreased the specificity to 83%. The most common IHC abnormality in MSI tumors was concurrent loss of MLH1/PMS2. Assessment of staining was straightforward in most cases but not in all. Staining inadequacies existed. Five stains (4 MLH1 and 1 MSH6) were not interpretable because of the lack of any internal positive control. Two percent to 10% of the cases (depending on the antibody assessed) had only focal weak staining; the highest frequency (10%) occurred with MLH1 antibody. PMS2 staining detected 7 MLH1-staining present MSI-H cases, thus partly accounting for the increased sensitivity with the 4-antibody panel. MSH6 staining identified 9 cases with loss of MSH6 alone, 6 of 9 were non-MSI-H, thus partly accounting for the decreased specificity with the 4-antibody panel. In conclusion, our results suggest that IHC is useful in detecting MSI in endometrial carcinoma. Although IHC has a lower sensitivity with more apparent staining inadequacies in detecting MSI in endometrial carcinoma than it does in colorectal carcinoma, its use in endometrial carcinoma may be an important adjunct when screening for hereditary cases. In the future, as prognostic and therapeutic implications of MSI phenotype become better defined, it may be reasonable to perform IHC for mismatch repair proteins in large numbers of endometrial carcinomas.
 ...
PMID:Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma. 1746 Apr 59

The objective is to determine the relationship between obesity and defects in DNA mismatch repair (MMR) in women with endometrial cancer and to establish whether our previous finding of a higher rate of previous malignancy in thinner women with endometrial cancer is related to these factors. Specimens from 109 patients with primary uterine cancer were used to create a tissue microarray, which was stained with antibodies against MMR genes MLH1, MSH2, MSH6, and PMS2. Genotyping of normal and tumor tissues for microsatellite instability (MSI) was performed. Patients were stratified by body mass index (BMI) and correlated with a history of previous malignancy and defects in MMR. The average BMI of the overall population was 33 kg/m(2). Defective MMR was seen in 22% of tumors. The mean BMI in patients with tumors with MSI was 30.5, compared with 33.8 in microsatellite stable (MSS) tumors (P= 0.06); MSS tumors were more commonly seen in patients with a BMI more than 40 (25% vs 5% in patients with tumors with MSI, P= 0.07). Prior to their diagnosis of endometrial cancer, 16/109 (15%) patients reported having a prior malignancy, 11 (69%) had breast cancer, and 1 had colorectal cancer. Patients with tumors with MSI had previous cancer in 17% of cases, compared with 14% of patients with MSS tumors (P= 0.75). Our previous finding of an increased rate of prior malignancy in thinner patients with endometrial cancer does not appear to be due to alterations in MMR, and hereditary nonpolyposis colorectal cancer-associated cancers are rarely the prior malignancy.
 ...
PMID:Correlation between patient weight and defects in DNA mismatch repair: is this the link between an increased risk of previous cancer in thinner women with endometrial cancer? 1746 51

Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly MLH1, MSH2, and MSH6, underlie Hereditary non-polyposis colorectal cancer (HNPCC) and are mostly family-specific, with few reported founder mutations in MSH2 (Ashkenazim) MLH1 (Finnish). No mutations in colon cancer susceptibility genes have ever been reported in Druze individuals, a Moslem related faith encompassing approximately 1,000,000 individuals worldwide. A novel MSH2 mutation is described in a Druze HNPCC family: a multigenerational family with 10 members in 4 generations affected with colorectal cancer (mean age of diagnosis 46.5 years), two with gastric cancer and one--endometrial cancer. Mutational analysis of the MSH2 gene using denaturing gradient gel electrophoresis (DGGE) and direct sequencing revealed the c.702delA mutation in codon 234 of exon 4 of the MSH2 gene leading to a premature early stop in codon 245, p.Thr234fsX245. Analysis of mutation-carrying or presumed carriers individuals' offspring, revealed 11/42 asymptomatic mutation carriers, age range 17-50 years. The mutation was not present in two additional Druze HNPCC families and 20 Druze sporadic colon cancer patients. This is the first mutation ever reported in a colon cancer susceptibility gene in a Druze family and it appears not to be a founder mutation in Druze individuals with HNPCC.
 ...
PMID:A novel MSH2 germline mutation in a Druze HNPCC family. 1766 Nov 83

The family histories of 130 individuals with documented hereditary non-polyposis colorectal cancer (HNPCC) (caused by mutations in mismatch-repair (MMR) genes MSH2 (n = 64), MLH1 (n = 62) or MSH6 (n = 4)) were obtained, and incidence of cancers in those families was compared to that in the general population. There were a total of 982 cancers in 723 individuals. Colorectal cancer (CRC) was the commonest type (64% and 55% in individuals from families with germline MLH1 and MSH2 mutations respectively). Median age at diagnosis of first CRC in MSH6 mutation families was 59 years compared to 45 years in both MLH1 and MSH2 mutation families. The relative risk (RR) of endometrial cancer was 55 in MSH2 mutation families, compared with 27 in MLH1 mutation families, and 37 in MSH6 mutation families; median age at diagnosis 49 years. Even within MSH2 families, endometrial cancer tended to cluster, with 28 of the 58 cases coming from families with three or more cases (P < 0.001). Absolute risk of endometrial cancer in MLH1 families was still greater than any other cancer (other than CRC). 5% of cancers in both MLH1 and MSH2 mutation families were gastric (RR = 12); 53% of these were diagnosed before 50 years. Seven cases of small intestinal cancer occurred in MSH2 and MLH1 mutation families (RR = 26). There were 13 cases of cancer of the ureter; all were in MSH2 families. These cancers tended to cluster within families (P < 0.001); three of seven families with urothelial cancer had such cases in two or more individuals; two others had kidney cancer. Nineteen of 27 ovarian cancers (70%) were in MSH2 mutation families and 70% of these were diagnosed before age 50 years. There were 9 cases of sebaceous skin cancer, 3 in two MLH1 and 6 in four MSH2 mutation families. Of 22 pancreatic cancers, 14 were known to be diagnosed before 60 years. Breast cancer RR was 1.7 overall. The type of mutation (truncating or other type, and site of mutation) showed no obvious correlation with the presence or absence of extra-colonic cancers in families.
 ...
PMID:Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). 1793 62

