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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most common genetic determinants of skin cancer are the genes that control skin color so that the genes expressed as black skin are protective. Within the white population variants at the MC1R locus are shown to increase susceptibility, and recent evidence suggests that polymorphisms in the OCA2 gene interact to modify risk. Other as-yet-unidentified pigment genes may also play a role in susceptibility to melanoma. Thus MC1R variants are the most common low-penetrance melanoma-susceptibility genes so far identified. Other putative low-penetrance susceptibility genes have been explored using candidate gene approaches. Good candidates such as the DNA repair gene XRCC3 and polymorphisms of EGF have been studied but excluded. Other candidates such as BRAF polymorphisms and variants at the CDKN2A locus remain to be fully investigated. More progress has been made in identifying high-penetrance genes, however. The most common (and probably the most penetrant) susceptibility locus is the CDKN2A locus coding for two tumor suppressor proteins, p16 and p14ARF. Mutations at this locus that impact p16, p14ARF or both proteins all increase susceptibility to melanoma. Families inheriting such mutants are at increased risk of cutaneous melanoma, and the penetrance is increased by residence in sunny climates and co-inheritance of MC1R variants. Some families also appear to be at increased risk of pancreatic cancer, but the determinants of susceptibility to pancreatic cancer are not yet understood. Very rare families have germline mutations in the CDK4 gene which impact on the p16 binding site. There are other high-penetrance susceptibility genes, however, which remain undiscovered. There is evidence of one at 1p22. The Melanoma Genetics Consortium (www.genomel.org) continues to explore this and the genetic epidemiology of the CDKN2A locus.
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PMID:The genetics of susceptibility to cutaneous melanoma. 1588 16

Carcinoid tumors and pancreatic endocrine tumors are uncommon neuroendocrine neoplasms, and their genetic alterations are not well characterized. These tumors have site-specific differences in neuroendocrine characteristics, clinical course and genetic alterations. We compared clinicopathological features and loss of heterozygosity of chromosomes 11q, 16q and 18, and BRAF gene mutations in 47 patients with neuroendocrine tumors including 16 with pancreatic endocrine tumors, 15 with nonileal carcinoid tumors and 16 with ileal carcinoid tumors. Patients with carcinoid tumors had more frequent history of alcohol consumption compared to patients with pancreatic endocrine tumors (P=0.02), and patients with ileal carcinoid tumors more frequently had liver metastasis compared to patients with nonileal carcinoid tumors and pancreatic endocrine tumors (P=0.02). Allelic loss of chromosome 11q was present in 21% of tumors, chromosome 16q in 13%, and chromosome 18 in 30%. These alterations differed with the anatomical subsite of tumor: allelic loss of chromosome 18 was present in 69% of ileal carcinoid tumors, 13% of nonileal carcinoid tumors and 6% of pancreatic endocrine tumors (P=0.001). In contrast to pancreatic endocrine tumors and nonileal carcinoid tumors, all 11 ileal tumors with loss of chromosome 18 had complete loss of both chromosomal arms. No BRAF mutations were identified. Complete allelic loss of chromosome 18 was associated with smaller tumor size (P=0.02). Our study indicates that genetic alterations vary by tumor subsite and clinicopathologic features, and ileal carcinoid tumors have distinctive clinicopathologic and genetic profiles.
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PMID:Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors. 1592 May 55

Multiple genetic alterations occur in melanoma, a lethal skin malignancy of increasing incidence. These include mutations that activate Ras and two of its effector cascades, Raf and phosphoinositide 3-kinase (PI3K). Induction of Ras and Raf can be caused by active N-Ras and B-Raf mutants as well as by gene amplification. Activation of PI3K pathway components occurs by PTEN loss and by AKT3 amplification. Melanomas also commonly show impairment of the p16(INK4A)-CDK4-Rb and ARF-HDM2-p53 tumor suppressor pathways. CDKN2A mutations can produce p16(INK4A) and ARF protein loss. Rb bypass can also occur through activating CDK4 mutations as well as by CDK4 amplification. In addition to ARF deletion, p53 pathway disruption can result from dominant negative TP53 mutations. TERT amplification also occurs in melanoma. The extent to which these mutations can induce human melanocytic neoplasia is unknown. Here we characterize pathways sufficient to generate human melanocytic neoplasia and show that genetically altered human tissue facilitates functional analysis of mutations observed in human tumors.
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PMID:Use of human tissue to assess the oncogenic activity of melanoma-associated mutations. 1595 21

