Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The main goal of this study was to examine the expression of DNA mismatch repair genes (MLH1, MSH2, PMS1 and PMS2), the adenomatous polyposis coli (APC) gene and growth arrest DNA damage inducible (GADD) genes (GADD34, GADD45 and GADD153) in the different stages of melanoma recurrences and metastases, and to identify any mutual consistencies in their expression pattern. All the cases of primary melanoma examined showed a reduced expression of DNA repair genes. These results demonstrate that disturbances of DNA repair begin in the early stages of melanoma. No significant differences were found in the expression of these markers between cutaneous melanomas and their recurrences and metastases (P> 0.05). Eighteen significant correlations between markers were found in the primary melanomas, and 10 significant correlations were observed in the first recurrences of melanoma. In contrast, 27 statistically significant relationships were demonstrated in metastatic lymph nodes. The different correlations found in primary and metastatic tumours confirmed the hypothetical difference in marker interaction in the diagnostic groups investigated. Our results suggest that DNA repair genes may play an important role in the recurrence and metastasis of melanomas.
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PMID:Comparative study of the expression of DNA mismatch repair genes, the adenomatous polyposis coli gene and growth arrest DNA damage genes in melanoma recurrences and metastases. 1119 75

Defects of DNA repair systems in cutaneous tumours are related to DNA mismatch repair genes (MLH1, MSH2, PMS1, PMS2) and Ku70/80 genes involved in double- strand repair. In this study we investigated the statistical relationship between these systems and DNA-ploidy-related parameters in 19 naevus cell naevi, 23 lentigos maligna, 76 primary melanomas and 31 melanoma metastases, applying the correlation coefficient according to Spearman. In naevi significant correlations were found between Ku70/80 gene expression and some ploidy-related parameters. In lentigos, additionally, some significant correlations between the expression of DNA mismatch repair genes were found. Similar results were demonstrated for primary melanomas. In metastases no one significant correlation between DNA mismatch repair genes and Ku-genes was present. We postulate that DNA mismatch repair genes and Ku70/80 genes are functionally independent and that some of them are able to influence ploidy-related parameters.
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PMID:Relationship between DNA mismatch repair genes expression, Ku-genes expression and ploidy-related parameters in the progression of pigmented lesions of the skin. 1249 70

The reference cancers associated with DNA mismatch repair (MMR)deficiency are the adenocarcinomas of patients with hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome. Sporadic gastrointestinal (GI) carcinomas, most commonly colorectal and gastric carcinomas, may also be associated with deficiencies of DNA mismatch repair. Deficiency in cellular MMR leads to wide-spread mutagenesis and neoplastic development and progression. An important diagnostic feature of MMR-deficient tumors is the high rate of mutations that accumulate in repetitive nucleotide regions, and these mutations are known as microsatellite instability(MSI). A standard panel of markers to test for MSI in tumors has been recommended and efficiently separates tumors into those with high, low, or no microsatellite instability (MSI-H, MSI-L, or MSS). Tumors characterized by MSI-H characteristically show loss of one of the main DNA MMR proteins, mLH1 or MSH2, and rarely MSH6 and PMS2, detected by immunohistochemistry (IHC). The combination of MSI testing and IHC for MMR proteins in tumors tissues is used to identify underlying DNA MMR deficiency andis clinically relevant screen patients who might have hereditary non-polyposis colorectal cancer for DNA repair gene germline testing. Increasing evidence demonstrates that tumors with a positive MSI status have lower lymph node metastases burden, and these patients have an overall improved survival, suggesting that the MSI and MMR status may contribute to decision making regarding treatment approaches. Updated guidelines for MSI and IHC for DNAMMR testing, and the biological and potential clinical implications of MMR deficiency and microsatellite instability in GI polyps and cancers are reviewed.
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PMID:Microsatellite instability and DNA mismatch repair deficiency testing in hereditary and sporadic gastrointestinal cancers. 1574 37

