Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The majority of tumors from patients affected by hereditary nonpolyposis colorectal cancer (HNPCC) exhibit a mutator phenotype characterized by widespread microsatellite instability (MSI) and somatic mutations in repeated sequences in several cancer-associated genes. An inverse relationship between MSI and chromosomal instability (CIN) has been demonstrated and HNPCC-associated tumors are generally characterized by diploid or near-diploid cells with few or no chromosomal rearrangements. We have studied MSI, somatic mutations in repeat-containing genes, DNA-ploidy, and cytogenetic aberrations in a colon carcinoma from a patient with a germline MLH1 mutation. Mutations in coding repeats were assessed in 10 macroscopically separate areas of the primary tumor and in two lymph nodes. Some of the genes studied (E2F4, MSH3, MSH6, TCF4, and TGFBRII) showed a consistent lack of mutations, whereas others (BAX, Caspase-5 and IGFIIR) displayed alterations in some tumor regions but not in others. The tumor had DNA-index 1.1-1.2 and a stable, aberrant karyotype with extra copies of chromosomes 7 and 12 and the structural aberrations i(1q), der(20)t(8;20), and der(22)t(1;22). The finding of CIN, MSI, and somatic mutations in coding repeats in this tumor suggests that these phenomena may act together in HNPCC tumorigenesis. Furthermore, the observed intratumoral heterogeneity of mutations in coding repeats implies these changes occur late in tumorigenesis and, thus, probably play a role in tumor progression rather than initiation.
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PMID:Cytogenetic aberrations and heterogeneity of mutations in repeat-containing genes in a colon carcinoma from a patient with hereditary nonpolyposis colorectal cancer. 1199 96

Differential gene methylation is observed in a variety of human malignancies. The study of the pattern of methylated genes helps to understand carcinogenesis and to identify potential marker tumor genes for clinical use. The differential methylated genes in undifferentiated nasopharyngeal carcinoma (NPC) of Chinese were studied by methylation-specific polymerase chain reaction (MSP). Methylation status of 11 tumor-associated genes (ARF, caspase-8, CDH1, CDKN2A, CDKN2B, MGMT, MLH1, RASSF1A, THBS1, TP73 and VHL) was studied in 30 primary undifferentiated NPC and paired peripheral blood of 12 patients. The methylation profile of NPC in order of frequency was CDH1 (50%), CDKN2B (50%), THBS1 (50%), RASSF1A (46%), MLH1 (40%), MGMT (28%), CDKN2A (23%), TP73 (20%), caspase-8 (7%), ARF (3%) and VHL (0%). Methylation of at least 1 gene was observed in 93% of primary NPC. Of the 12 patients with at least 1 methylated gene in the primary tumor, all 12 (100%) patients had at least 1 of the methylated gene promoter detectable in their peripheral blood. The results show high frequency of methylation in NPC and the potential of using methylation as peripheral blood tumor marker in screening NPC.
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PMID:Differential gene methylation in undifferentiated nasopharyngeal carcinoma. 1263 81

The case of a 46-year-old female with umbilical metastasis as a first sign of an ovarian carcinoma is reported with the results of immunohistochemical analysis of primary tumor and lymph node and umbilical metastases. All specimens were positive for cytokeratin 7, CA 125, E-cadherin, alpha-, beta-, and gamma-catenin, as well as for MSH2. Staining with cytokeratin 20 and MLH1 was negative, and Ki-67 labeled from 5% (in the center of the lesions) to over 25% (at the periphery of the lesions) of the nuclei. Beta-catenin showed membranous positivity in the central parts and absence of staining at the periphery of ovarian tumor and umbilical metastasis, whereas lymph node metastasis presented with uniform reaction throughout. The results of immunohistochemical staining could point to the mechanisms employed by malignant tumors during invasion and growth of metastasis and suggest the possible role of the microenvironment in the expression of some adhesion molecules on tumor cells.
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PMID:Umbilical metastasis (Sister Joseph's nodule) as a first sign of a disseminated ovarian carcinoma: comparative immunohistochemical analysis of primary tumor and its metastases. 1582 29

