Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0001430 (adenoma)
21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The fundamental view that colon adenocarcinomas arise only from conventional adenomas has been challenged by the now recognized hyperplastic polyp-serrated adenoma-adenocarcinoma pathway. This article describes the history of the serrated adenoma (both the traditional serrated adenoma and the sessile serrated adenoma) as well as the histology and endoscopic appearance of these lesions in comparison with hyperplastic polyps and mixed polyps. Although the exact pathway is the subject of ongoing research, compelling histologic associations and molecular phenotypes that define the model of the serrated polyp-carcinoma sequence, including microsatellite instability, BRAF/KRAS mutations, and CpG island methylator phenotype, provide strong evidence that this is a genuine pathway. Management of serrated neoplasia of the colon includes careful colonoscopy, complete removal of colonic polyps, sampling fields of diminutive polyps of the rectosigmoid, and basing surveillance on histology of removed polyps.
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PMID:Significance of serrated polyps of the colon. 1879 25

We describe a case of solid cell nest hyperplasia associated with papillary thyroid carcinoma in a 48-year-old man with goiter. The entire gland was examined; in 1 section, the cells of 1 solid cell nest were in close contact with a follicular variant of papillary microcarcinoma. A second follicular variant of papillary microcarcinoma, 1 follicular adenoma, hyperplastic nodules, and some lymphoid aggregates were also found. Scattered p63-positive cells were found in the second papillary microcarcinoma. After microdissection, the same BRAF(V600E) mutation was found both in a pool of 5 solid cell nests and in the adjacent papillary microcarcinoma. BRAF(V600E) mutation and the previously unreported BRAF(G593D) mutation along with p.G606G silent change were found in the second papillary microcarcinoma, but no mutations were detected in the follicular adenoma or in the 2 other pools of solid cell nests screened for BRAF gene mutations. These findings support a histogenetic link between the main cells of solid cell nests and papillary thyroid carcinoma, and suggest solid cell nest hyperplasia as a precursor lesion of papillary thyroid carcinoma.
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PMID:BRAF mutation in solid cell nest hyperplasia associated with papillary thyroid carcinoma. A precursor lesion? 1926 16

In colorectal cancer, BRAF and KRAS oncogenes are mutated in about 15% and 35% respectively at approximately the same stage of the adenoma-carcinoma sequence. Since these two mutations rarely coexist, further analysis to dissect their function of transformation in colon cancer is required. Caco-2 human colon adenocarcinoma cells were stably transfected with BRAF(V600E) (Caco-BR cells) or KRAS(G12V) (Caco-K cells) oncogenes. BRAF(V600E) is more efficient in transforming Caco-2 cells and altering their morphology. The dominant nature of BRAF(V600E) is evident by its ability to render Caco-2 cells tumorigenic in vivo all be it through selective extracellular signal-related kinase (ERK) 2 phosphorylation and high levels of cyclin D1. As a consequence, the cell cycle distribution of parental cells is altered and microsatellite instability is introduced. Attenuated ERK activation observed correlated with KSR downregulation by BRAF(V600E) without further implications to signaling. Highly activated ERK in case of KRAS(G12V) (Caco-K cells) leads to mild transformation causing Caco-K cells to express premature senescence-related markers and acquire growth factor-dependent viability. Interestingly, BRAF(WT)gets equally activated by upstream KRAS mutations present in colon adenocarcinoma cells such as DLD-1 and SW620. Taken together, these results suggest that the two oncogenes have different transforming capability in colon cancer, although they both use the mitogen-activated protein (MAP) kinase pathway to carry out their effect. In general, BRAF(V600E) presents greater potential in mediating tumorigenic effect as compared to KRAS(G12V) both in vivo and in vitro. These findings may have implications in personalised diagnosis and targeted therapeutics.
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PMID:BRAF(V600E) efficient transformation and induction of microsatellite instability versus KRAS(G12V) induction of senescence markers in human colon cancer cells. 1988 48

The serrated pathway of colorectal carcinogenesis is heterogeneous with respect to its precursor lesions, molecular alterations and its prognosis. The low-risk-subtype of serrated adenocarcinomas is less frequent (<20% of all serrated adenocarcinomas) and characterized by proximal location, BRAF-mutation, high CpG-island methylation with loss of MLH1-expression and MSI-H phenotype. The assumed precursor lesion of this subtype is the sessile serrated adenoma and the 5-year overall survival is >70%. The high-risk-subtype is more frequent (>80% of all serrated adenocarcinomas) and characterized by distal location, KRAS mutation, MSI-L/MSS phenotype, lower CpG-island methylation, and possible p53 accumulation. The assumed precursor lesion is the traditional serrated adenoma and the prognosis is unfavorable (<30% 5-year overall survival). The analysis of MSI status, KRAS and BRAF mutational status and immunohistochemical analyses of hMLH1 and p53 expression enables the distinction between these two subtypes and is therefore clinically relevant, especially since treatment options for the two subtypes may differ in the future.
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PMID:[Serrated pathway of colorectal carcinogenesis]. 1992 Nov 96