Mutations in genes of the DNA mismatch repair system (MMR) are strongly linked to the development of hereditary non-polyposis colorectal cancer and play a significant role in sporadic cancer too. Besides the repair of chromosomal mismatches produced during replication, the MMR is the linkage of DNA mismatches to cell cycle control. Proteins of the MMR are necessary for the induction of apoptosis in response to non-tolerable amounts of DNA damage. We correlated the immunoreactivity of the MMR proteins hMSH2, hMLH1 and PMS2 to the immunoreaction of p53, the proliferation marker Ki67 and clinical prognosis factors such as tumor grading and staging, steroid receptor expression and hemangiosis carcinomatosa or lymphangiosis carcinomatosa in 200 samples from patients with diagnosed breast cancer. No correlation could be detected among the expression of the three MMR-proteins hMSH2, hMLH1 and PMS2. The expression of hMSH2 correlated positively with the expression of p53, with the appearance of distant metastases, low differentiation and the appearance of hemangiosis carcinomatosa and lymphangiosis carcinomatosa, while it negatively correlated with the expression of the estrogen receptor. No correlation was detected between hMLH1 or PMS2 and any of the investigated factors. The expression of hMSH2 seems to be related with predictors of an unfavorable course of disease in breast cancer.
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PMID:Immunohistochemistry of proteins for DNA mismatch repair in correlation to prognostic factors of mammarian cancer. 1739 69

Prognostic factors for ampullary carcinomas (ACs) are poorly defined. Fifty three resected ACs were analyzed for CDX2, MUC1, MUC5AC, MUC6, MUC2, and for mismatch repair proteins (hMLH1, hMSH2, PMS2, hMSH6) using immunohistochemistry. Microsatellite instability (MSI) status was evaluated by fluorescently labeled PCR using an automated sequencer. Univariate and multivariate analysis was performed for clinicopathological, immunohistochemical and molecular parameters. CDX2 was found in 32 out of 53 (60%) ACs with a significantly higher frequency among intestinal ACs compared with biliopancreatic (BP) ACs. The MUC1, MUC5AC, MUC6, MUC2 apomucins were expressed in 75, 43, 39, and 28% of ACs, respectively, with a significantly higher coexpression of MUC1/MUC5AC in BP ACs. MSI and loss of expression of hMLH1/PMS2 or hMSH2/hMSH6 proteins were observed only in intestinal ACs. Factors significantly correlated with improved survival in the univariate analysis were: low stage, absence of lymph nodes metastases, negative surgical margins (R0 status), and presence of MSI. In the multivariate analysis, stage was the only independent prognostic factor of survival. We conclude that stage is the only independent prognostic factor of survival in the multivariate analysis, whereas histological criteria and the immunohistochemical expression of apomucins and CDX2 are helpful in the classification and understanding of the histogenesis of ACs.
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PMID:Prognostic factors for ampullary adenocarcinomas: tumor stage, tumor histology, tumor location, immunohistochemistry and microsatellite instability. 1765 61

The purpose of our study was to demonstrate that distinct cytogenetic alterations in the most common subtype of renal cell cancer, clear cell renal cell carcinoma (ccRCC), are reflected in protein expression profiles. We performed conventional cytogenetics and immunohistochemical analysis for cytokeratins (CKs) on 126 ccRCCs. Protein expression was evaluated in situ using a semiautomated quantitative system. The results were validated using an independent cohort of 209 ccRCCs with long-term follow-up. Cytogenetic alterations were identified in 96 of 126 ccRCCs, most of them involving chromosome 3 through loss, deletion or translocation. Expression of CKs and E-cadherin in ccRCC was associated with lack of cytogenetic alterations and low nuclear grade. In the validation set, CK7 and CK19 protein expression was associated with better clinical outcome. At the multivariate level, the best model included metastatic status and CK19 expression. Expression microarray analysis on 21 primary ccRCCs and 14 ccRCC metastases identified genes significantly associated with CK7 and CK19 expressing ccRCCs. Two novel ccRCC biomarkers associated with the CK7 positive ccRCC phenotype, PMS2 and MT1-MMP (MMP14), were further validated. We conclude that the variability observed for CK expression in ccRCC can be explained by genetic heterogeneity. Distinct molecular subtypes of ccRCC with prognostic relevance were identified, and the CK7/CK19 expressing subtype is associated with better outcome.
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PMID:Association of cytokeratin 7 and 19 expression with genomic stability and favorable prognosis in clear cell renal cell cancer. 1847 71

