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

The MLH3 gene is one of the five mismatch repair (MMR) genes associated with hereditary nonpolyposis colorectal cancer (HNPCC). Eighteen different inherited MLH3 mutations have been reported as pathogenic in an international mutation database. In several cases, a mutation was found in a patient without a family history suggestive of inherited cancer susceptibility. In some cases, a similar mutation was also found in sporadic patients and/or healthy controls. Four patients carried an MLH3 mutation together with another inherited MMR gene variation. No functional analyses have been performed to assess the pathogenicity of these 18 mutations. MLH3 has been assumed to be less important in MMR than the other HNPCC susceptibility genes MSH2, MSH6, MLH1, and PMS2, and accordingly a low-risk gene for colorectal cancer (CRC). To assess the significance of the inherited sequence variations in MLH3, we functionally characterized seven missense mutations (Q24E, R647C, S817G, G933C, W1276R, A1394T, E1451K) scattered throughout the MLH3 polypeptide. The mutations were found in CRC or endometrial cancer patients and reported as pathogenic. Our study showed that the seven mutated MLH3 proteins, in complex with their counterpart MLH1 (MutLgamma), repaired mismatches as the wild type MutLgamma but worse than a heterodimer of MLH1 and PMS2 (MutLalpha). The results confirm that MutLgamma is a less efficient MMR complex than MutLalpha and show that the MLH3 mutations alone do not interfere with MMR. Further studies are needed to evaluate the pathogenicity of MLH3 mutations in compound with other MMR mutations.
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PMID:The first functional study of MLH3 mutations found in cancer patients. 1852 50

Mono-allelic germline mutations in mismatch repair (MMR) genes lead to Lynch syndrome, an autosomal dominant syndrome with an increased risk of predominantly colorectal and endometrial cancers. Bi-allelic germline mutations in MMR genes predispose to haematological malignancies, brain tumours, gastrointestinal tumours, polyposis and features of neurofibromatosis type 1 in early childhood.We report a brother and a sister with bi-allelic germline mutations in MSH2; a pathogenic deletion of the first 6 exons and a variant of the initiation codon (c.1A>G (p.Met1?)), whereas their phenotypes (four colorectal cancers, small bowel carcinoma and 15 adenomas at age 39 and 48, and colorectal cancer, endometrial cancer and four adenomas at age 33 and 44, respectively) are more suggestive of a mono-allelic pathogenic MMR gene mutation. The carcinomas showed microsatellite instability in the presence of MLH1, PMS2, MSH2 and MSH6 proteins, indicating that the variant c.1A>G leads to an alternative protein with reduced activity that is retained in the tumours.Our data suggest that the MSH2 variant c.1A>G (p.Met1?) should not be considered as a regular pathogenic mutation that leads to a strongly increased cancer risk, though it possibly contributes to a more severe phenotype when combined with a truncating mutation on the other allele.
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PMID:Compound heterozygosity for two MSH2 mutations suggests mild consequences of the initiation codon variant c.1A>G of MSH2. 1878 Nov 92

High rates of early colorectal cancers are observed in Tunisia suggesting high genetic susceptibility. Nevertheless, up to now no molecular studies have been performed. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent cause of inherited colorectal cancer. It is caused by constitutional mutations in the DNA mismatch repair (MMR) genes. Here, we investigated a Tunisian family highly suspected of hereditary nonpolyposis colorectal cancer (HNPCC). Six patients were diagnosed with a colorectal or an endometrial cancer at an early age, including one young female who developed a colorectal cancer at 22 years and we tested for germline mutations in MMR genes. MMR genes were tested for rearrangements by MLPA (MLH1, MSH2) and the presence of point mutations by sequencing (MLH1, MSH2, MSH6). Moreover, tumors were analyzed for microsatellite instability and expression of MMR proteins, as well as for somatic rearrangements in MLH1 and MSH2 by MLPA. MMR gene analysis by MLPA revealed the presence of a large deletion in MLH1 removing exon 6. Sequence analysis of the breakpoint region showed that this rearrangement resulted from a homologous unequal recombination mediated by a repetitive Alu sequence. Moreover, tumors harbored biallelic deletion of MLH1 exon 6 and loss of heterozygosity at MLH1 intragenic markers, suggesting duplication of the rearranged allele in the tumor. This germline MLH1 rearrangement was associated to a severe phenotype in this family. This is the first report of a molecular analysis in a Tunisian family with HNPCC.
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PMID:Identification and characterization of a novel MLH1 genomic rearrangement as the cause of HNPCC in a Tunisian family: evidence for a homologous Alu-mediated recombination. 1879 5