We analyzed RASSF1A and NORE1A methylation and BRAF mutation in 89 thyroid tumors, 42 non-neoplastic thyroid tissues and three thyroid tumor cell lines using polymerase chain reaction (PCR), methylation-specific PCR, Western blotting and DNA sequencing in order to study thyroid tumor pathogenesis and progression. RASSF1A promoter methylation was present in all three thyroid cell lines and in 27/78 (35%) of benign and malignant thyroid tumors. We showed for the first time that there was generally good agreement between RASSF1A methylation status and RASSF1A protein expression. We also examined for the first time NORE1A promoter region methylation in thyroid cell lines and primary tumors and showed that two of three thyroid cell lines were methylated in the NORE1A promoter region, while all primary thyroid tumors analyzed (n=51) were unmethylated. BRAF mutation was present in 38% of papillary thyroid carcinomas (PTC), including 20% of PTC with a follicular variant pattern and 67% of the tall cell variant of PTC. Hyalinizing trabecular tumors (n=23), which had nuclear features similar to PTC, did not have BRAF mutations, indicating that the presence of BRAF mutations can help to separate these two tumor types. Phospho-MEK expression was increased in the NPA cell line, which had a BRAF mutation, supporting the importance of the BRAF pathway alterations in PTC pathogenesis. These results indicate that RASSF1A epigenetic changes are an early event in thyroid tumor pathogenesis and progression and that NORE1A methylation is uncommon in primary thyroid tumors. BRAF mutation occurs later in thyroid tumor progression and is restricted mainly to PTC and anaplastic thyroid carcinoma.
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PMID:RASSF1A and NORE1A methylation and BRAFV600E mutations in thyroid tumors. 1598 Aug 87

Rb is a tumor suppressor that represses the expression of E2F regulated genes required for cell cycle progression. It is inactivated in melanomas and other cancer cells by phosphorylation catalyzed by persistent cyclin dependent kinase (CDK) activity. CDK activity is sustained in melanoma cells mostly by the elimination of the CDK inhibitor p16INK4A and by high levels of cyclins whose expression is maintained by stimuli emanating from activated cell surface receptors and/or mutated intracellular intermediates, such as N-Ras and B-Raf. However, Rb also suppresses the expression of apoptosis genes, and its presence protects normal melanocytes from cell death. Its high expression in human melanoma cells and tumors suggests a similar role in malignant cells as well. The differential release and suppression of E2F transcriptional activity is likely to depend on promoter-specific E2F/Rb interaction. Phosphorylated Rb is displaced from cell cycle genes but not from others. In addition, Rb gene repression is dependent on the nature of Rb-E2F interaction and the activity of the Rb-bound proteins recruited to the promoter. Deciphering the differences in Rb/E2F complex formation in normal and malignant melanocytes is likely to shed light on the mechanism by which Rb can exert tumor suppressing and promoting activities in this cellular system. The Rb/E2F pathway provides opportunities for efficient therapy at multiple levels. Novel drugs can reactivate Rb potential to suppress growth cycle promoting genes. In addition, the high E2F transcriptional activity in melanoma cells can be exploited to deliver cytotoxic molecules specifically to tumors, sparing the normal tissues.
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PMID:Rb/E2F: a two-edged sword in the melanocytic system. 1598 42