Carcinomas of the endometrium and ovary with undifferentiated components are uncommon neoplasms that are likely underdiagnosed. They are important to recognize as they have been shown to be clinically aggressive. We identified 32 carcinomas with undifferentiated components as defined by Silva and co-workers, 26 endometrial and 6 of ovarian origin. The patient age ranged from 21 to 76 years (median 55); 40% of patients were <or=50 years of age. Most patients (58% of endometrial and 83% of ovarian carcinomas with undifferentiated components) presented at advanced stages (FIGO III-IV). Pelvic and para-aortic lymph nodes were the most frequent sites of metastases. Twenty tumors, entirely undifferentiated, consisted of sheets of dyshesive, ovoid cells with uniform, large vesicular nuclei, whereas 12 tumors contained combinations of differentiated endometrioid adenocarcinoma with undifferentiated components. Although most undifferentiated tumors had a monotonous cytologic appearance without prominent stroma, six showed focal nuclear pleomorphism and eight cases had variably sized zones of rhabdoid cells in a background of myxoid stroma. The tumors were frequently misdiagnosed; they received a wide range of diagnoses, including FIGO grade 2 or 3 endometrioid carcinoma, carcinosarcoma, high-grade sarcoma including endometrial stromal sarcoma, neuroendocrine carcinoma, lymphoma, granulosa cell tumor and epithelioid sarcoma. Up to 86% of the cases showed focal, but strong keratin and/or epithelial membrane antigen staining, with CK18 being the most frequently positive keratin stain. They were predominantly negative for neuroendocrine markers, smooth muscle markers and estrogen receptor/progesterone receptor. Mismatch repair protein expression by immunohistochemistry was evaluated in 17 cases, and 8 (47%) were abnormal (7 with loss of MLH1/PMS2 and 1 with MSH6 loss). Follow-up was available for 27 patients, although it was very short in many cases, ranging from 0.5 to 89 months (median 9 months). Eleven patients (41%) died of the disease in 0.5-20 months, four are alive with disease and twelve patients have no evidence of disease. Endometrial and ovarian carcinomas with undifferentiated components have a broad histologic differential diagnosis, but they show specific histologic features that should enable accurate diagnosis. These tumors can occur in young women, may be associated with microsatellite instability and behave in a clinically aggressive manner.
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PMID:Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms. 2030 18

The tumorigenesis of human nonpolyposis colorectal cancer was reported to be connected with the mutations in DNA mismatch repair genes. The main aim of this study was to check the epression of 4 proteins MLH1, MSH2, PMS1 and PMS2 responsible for mismatch DNA repair in naevi and melanomas. Fifty-one naevi, 78 primary melanomas, 30 lymphatic and 7 organ melanoma metastases were stained for the presence of MLH1, MSH2, PMS1 and PMS2. All proteins were preserved in 88% of naevi and only in 37% of primary melanomas, 17% of lymphatic metastases and in none of the distant metastases. The difference of expression of all 4 proteins between naevi and melanomas was highly significant (p<0.01). MLH1 and MSH2 correlated significantly with each other as well with the follow-up of patients. On the basis of our results one can conclude that the defect of mismatch DNA repair plays an important role in both tumorigenesis of melanoma and metastatic spread of tumour.
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PMID:Decreased expression of MLH1, MSH2, PMS1 and PMS2 in pigmented lesions indicates accumulation of failed DNA repair along with malignant transformation and tumour progression. 2159 Jan 18