The benign serrated architecture of the hyperplastic polyp has now been recognized in morphologically similar lesions with potential for transformation to colorectal carcinoma: the sessile serrated adenoma (SSA), traditional serrated adenoma (TSA), and mixed polyp. These represent a group of serrated polyps with potential to evolve into colorectal cancer through a different molecular pathway than the traditional adenoma-carcinoma sequence, called the serrated pathway. Genetic characteristics involve a defect in apoptosis caused by BRAF and K-ras mutations that create distinct histologic characteristics of atypia in serrated architectural distortion of the crypts. An evidence-based algorithm for the clinical management of this polyp has yet to be determined. Current recommendations suggest these lesions be managed similar to conventional adenomas. The histology of serrated polyps is reviewed, as well as the common characteristics, and implications for treatment and surveillance.
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PMID:Management of serrated adenomas and hyperplastic polyps. 2001 38

Fine-needle aspiration biopsy (FNAB) is currently the most sensitive and specific tool for the presurgical differential diagnosis of thyroid malignancy, but has also substantial limitations. While approximately 75% of FNAB reveal benign lesions and 5% already cytologically prove malignancy, up to 20% of FNAB show follicular proliferation for which follicular adenoma, follicular carcinoma, and follicular variant of papillary carcinoma can only be distinguished histologically, thus requiring thyroid surgery. However, new biomarkers that might improve the accuracy of FNAB come along with the discovery of more and more details of the molecular etiology of thyroid tumors. So far molecular testing for somatic mutations is most promising (e.g., BRAF), since the proposed biomarkers from mRNA- and miRNA-expression studies need further evaluation, especially in FNAB samples. Nevertheless, the application of molecular markers will significantly improve thyroid tumor diagnosis and thus it will help to prevent unnecessary surgeries and it will also help to guide mutation-specific targeted therapies.
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PMID:Molecular fine-needle aspiration biopsy diagnosis of thyroid nodules by tumor specific mutations and gene expression patterns. 2008 61

We have recently shown that a study population of patients with at least 1 sessile serrated adenoma (SSA) are 4 times more likely to harbor synchronous serrated polyps [SSAs, traditional serrated adenomas (TSAs) and right sided hyperplastic polyps] than a unselected population of patients. However, 35% of the polyps in the study patients were conventional adenomas (CAds). We hypothesized that the CAds in these study patients would have histologic and molecular differences compared with CAds from a control population without sessile serrated adenomas. To this end, 104 study and 79 control CAds were analyzed according to 9 histologic criteria. A subset of these polyps was also screened for BRAF mutations, KRAS mutations, CpG island methylation, and MUC6 expression. A total of 31 study CAds and 2 control CAds had atypical histologic features (bright cytoplasmic eosinophilia +/- focal serrations and crypt dilatation). None of the adenomas tested had mutations in BRAF or KRAS. Evidence of low levels of CpG island methylation was seen in 35% of the atypical CAds and in only 4.5% of the typical CAds. In addition, these atypical CAds were more likely to express MUC6. Thus, the presence of cytoplasmic eosinophilia with or without focal serrations and crypt dilatation identifies a subset of CAds with characteristics of the serrated neoplasia pathway. These atypical CAds occur more commonly in patients predisposed to developing SSAs and suggest the presence of a mucosal field defect in these patients.
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PMID:Identification of histologically distinct conventional adenomas that arise predominately in patients with sessile serrated adenomas. 2011 68

The pathogenesis and risk of malignancy of traditional serrated adenomas (TSAs) are unclear. In North America, TSAs are relatively uncommon, occur mainly in the left colon, and in some studies, have not been shown to have a strong association with hyperplastic polyp (HPP) or sessile polyp adenoma (SSA) precursor lesions. In the Far East, and particularly in Korea, TSAs are more common and occur both in the left and right colon. However, the pathogenesis of TSAs in Korean patients, and the similarity to those that occur in North America, have never been evaluated. The purpose of this study was to determine the frequency and type of precursor lesion in TSAs, and to determine the molecular profile according to the grade of histologic dysplasia and/or cancer and anatomic location of the colon in a cohort of Korean patients. One hundred and twelve TSAs were evaluated pathologically and categorized according to the grade of dysplasia (either low or high grade) and the presence or absence of adenocarcinoma. TSAs were also separated into those with serrated versus conventional adenomatous dysplasia. As controls 35 conventional adenomas were evaluated, 14 of which had adenocarcinoma. All lesions were evaluated for the presence and type of precursor lesions and for KRAS and BRAF mutations and methylation of MGMT, hMLH1, and APC. A nondysplastic precursor lesion (HPP or SSA) was identified in 35 TSAs (31.3%). TSAs with a precursor lesion were more commonly found in the right colon compared with the left colon (P=0.03). Mutations of KRAS and BRAF and methylation of MGMT, hMLH1, and APC were present in 29%, 55%, 63%, 56%, and 37% of TSAs, respectively. TSAs with high-grade dysplasia and intramucosal adenocarcinoma showed a significantly higher frequency of KRAS mutation and MGMT methylation, and a significantly lower frequency of BRAF mutations, compared with TSAs with low-grade dysplasia (P<0.05). KRAS mutations were more prevalent in TSAs from the left colon and correlated significantly with higher grades of dysplasia. In a subgroup of TSAs in which both the precursor and neoplastic components were evaluated, a similar molecular profile was shown in both types of epithelium. Our results suggest that up to one-third of TSAs show a histologically identifiable nondysplastic HPP or SSA precursor lesion, particularly in lesions from the right colon. The development of KRAS mutations and methylation of MGMT may herald the onset of an aggressive phenotype in the neoplastic progression of TSAs and also suggests that a fusion between the serrated pathway of carcinogenesis and the chromosomal instability pathway may occur in some TSAs. Further studies are needed to determine the natural history and risk of malignancy of TSAs, specifically related to the anatomic site of development.
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PMID:KRAS mutations in traditional serrated adenomas from Korea herald an aggressive phenotype. 2030 37