Endometrial cancer is frequent in MMR-mutation carriers. Estimates of annual incidence rates have, however, been based on retrospective studies. The purpose of our study was to prospectively assess the incidence rates of endometrial cancer in women either having a mutation in one of the four MMR genes MLH1, MSH2, MSH6 or PMS2 (Mut+) or belonging to families meeting the revised Amsterdam criteria in which no MMR mutation was detected (Ams+). Eight out of 80 Mut+ (10%) contracted invasive endometrial cancer compared to 1/171 (0.6%) of the Ams+ (P = 0.0006). The annual incidence rate after first control was 2.5% in Mut+ and 0.2% in Ams+. Two of the 8 Mut+ women (25%) had synchronous gynaecological tumours. The numbers included did not allow for firm conclusions, but the results are in keeping with the notion that the inherited colon-endometrial cancer syndrome may be restricted to carriers of MMR mutations.
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PMID:High risk of endometrial cancer in colorectal cancer kindred is pathognomonic for MMR-mutation carriers. 1884 95

Germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2 can cause Lynch syndrome. This syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominantly-inherited disorder predominantly characterized by colorectal and endometrial cancer. Truncating MMR gene mutations generally offer a clear handle for genetic counseling and allow for presymptomatic testing. In contrast, the clinical implications of most missense mutations and small in-frame deletions detected in patients suspected of having Lynch syndrome are unclear. We have constructed an online database, the Mismatch Repair Gene Unclassified Variants Database (www.mmruv.info), for information on the results of functional assays and other findings that may help in classifying these MMR gene variants. Ideally, such mutations should be clinically classified by a broad expert panel rather than by the individual database curators. In addition, the different MMR gene mutation databases could be interlinked or combined to increase user-friendliness and avoid unnecessary overlap between them. Both activities are presently being organized by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT; www.insight-group.org).
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PMID:A database to support the interpretation of human mismatch repair gene variants. 1895 42

Hereditary non-polyposis colorectal cancer is a cancer predisposition syndrome known to be caused by heterozygous germline mutations in DNA mismatch repair genes (MMR) most commonly hMLH1, hMSH2, hMSH6. Heterozygous mutations in one of these genes confer an increased risk, mainly for colon and endometrial cancer. Recently, several publications identified that biallelic mutations in the MMR genes are associated with a more severe phenotype, including childhood malignancies and signs of neurofibromatosis type I (NF1). We report on a non-consanguineous Ashkenazi Jewish family with two affected siblings with features of NF1, colon cancer and astrocytoma at age 13 and 14. Their mother developed endometrial cancer at age 54. Their father had leukoplakia of the vocal cords with a family history of pancreatic cancer. Molecular and pathology studies were done on the tumor tissue and on genomic DNA of family members. Tumor testing demonstrated a high degree of microsatellite instability (MSI analysis), expression of MLH1 and absence of expression of both MSH2 and MSH6 proteins. A biallelic c.1906G > C (p.A636P) mutation in the hMSH2 gene was detected in the blood of one affected child. Parental genetic testing showed that each parent was heterozygote for the mutation. The c.1906G > C mutation is a founder mutation in the Ashkenazi Jewish population. To our knowledge this is the first report of homozygosity for this founder mutation.
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PMID:Homozygosity of MSH2 c.1906G-->C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I. 1910 24

Hereditary nonpolyposis colorectal cancer (HNPCC) is primarily linked to colorectal and endometrial cancer, but is associated with a broad tumor spectrum. Though not formally part of the syndrome, occasional sarcomas have been reported in individuals with HNPCC. We used the national Danish HNPCC-register to identify HNPCC families in which sarcomas had been diagnosed. Fourteen sarcomas were identified in families with mutations in MSH2, MSH6, and MLH1. The median age at sarcoma diagnosis was 43 (15-74) years. Soft tissue sarcomas predominated followed by uterine sarcomas and eight histopathological subtypes were represented with recurrent diagnoses of liposarcoma, leiomyosarcoma, and carcinosarcoma. Tumor tissue from eight cases was available for analysis of mismatch-repair (MMR) status using immunohistochemical staining and analysis of microsatellite instability, which revealed MMR defects in six of the eight tumors investigated. This suggests that sarcomas may be part of the HNPCC tumor spectrum and that colorectal cancer should be considered in the family history of sarcoma patients.
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PMID:Sarcomas associated with hereditary nonpolyposis colorectal cancer: broad anatomical and morphological spectrum. 1913 Mar