Only few clinical factors predict the prognosis of patients with Ewing tumors. Unfavorable outcome is associated with primary metastatic disease, age > 15 years, tumor volume above 200 ml, and the histological response to chemotherapy. The aim of this study was to elucidate the prevalence and clinical impact of microsatellite instability (MSI) together with the relation between MSI and mismatch repair protein expression in Ewing tumors. DNA from 61 primary Ewing tumors and 11 Ewing tumor cell lines was extracted and microsatellite analysis for the detection of instability or loss of heterozygosity was performed for the five markers of the Bethesda panel BAT25, BAT26, D5S346, D2S123, and D17S250, which represents the established marker panel for the analysis of hereditary non-polyposis colorectal carcinoma (HNPCC) patients. In addition, single nucleotide repeat regions of the two tumor genes BAX and transforming growth factor receptor II (TGFBR2) were also included. All of the 61 samples were suitable for LOH analysis and 55 for the determination of MSI-status. LOH of these microsatellite markers was detected in 9 of the 61 patients (14.8%). Over all, genetic instability, i.e. MSI and/or LOH, was detected in 17 tumors (27.9%). One out of the 11 tumor cell lines (STA ET1) was characterized by instability of all the five Bethesda markers, while from primary tumor samples, only one showed MSI in more than one microsatellite marker (D5S346 and D17S250, MSI-high). Eight of the fifty-five patients (14.5%) showed instability of one microsatellite locus (MSI-low). No instability was detected in BAT26, D2S123, BAX and TGFBR2. There was no significant correlation between MSI and loss of expression of mismatch repair proteins MLH1, MSH2, or MSH6. The impairment of the p53 signaling pathway (expression of TP53 and/or MDM2 by immunohistochemistry) was significantly associated with reduced overall survival (15 of 49 patients (30.6%), P = 0.0410, log-rank test). We conclude that MSI is not prevalent in Ewing tumor and that the nature of instability differs from the form observed in colorectal carcinoma, the model tumor of MSI. This is documented by the different pattern of MSI (no BAT26 instability) in Ewing tumors and the lack of a strict correlation between MSI-high and loss of expression of MSH2, MSH6 and MLH1.
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PMID:Microsatellite instability in Ewing tumor is not associated with loss of mismatch repair protein expression. 1753 Feb 87

Abstract Background. Mismatch repair (MMR) status has been reported as a prognostic and predictive factor in sporadic colorectal cancer (CRC). The purpose of this study was to determine the prognostic and predictive value of MMR protein expression in the adjuvant setting. Patients and methods. The MMR status in the primary tumor was retrospectively assessed on paraffin-embedded formalin-fixed samples from 1 006 patients with sporadic CRC (488 stage II and 518 stage III) using immunohistochemical analysis (IHC) of MLH1 and MSH2 expression. The patients were included in adjuvant Nordic trials between 1991 and 1996 randomly assigned to surgery alone or surgery plus adjuvant 5-fluorouracil (5-FU)-based chemotherapy. Data was censored at 120 months after surgery. Results. One hundred fifty-seven patients (15.6%) showed a loss of MMR protein expression (139 MLH1 negative, 15 MSH2 negative and 3 MLH1 and MSH2 negative) and were classified as MMR protein negative. A normal MMR protein expression was found in 849 patients who were defined as MMR protein positive. MMR protein expression was a significant prognostic marker in the entire study group with a better overall survival (OS) among patients with MMR protein negative tumors compared to patients with MMR protein positive tumors (p=0.01). In a multivariate analysis the MMR protein expression was significantly associated with OS, (HR 0.70 [95% CI, 0.40 to 0.99]; p=0.01). The MMR status did not predict survival benefit from adjuvant 5-FU-based chemotherapy. Conclusion. This study reveals that IHC of MLH1 and MSH2 expression can yield important prognostic information but is not a predictive factor for adjuvant 5-FU-based chemotherapy in sporadic CRC.
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PMID:Mismatch repair protein expression is an independent prognostic factor in sporadic colorectal cancer. 2030 45

