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Yangang Wang - One of the best experts on this subject based on the ideXlab platform.
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high prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol 3 kinase akt pathway in Thyroid tumors
The Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Yangang Wang, Hongyu Yu, Wei Wang, Meiju Ji, Shihua Zhao, Stephen Condouris, Michael Mingzhao XingAbstract:Context: Genetic alterations in the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and their role in Thyroid tumor pathogenesis in Chinese people remain undefined. Objective: The objective of the study was to examine the major genetic alterations and their relationship in the PI3K/Akt pathway in differentiated Thyroid tumors in a Chinese cohort. Design: We used real-time quantitative PCR for the analysis of PIK3CA copy gain and direct DNA sequencing for the detection of PIK3CA, RAS, and PTEN mutations on genomic DNA isolated from 234 Thyroid tumors, including 31 follicular Thyroid cancer (FTC), 141 papillary Thyroid cancer (PTC), and 62 follicular Thyroid Adenoma (FTA). Results: We found PIK3CA copy gain (defined as four or more copies) in nine of 31 FTC (29%), 20 of 141 PTC (14%), and five of 62 FTA (8%); PIK3CA gene mutations in four of 31 FTC (13%), one of 141 PTC (1%), and none of 62 FTA (0%); Ras mutations in three of 31 FTC (10%) and none of the 141 PTC and 62 FTA; and PTEN mutations in two of 31 ...
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genetic alterations and their relationship in the phosphatidylinositol 3 kinase akt pathway in Thyroid cancer
Clinical Cancer Research, 2007Co-Authors: Peng Hou, Yangang Wang, Stephen Condouris, Dingxie Liu, Yuan Shan, Kimberley Studeman, Ariel Trink, Adel K Elnaggar, Giovanni Tallini, Vasily VaskoAbstract:Purpose: To investigate the overall occurrence and relationship of genetic alterations in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in Thyroid tumors and explore the scope of this pathway as a therapeutic target for Thyroid cancer. Experimental Design: We examined collectively the major genetic alterations and their relationship in this pathway, including PIK3CA copy number gain and mutation, Ras mutation, and PTEN mutation, in a large series of primary Thyroid tumors. Results: Occurrence of any of these genetic alterations was found in 25 of 81 (31%) benign Thyroid Adenoma (BTA), 47 of 86 (55%) follicular Thyroid cancer (FTC), 21 of 86 (24%) papillary Thyroid cancer (PTC), and 29 of 50 (58%) anaplastic Thyroid cancer (ATC), with FTC and ATC most frequently harboring these genetic alterations. PIK3CA copy gain was associated with increased PIK3CA protein expression. A mutual exclusivity among these genetic alterations was seen in BTA, FTC, and PTC, suggesting an independent role of each of them through the PI3K/Akt pathway in the tumorigenesis of the differentiated Thyroid tumors. However, coexistence of these genetic alterations was increasingly seen with progression from differentiated tumor to undifferentiated ATC. Their coexistence with BRAF mutation was also frequent in PTC and ATC. Conclusions: The data provide strong genetic implication that aberrant activation of PI3K/Akt pathway plays an extensive role in Thyroid tumorigenesis, particularly in FTC and ATC, and promotes progression of BTA to FTC and to ATC as the genetic alterations of this pathway accumulate. Progression of PTC to ATC may be facilitated by coexistence of PI3K/Akt pathway–related genetic alterations and BRAF mutation. The PI3K/Akt pathway may thus be a major therapeutic target in Thyroid cancers.
Michael Mingzhao Xing - One of the best experts on this subject based on the ideXlab platform.
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association of pten gene methylation with genetic alterations in the phosphatidylinositol 3 kinase akt signaling pathway in Thyroid tumors
Cancer, 2008Co-Authors: Peng Hou, Michael Mingzhao XingAbstract:BACKGROUND. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays an important role in Thyroid tumorigenesis and progression. Genetic alterations, particularly PIK3CA amplification and mutations and ras mutations, are the major cause of aberrant activation of this pathway in Thyroid tumors. Epigenetic silencing of the PTEN gene, a negative regulator of the PI3K/AKT pathway, also occurs in Thyroid tumors, but its relationship with genetic alterations in this pathway is unclear. METHODS. By using quantitative methylation-specific polymerase chain reaction, the authors examined PTEN methylation and its relationship with genetic alterations in the PI3K/AKT pathway in various types of Thyroid tumors. RESULTS. The authors found PTEN methylation to become progressively higher from benign Thyroid Adenoma to follicular Thyroid cancer and to aggressive anaplastic Thyroid cancer, which harbored activating genetic alterations in the PI3K/AKT pathway correspondingly with a progressively higher prevalence. The association of PTEN methylation was seen with both overall genetic alterations and individual genetic alterations, particularly PIK3CA alterations and ras mutations, in the PI3K/AKT pathway within each of the 3 types of Thyroid tumors. In contrast, no such relationship was observed for the tumor suppressor gene RASSF1A. CONCLUSIONS. The authors found an interesting association of PTEN methylation with the activating genetic alterations in the PI3K/AKT pathway in Thyroid tumors. This finding is consistent with a model in which aberrant methylation and hence silencing of the PTEN gene, which coexists with activating genetic alterations of the PI3K/AKT pathway, may enhance the signaling of this pathway aberrantly activated by genetic alterations and hence contribute to the progression of Thyroid tumors. Cancer 2008. © 2008 American Cancer Society.