Lynch syndrome (LS) is an autosomal dominant inherited disease that is associated with an increased risk for colorectal and endometrial cancer due to germline mutations in mismatch-repair (MMR) genes. Whereas primary tumors in this syndrome are widely recognized, the relative risk(s) of secondary malignancies, particularly breast cancer, in LS patients are still poorly characterized. To provide an improved assessment of these risks, MMR status was evaluated in secondary tumors from a series of patients with index tumors of known MMR status (both proficient and deficient). A total of 1252 tumors (index tumors) and all secondary malignancies were tested for MMR by immunohistochemistry (MSH2, MSH6, MLH1, PMS2) between 1992 and 2013. Tumors with MLH1/PMS2 deficiency were tested for hypermethylation or BRAF mutation, when appropriate. Of the 1252 index tumors, 162 were MMR deficient (dMMR), and, of that subset, 32 secondary tumors were identified (19.7%). In contrast, 80 secondary tumors were identified in the proficient (intact) group (7.3%). Although secondary malignancies were more common in the dMMR group (P=0.0001), there was no trend in tumor type. Specifically, breast cancer was not overly represented in the dMMR group. When secondary tumors had dMMR, they were more likely to have deficiency in MSH2/MSH6 than in MLH1/PMS2 (P=0.01). Of the patients with tumors exhibiting dMMR, women were more likely to have a dMMR secondary tumor in this series (P=0.0001); however, breast cancer was not overly represented, and our study provides no evidence that it is more frequent in LS. MSH2/MSH6 deficiency is more commonly associated with a secondary tumor compared with MLH1/PMS2 deficiency, when methylation/BRAF status is taken into account.
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PMID:Risk of secondary malignancy (including breast) in patients with mismatch-repair protein deficiency. 2492 35

AT-rich interactive domain-containing protein 1A (ARID1A), a chromatin remodeling gene recently discovered to be a tumor suppressor in ovarian cancers, has been found to be mutated at low frequencies in many other tumors including colorectal carcinoma (CRC). An association between ARID1A alteration and DNA mismatch repair (MMR) deficiency has been implicated; understanding this association may facilitate the understanding of the role of ARID1A in the various tumors. In this pilot study, we analyzed the immunohistochemical expression of ARID1A in a consecutive series of 257 CRCs that fulfilled a set of relaxed criteria for Lynch syndrome screening; 59 (23%) were MMR deficient by immunohistochemistry (44 MLH1/PMS2 deficient, 9 MSH2/MSH6 deficient, 4 MSH6 deficient, and 2 PMS2 deficient). ARID1A loss was observed in 9% (22/257) of the cohort: 24% of MMR-deficient tumors (14/59, 13 of the 14 being MLH1/PMS2 deficient) and 4% of MMR-normal tumors (8/198) (P < .05). MLH1 (mutL homolog 1) promoter hypermethylation was observed in 10 of the 13 MLH1/PMS2-deficient/ARID1A-loss tumors, indicating an association between ARID1A loss and sporadic microsatellite unstable CRCs. Among the MMR-deficient cases, ARID1A loss correlated with old age (P = .04), poor tumor differentiation (P < .01), medullary histology (P < .01), and an increased rate of nodal and distant metastasis (P = .03); these patients also trended toward a worse 5-year overall survival. Among MMR-normal tumors, no differences in clinicopathological features were detected between the groups stratified by ARID1A. In conclusion, our results suggest that ARID1A loss may be linked to a specific subset of sporadic microsatellite unstable CRCs that may be medullary but is more likely to present with metastatic disease, warranting further investigation.
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PMID:Immunohistochemical detection of ARID1A in colorectal carcinoma: loss of staining is associated with sporadic microsatellite unstable tumors with medullary histology and high TNM stage. 2531 44


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