The goal was to determine recurrent or second primary status for late stomal malignancies, 16 and 17 years post-total laryngectomy in two laryngeal squamous cell carcinoma (LSCC) patients, based on DNA methylation signatures and HPV typing. Adopting a literature review based definition of late stomal recurrences as new primaries at the site of the stoma or neopharynx occurring >5 years after total laryngectomy, we employed a multi-gene candidate approach to examine promoter methylation in 24 tumor suppressor genes and PCR-based assays for HPV status offered additional insights into whether the late stomal tumors post-total laryngectomy were related or not. The primary tumor for Patient 1 was negative for HPV but had aberrant hypermethylation of APC, MLH1 and BRCA1. The stomal biopsy 17-years later showed presence of HPV-16 without any methylated genes. In Patient 2, HPV-11 and promoter methylation of APC identified in the primary tumor was also observed in the stomal malignancy 16 years post-total laryngectomy. Additional information provided by molecular typing for HPV and methylation markers underscored Patient 1's and 2's late stomal presentation as most likely a second primary and recurrence, respectively. DNA methylation markers are particularly advantageous because DNA methylation is an early event in tumorigenesis, and the epigenetic modification, 5-methylcytosine, is a stable marker. Molecular marks to discern genetic heterogeneity or relatedness of stomal malignancies several years post-total laryngectomy can provide clues to their status as either second primaries or likely recurrences. Our results support the hypothesis that a subset of stomal recurrences after total laryngectomy represents second primary tumors.
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PMID:Molecular characterization of late stomal recurrence following total laryngectomy. 2122 33

Epigenetic silencing of the O(6) -methylguanine-DNA methyltransferase (MGMT) gene promoter is associated with prolonged survival in glioblastoma patients treated with temozolomide (TMZ). We investigated whether glioblastoma recurrence is associated with changes in the promoter methylation status and the expression of MGMT and the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 in pairs of primary and recurrent glioblastomas of 80 patients, including 64 patients treated with radiotherapy and TMZ after the first operation. Among the primary tumors, the MGMT promoter was methylated in 31 patients and unmethylated in 49 patients. In 71 patients (89%), the MGMT promoter methylation status of the primary tumor was retained at recurrence. MGMT promoter methylation, but not MGMT protein expression, was associated with longer progression-free survival, overall survival and postrecurrence survival (PRS). Moreover, PRS was increased under salvage chemotherapy. Investigation of primary and recurrent glioblastomas of 43 patients did not identify promoter methylation in any of the four MMR genes. However, recurrent glioblastomas demonstrated significantly lower MSH2, MSH6 and PMS2 protein expression as detected by immunohistochemistry. In conclusion, reduced expression of MMR proteins, but not changes in MGMT promoter methylation, is characteristic of glioblastomas recurring after the current standards of care.
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PMID:Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. 2142 58

Microsatellite instability (MSI) is caused by defective mismatch repair (MMR) and is one of the very few molecular markers with proven clinical importance in colorectal cancer with respect to heredity, prognosis, and treatment effect. The gene expression of the MMR gene MSH2 may be a quantitative marker for the level of MMR and a potential molecular marker with clinical relevance. The aim was to investigate the gene expression of MSH2 in primary operable colorectal cancer in correlation with MSI, protein expression, and promoter hypermethylation. In a cohort of 210 patients, the primary tumor and lymphnode metastases were analyzed with immunohistochemistry, methylation and MSI analyses, and quantitative polymerase chain reaction (PCR). The median gene expression of MSH2 was 1.00 (range 0.16-11.2, quartiles 0.70-1.51) and there was good agreement between the gene expression in primary tumor and lymph node metastasis (Spearman's rho = 0.57, p < 0.001, n = 73). The validity of gene expression analysis was made probable by a significant correlation to protein expression (p = 0.005). MSI was most often caused by deficient MLH1 and was not correlated to MSH2 expression. Hypermethylation of the MSH2 gene promoter was only detected in 14 samples and only at a low level with no correlation to gene expression. MSH2 gene expression was not a prognostic factor for overall survival in univariate or multivariate analysis. The gene expression of MSH2 is a potential quantitative marker ready for further clinical validation.
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PMID:Gene expression of the mismatch repair gene MSH2 in primary colorectal cancer. 2173 24