It is well-established that germline mutations in the mismatch repair genes MLH1, MSH2, and MSH6 cause Lynch syndrome. However, mutations in these three genes do not account for all Lynch syndrome (suspected) families. Recently, it was shown that germline mutations in another mismatch repair gene, PMS2, play a far more important role in Lynch syndrome than initially thought. To explore this further, we determined the prevalence of pathogenic germline PMS2 mutations in a series of Lynch syndrome-suspected patients. Ninety-seven patients who had early-onset microsatellite instable colorectal or endometrial cancer, or multiple Lynch syndrome-associated tumors and/or were from an Amsterdam Criteria II-positive family were selected for this study. These patients carried no pathogenic germline mutation in MLH1, MSH2, or MSH6. When available, tumors were investigated for immunohistochemical staining (IHC) for PMS2. PMS2 was screened in all patients by exon-by-exon sequencing. We identified four patients with a pathogenic PMS2 mutation (4%) among the 97 patients we selected. IHC of PMS2 was informative in one of the mutation carriers, and in this case, the tumor showed loss of PMS2 expression. In conclusion, our study confirms the finding of previous studies that PMS2 is more frequently involved in Lynch syndrome than originally expected.
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PMID:PMS2 involvement in patients suspected of Lynch syndrome. 1913 47

Women with hereditary nonpolyposis colorectal cancer (HNPCC) have a high risk for endometrial cancer (EC) and frequently present with a gynecologic cancer as their first or sentinel malignancy. Identification of these patients is important given their personal and family risk for synchronous and metachronous tumors. The revised Bethesda Guidelines provide screening criteria for HNPCC in colorectal cancers. However, there are currently no such screening recommendations for women with endometrial carcinoma. We applied some of the colorectal cancer screening criteria, including age and tumor morphology, to endometrial endometrioid carcinoma. The purpose of this study was to describe patient and tumor characteristics and to assess the ability of these criteria to enhance detection of mismatch repair (MMR) deficiency, and hence HNPCC in EC. Immunohistochemistry (IHC) for DNA mismatch repair (IHC-MMR) proteins was performed in a defined subset of patients with EC. This included women younger than 50 years of age and women >or=50 years whose tumors showed morphologic features suggestive of MMR deficiency (TM-MMR). The extent of IHC-MMR in the older patient group was compared with that in a comparison group of EC >or=50 years that was previously analyzed for microsatellite instability status. Seventy-one patients met the selection criteria for IHC testing; 32 (45%) showed abnormal results. The rate of IHC abnormality in the younger group was approximately 30% with a nearly equal distribution of MLH1/PMS2 and MSH2/MSH6 abnormalities. In the older age group, TM-MMR triggered IHC analysis in 31 of 34 cases. Of these, 18 cases showed loss of IHC-MMR (58% of cases), 7 with loss of MSH2/MSH6. In contrast, the rate of microsatellite instability in the comparison group was only 21%. The IHC abnormal group showed more frequent tumor infiltrating lymphocytes, dedifferentiated EC, more tumors centered in the lower uterine segment, and more frequent synchronous clear cell carcinomas of the ovary than tumors with a normal immunophenotype. Although many of the patients with loss of IHC-MMR showed personal and/or family history (13 of 32) of HNPCC-associated tumors, most did not. Tumor morphology (TM-MMR) along with IHC-MMR enhances the detection of EC patients at risk of HNPCC.
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PMID:Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities. 1923 76

Studies on mutations and mutation frequencies of the MSH6 gene, which mainly focus on new types of mutations in small samples, have been published ever since the first report of MSH6 mutation in two atypical hereditary non-polyposis colorectal cancer patients. However, the results remain inconsistent. Therefore, a systematic review was conducted and a meta-analysis was undertaken to determine the frequency of MSH6 mutation in colorectal and endometrial cancers. From 27 studies, 180 cases with MSH6 mutation in a total of 3196 cases were detected. In colorectal and endometrial cancers the MSH6 mutation frequency is 7.2 and 9.6%, respectively. MSH6 mutation frequency was 10.4% in hereditary non-polyposis colorectal cancer patients, 7.1% in atypical hereditary non-polyposis colorectal cancer patients, and 5.9% in sporadic patients. The frequency of MSH6 mutation in high microsatellite instability (MSI-H) was 11.6% and in low microsatellite instability (MSI-L) cases was (13.3%), which were higher than in microsatellite stability (MSS) cases (1.7%). The mean age of the earliest onset of colorectal and endometrial cancers in MSH6 mutation carriers was 51.2 and 56.5 yr, respectively. Data suggest that the frequency of MSH6 mutation is higher in hereditary non-polyposis colorectal cancer patients than in atypical hereditary non-polyposis colorectal cancer and sporadic patients. MSH6 mutation frequency was also higher in endometrial than colorectal cancers. The mean age of earliest onset of endometrial cancer (56.5 yr) is older than for colorectal cancer (51.2 yr) in carriers of MSH6 mutation. Our results provide evidence for clinical genetic testing and counseling.
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PMID:Meta-analysis of MSH6 gene mutation frequency in colorectal and endometrial cancers. 1949 30


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