Endometrial cancer is the second most common cancer in hereditary nonpolyposis colorectal cancer (HNPCC). It has often been overlooked to explore the possibility of HNPCC in endometrial cancer patients. Our study was to investigate how many HNPCC patients existed among endometrial cancer patients. Among patients who underwent hysterectomy for endometrial cancer at Seoul National University Hospital from 1996 to 2004, 113 patients were included, whose family history and clinical data could be obtained and tumor specimens were available for microsatellite instability (MSI) testing and immunohistochemical (IHC) staining of MLH1, MSH2 and MSH6 proteins. There were 4 (3.5%) clinical HNPCC patients fulfilling the Amsterdam criteria II, and 2 (2/4, 50%) of them carried MSH2 germline mutations. There were also 8 (7.1%) suspected HNPCC (s-HNPCC) patients fulfilling the revised criteria for s-HNPCC, and one (1/8, 12.5%) of them revealed MLH1 germline mutation. In 101 patients, who were not clinical HNPCC or s-HNPCC, 11 patients showed both MSI-high and loss of expression of MLH1, MSH2 or MSH6 proteins, and 2 (2/11, 18.2%) of them showed MSH6 germline mutations. In 113 patients with endometrial cancer, we could find 5 (4.4%) HNPCC patients with MMR germline mutation and 2 (1.8%) clinical HNPCC patients without identified MMR gene mutation. Family history was critical in detecting 3 HNPCC patients with MMR germline mutation, and MSI testing with IHC staining for MLH1, MSH2 and MSH6 proteins was needed in the diagnosis of 2 HNPCC patients who were not clinical HNPCC or s-HNPCC, especially for MSH6 germline mutation.
 ...
PMID:Hereditary nonpolyposis colorectal cancer in endometrial cancer patients. 1797 65

Lynch syndrome is the predisposition to visceral malignancies that are associated with deleterious germline mutations in DNA mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2. Muir-Torre syndrome is a variant of Lynch syndrome that includes a predisposition to certain skin tumors. We determined the frequency of Muir-Torre syndrome among 50 Lynch syndrome families that were ascertained from a population-based series of cancer patients who were newly diagnosed with colorectal or endometrial carcinoma. Histories of Muir-Torre syndrome-associated skin tumors were documented during counseling of family members. Muir-Torre syndrome was observed in 14 (28%) of 50 families and in 14 (9.2%) of 152 individuals with Lynch syndrome. Four (44%) of nine families with MLH1 mutations had a member with Muir-Torre syndrome compared with 10 (42%) of 24 families with MSH2 mutations (P = .302). Families who carried the c.942+3A>T MSH2 gene mutation had a higher frequency of Muir-Torre syndrome than families who carried other mutations in the MSH2 gene (75% vs 25%; P = .026). Muir-Torre syndrome was not found in families with mutations in the MSH6 or PMS2 genes. Our results suggest that Muir-Torre syndrome is simply a variant of Lynch syndrome. Screening for Muir-Torre syndrome-associated skin lesions among patients with Lynch syndrome is recommended.
 ...
PMID:The frequency of Muir-Torre syndrome among Lynch syndrome families. 1827 Mar 43

Ovarian malignancies occurring in the setting of hereditary nonpolyposis colorectal carcinoma syndrome typically present in young women, often as the first or "sentinel" cancer, but the frequency of microsatellite instability (MSI) and mismatch repair (MMR) defects in ovarian surface epithelial malignancies in women <or=50 years of age is neither well known nor well tested. Fifty-two ovarian surface epithelial carcinomas, including 4 with synchronous endometrial carcinomas, were identified in patients 50 years of age or younger and evaluated for evidence of MSI and MMR protein deficiency. Each case was tested for MSI by multiplex polymerase chain reaction amplification of the National Cancer Institute reference panel (BAT25, BAT26, D2S123, D5S346, and D17S250) and deficiency of MMR protein expression by immunohistochemistry (MLH1, MSH2, MSH6, and PMS2). MMR protein expression and MSI (in a subset of cases) were also evaluated in 50 unselected ovarian serous tumors of low malignant potential , a tumor common in younger women. Defects in MMR were detected in 5 of 52 (10%) ovarian carcinomas by at least 1 testing method, including 2 of 4 (50%) ovarian cancers presenting with synchronous endometrial cancer. Three of the 5 (60%) ovarian carcinomas were clear cell carcinomas (17% of all pure clear cell carcinomas) and the remaining 2 were high-grade carcinomas with endometrioid and mixed histology. Loss of MSH2 and MSH6 was detected in all of the affected clear cell carcinomas and a synchronous endometrial cancer with endometrioid histology. Loss of 1 or more MMR proteins was initially noted in 10/50 ovarian serous tumors of low malignant potential on tissue microarray, but further testing on full tissue sections showed intact protein expression and microsatellite stability in all informative cases. This study demonstrates a 10% rate of MMR-deficient ovarian cancer in women <or=50 years of age. MMR-deficient ovarian cancer is frequently associated with loss of expression of MSH2 and MSH6 proteins and clear cell histology. The occurrence of MMR inactivation in a significant proportion of ovarian clear cell carcinomas (17% in this study) suggests that this tumor may warrant targeted testing in women <or=50 years of age.
 ...
PMID:Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger. 1846 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>