Most genetic studies in colorectal carcinomas have focused on those abnormalities that are acquired by primary tumors, particularly in the transition from adenoma to carcinoma, whereas few studies have compared the genetic abnormalities of primary versus paired metastatic samples. In this study, we used high-density 500K single-nucleotide polymorphism arrays to map the overall genetic changes present in liver metastases (n=20) from untreated colorectal carcinoma patients studied at diagnosis versus their paired primary tumors (n=20). MLH1, MSH2 and MSH6 gene expression was measured in parallel by immunohistochemistry. Overall, metastatic tumors systematically contained those genetic abnormalities observed in the primary tumor sample from the same subject. However, liver metastases from many cases (up to 8 out of 20) showed acquisition of genetic aberrations that were not found in their paired primary tumors. These new metastatic aberrations mainly consisted of (1) an increased frequency of genetic lesions of chromosomes that have been associated with metastatic colorectal carcinoma (1p, 7p, 8q, 13q, 17p, 18q, 20q) and, more interestingly, (2) acquisition of new chromosomal abnormalities (eg, losses of chromosomes 4 and 10q and gains of chromosomes 5p and 6p). These genetic changes acquired by metastatic tumors may be associated with either the metastatic process and/or adaption of metastatic cells to the liver microenvironment. Further studies in larger series of patients are necessary to dissect the specific role of each of the altered genes and chromosomal regions in the metastatic spread of colorectal tumors.
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PMID:Unique genetic profile of sporadic colorectal cancer liver metastasis versus primary tumors as defined by high-density single-nucleotide polymorphism arrays. 2222 38

It is unknown whether the type and grade of a primary endometrial carcinoma is reliably maintained in recurrence. All matched primary and recurrent endometrial carcinomas diagnosed from 2000 to 2010 at our institution were identified; 34 cases had available slides. Histologic classification was performed using modifications to the World Health Organization criteria. Immunohistochemical analysis for p53, p16, progesterone receptor (PR), and DNA mismatch-repair proteins (MMR) (MLH1, MSH2, MSH6, and PMS2) was performed. Endometrioid carcinoma recurrences were mostly local, whereas serous carcinoma recurrences were mostly peritoneal. Compared with endometrioid carcinoma patients, serous carcinoma patients were older, presented at high stage, and had shorter survival. Serous carcinomas were the most common recurrent endometrial carcinoma (18/34 cases). Overall, 21 cases (62%) displayed similar morphology when comparing primary and recurrent carcinomas, whereas 13 displayed discordant morphology. Seven of 13 endometrioid carcinomas (54%) had a morphologically discordant recurrence, compared with 3 of 14 serous carcinomas (21%), 1 of 4 morphologically ambiguous carcinomas (25%), and both mixed epithelial carcinomas. Serous and morphologically ambiguous carcinomas therefore demonstrated relative morphologic fidelity compared with endometrioid carcinomas. Four morphologically discordant cases demonstrated either pure clear cell carcinoma or clear cell features at recurrence. Seven of 23 matched pairs displayed discordant PR results, with 5 cases, including both endometrioid and serous carcinomas, showing diminished PR expression at recurrence. p53, p16, and DNA MMR staining results were generally concordant when evaluating matched pairs, with only occasional exceptions. Sixty-four percent of all pure endometrioid carcinomas and mixed epithelial carcinomas with an endometrioid component showed loss of expression of MLH1 and/or PMS2; no serous carcinoma demonstrated this abnormality. Clinical and immunohistochemical data supported the use of modifications to the World Health Organization diagnostic criteria. More importantly, the data suggest that when confronted with recurrent endometrial carcinoma, particularly a serous carcinoma, it is reasonable to base therapeutic decisions on the type of the primary tumor, especially if sampling or excising the recurrent tumor is problematic. However, in light of the PR results, sampling a recurrent endometrioid carcinoma may be worthwhile if hormonal therapy is planned. Recurrent endometrioid carcinoma may be enriched for tumors with DNA MMR abnormalities.
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PMID:Clinicopathologic analysis of matched primary and recurrent endometrial carcinoma. 2315 67


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