The follicular variant of papillary thyroid carcinoma usually presents as an encapsulated tumor and less commonly as a partially/non-encapsulated infiltrative neoplasm. The encapsulated form rarely metastasizes to lymph node, whereas infiltrative tumor often harbors nodal metastases. The molecular profile of the follicular variant was shown to be close to the follicular adenoma/carcinoma group of tumors with a high RAS and very low BRAF mutation rates. A comprehensive survey of oncogenic mutations in the follicular variant of papillary thyroid carcinoma according to its encapsulated and infiltrative forms has not been performed. Paraffin tissue from 28 patients with encapsulated and 19 with infiltrative follicular variant were subjected to mass spectrometry genotyping encompassing the most significant oncogenes in thyroid carcinomas: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1 and other related genes. There was no difference in age, gender, tumor size and angioinvasion between encapsulated or infiltrative tumors. Infiltrative carcinomas had a much higher frequency of extrathyroid extension, positive margins and nodal metastases than encapsulated tumors (P<0.05). The BRAF 1799T>A mutation was found in 5 of 19 (26%) of the infiltrative tumor and in none of the encapsulated carcinomas (P=0.007). In contrast, RAS mutations were observed in 10 of 28 (36%) of the encapsulated group (5 NRAS_Q61R, 3 HRAS_Q61, 1 HRAS_G13C and 1 KRAS_Q61R) and in only 2 of 19 (10%) of infiltrative tumors (P=0.09). One encapsulated carcinoma showed a PAX8/PPARgamma rearrangement, whereas two infiltrative tumors harbored RET/PTC fusions. Encapsulated follicular variant of papillary thyroid carcinomas have a molecular profile very close to follicular adenomas/carcinomas (high rate of RAS and absence of BRAF mutations). Infiltrative follicular variant has an opposite molecular profile closer to classical papillary thyroid carcinoma than to follicular adenoma/carcinoma (BRAF>RAS mutations). The molecular profile of encapsulated and infiltrative follicular variant parallels their biological behavior (ie, metastatic nodal and invasive patterns).
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PMID:Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns. 2052 88

The diagnostic approach to thyroid nodules generally starts with FNA cytology. However, approximately one-fifth of cytologic evaluations yield indeterminate cytological findings but only 20% of cases with indeterminate thyroid nodule cytology have a cancer diagnosis, emphasizing the need for an effective ancillary test based on FNA material to help prevent unnecessary surgery. Detection of BRAFV600E mutation, the genetic signature of papillary thyroid carcinoma (PTC) in FNA material provides an invaluable diagnostic adjunct to overcome the limitations of FNA cytology. There are many ways to detect V600E, such as direct DNA sequencing, allele-specific PCR and hybridization-based colorimetric methods. In this study, a newer simple PCR method is presented that removes requirements for sequencing special equipment and commercial kits. Two forward primers including the mutant sequence specific (F2), and one common reverse (R) primer were optimized to generate a 241 bp fragment (F1R), an internal PCR control, and a 141 bp fragment (F2R) denoting the presence of V600E. Sensitivity studies revealed that the assay is capable of detecting V600E even in 1 ng of DNA. Direct sequencing data of 241 bp F1R fragment proved the specificity of the assay. For validation studies of the sequence specific multiplex PCR assay, archival FNA slides were used in a group of thyroid lesions including PTC, follicular carcinoma, follicular adenoma, Hashimoto thyroiditis, and benign thyroid nodules. The newer PCR-based method presented in this study is a practical, inexpensive one-step assay to detect the BRAF T1796A mutation on FNA samples.
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PMID:A valuable adjunct to FNA diagnosis of papillary thyroid carcinoma: in-house PCR assay for BRAF T1799A (V600E). 2060 44


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