To understand immune responses to human cancer and develop more effective immunotherapy, human tumor antigens has been isolated using various immunological methods with tumor reactive T cells or antibodies obtained from patients with melanoma. During the process of tumor antigen isolation, various molecules with genetic alterations or over-expression in tumor cells, which may be involved in proliferation, differentiation, or survival of various cancer cells, were identified. In melanoma, abnormal molecules with mutations including beta -catenin, CDK4, and BRAF, and molecules with increased expression including Survivin, were immunologically detected. Therefore, immunological isolation of human tumor antigens contributes to the identification of important molecules including altered signaling molecules involved in melanoma formation.
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PMID:Immunological detection of altered signaling molecules involved in melanoma development. 1598 43

Serrated neoplasm of the colorectum raised many as-yet unanswered issues. To characterize serrated neoplasia pathway, we investigated BRAF and KRAS mutations in 35 traditional serrated adenomas. BRAF exons 11 and 15, and KRAS exon 2 were amplified by polymerase chain reaction and directly sequenced. BRAF V599E mutation was found in 27 serrated adenomas (77.1%), and KRAS mutations were found in 3 (8.6%) of 35 traditional serrated adenomas. In 13 cases, mixed polyps composed of traditional serrated adenomas and hyperplastic (serrated) polyps were observed, and seven of them showed the same BRAF mutations in both components. Somatic mutations of BRAF and KRAS genes were mutually exclusive. These findings suggest that BRAF mutations are early and a critical event in the serrated adenomas, and most serrated adenomas in both sides of colon may progress from microvesicular hyperplastic polyps via BRAF mutations, and some left-sided serrated adenomas develop via KRAS mutations.
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PMID:Tracing origin of serrated adenomas with BRAF and KRAS mutations. 1599 Oct 7

Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumour progression.
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PMID:Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. 1600 Oct 50

Thyroid cancer poses a significant clinical challenge, and our understanding of its pathogenesis is incomplete. To gain insight into the pathogenesis of papillary thyroid carcinoma, transcriptional profiles of four normal thyroids and 51 papillary carcinomas (PCs) were generated using DNA microarrays. The tumors were genotyped for their common activating mutations: BRAF V600E point mutation, RET/PTC1 and 3 rearrangement and point mutations of KRAS, HRAS and NRAS. Principal component analysis based on the entire expression data set separated the PCs into three groups that were found to reflect tumor morphology and mutational status. By combining expression profiles with mutational status, we defined distinct expression profiles for the BRAF, RET/PTC and RAS mutation groups. Using small numbers of genes, a simple classifier was able to classify correctly the mutational status of all 40 tumors with known mutations. One tumor without a detectable mutation was predicted by the classifier to have a RET/PTC rearrangement and was shown to contain one by fluorescence in situ hybridization analysis. Among the mutation-specific expression signatures were genes whose differential expression was a direct consequence of the mutation, as well as genes involved in a variety of biological processes including immune response and signal transduction. Expression of one mutation-specific differentially expressed gene, TPO, was validated at the protein level using immunohistochemistry and tissue arrays containing an independent set of tumors. The results demonstrate that mutational status is the primary determinant of gene expression variation within these tumors, a finding that may have clinical and diagnostic significance and predicts success for therapies designed to prevent the consequences of these mutations.
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PMID:Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. 1600 66

Papillary thyroid carcinoma is the most common malignancy of the thyroid. It is a well-differentiated tumor and the majority behaves in an indolent fashion. The pathologic diagnosis of papillary carcinoma in both cytology and histologic specimens is based upon demonstration of typical nuclear morphology. Using these morphologic criteria, most papillary cancers can be diagnosed with ease, except cases in which there is a paucity of diagnostic nuclear features. Despite advances in the treatment of thyroid cancer, disease recurrences and metastasis can be observed in 20% of cases. Recently, many advances have been made in the pathogenesis of papillary thyroid carcinoma. The notable genetic events include Ret/PTC rearrangements, Ras and BRAF gene mutations. The identification of these has also led to their use in diagnosis and predicting prognosis of papillary thyroid carcinoma. In addition, these involved genes may also serve as targets for cancer chemotherapy in patients where standard thyroid cancer treatment is not effective.
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PMID:Pathologic diagnosis of papillary thyroid carcinoma: today and tomorrow. 1601 75


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