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high prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol 3 kinase akt pathway in Thyroid tumors
The Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Yangang Wang, Hongyu Yu, Wei Wang, Meiju Ji, Shihua Zhao, Stephen Condouris, Michael Mingzhao XingAbstract:Context: Genetic alterations in the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and their role in Thyroid tumor pathogenesis in Chinese people remain undefined. Objective: The objective of the study was to examine the major genetic alterations and their relationship in the PI3K/Akt pathway in differentiated Thyroid tumors in a Chinese cohort. Design: We used real-time quantitative PCR for the analysis of PIK3CA copy gain and direct DNA sequencing for the detection of PIK3CA, RAS, and PTEN mutations on genomic DNA isolated from 234 Thyroid tumors, including 31 follicular Thyroid cancer (FTC), 141 papillary Thyroid cancer (PTC), and 62 follicular Thyroid Adenoma (FTA). Results: We found PIK3CA copy gain (defined as four or more copies) in nine of 31 FTC (29%), 20 of 141 PTC (14%), and five of 62 FTA (8%); PIK3CA gene mutations in four of 31 FTC (13%), one of 141 PTC (1%), and none of 62 FTA (0%); Ras mutations in three of 31 FTC (10%) and none of the 141 PTC and 62 FTA; and PTEN mutations in two of 31 ...
Charis Eng - One of the best experts on this subject based on the ideXlab platform.
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somatic mutation and germline variants of minpp1 a phosphatase gene located in proximity to pten on 10q23 3 in follicular Thyroid carcinomas
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Oliver Gimm, Patricia L M Dahia, Charis Eng, Hongbo Chi, Aurel Perren, Raoul Hinze, Paul Komminoth, Henning Dralle, Paul R ReynoldsAbstract:Various genes have been identified to play a role in the pathogenesis of follicular Thyroid tumors. Cowden syndrome is the only known familial syndrome with an increased risk of both follicular Thyroid Adenoma (FA) and carcinoma (FTC). Germline mutations in the tumor suppressor gene PTEN, which encodes a dual-specificity phosphatase, have been found in up to 80% of patients with Cowden syndrome suggesting a role of PTEN in the pathogenesis of follicular Thyroid tumors. Although somatic intragenic mutations in PTEN, which maps to 10q23.3, are rarely found in follicular tumors, loss of heterozygosity (LOH) of markers within 10q22-24 occurs in about 25%. Recently, another phosphatase gene, MINPP1, has been localized to 10q23.3. MINPP1 has the ability to remove 3-phosphate from inositol phosphate substrates, a function that overlaps that of PTEN. Because of this overlapping function with PTEN and the physical location of MINPP1 to a region with frequent LOH in follicular Thyroid tumors, we considered it to be an excellent candidate gene that could contribute to the pathogenesis of follicular Thyroid tumors. We analyzed DNA from tumor and corresponding normal tissue from 23 patients with FA and 15 patients with FTC for LOH and mutations at the MINPP1 locus. LOH was identified in four malignant and three benign tumors. One of these FTCs with LOH was found to harbor a somatic c.122C > T or S41L mutation. We also found two germline sequence variants, c.809A > G (Q270R) and IVS3 + 34T > A. The c.809A > G variant was found in only one patient with FA but not in patients with FTC or normal controls. More interestingly, IVS3 + 34T > A was found in about 15% of FA cases and normal controls but not in patients with FTC. These results suggest a role for MINPP1 in the pathogenesis of at least a subset of malignant follicular Thyroid tumors, and MINPP1 might act as a low penetrance predisposition allele for FTC.
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differential loss of heterozygosity in the region of the cowden locus within 10q22 23 in follicular Thyroid Adenomas and carcinomas
Cancer Research, 1997Co-Authors: Deborah J Marsh, Jan Zedenius, Catharina Larsson, Zimu Zheng, H Kremer, George W Padberg, Michel Longy, Charis EngAbstract:The susceptibility gene for Cowden disease (CD), an autosomal dominant inherited cancer syndrome, has recently been mapped to an approximately 6-cM interval on chromosome subband 10q22–23 between the markers D10S541 and D10S564 . CD is characterized by hamartomas of many organ systems, including the Thyroid, breast, skin, and gastrointestinal tract, as well as carcinoma of the Thyroid and breast. Follicular Thyroid Adenomas and carcinomas are significant component tumors in CD; thus, we sought to examine their sporadic counterpart tumors for loss of heterozygosity (LOH) of microsatellite markers in the 20-cM region within and flanking the Cowden critical interval. In all, 38 sporadic Thyroid tumors were analyzed. LOH within the CD interval was observed in 5 of 19 (26%) follicular Thyroid Adenomas and 1 of 9 (11%) Hurthle cell Adenomas. Furthermore, of these Adenomas with LOH, 3 of 4 (75%) were atypical follicular Adenomas, whereas 2 of 15 (13%) were typical follicular Adenomas. Surprisingly, no LOH was detected in this region in 10 follicular carcinomas. The shortest region of overlap includes the markers D10S1735 and D10S1739 . If the LOH observed in these sporadic tumors is related to the CD gene, then the Cowden critical interval can be revised to lie within the interval defined by D10S579 and D10S564 . LOH in this narrow interval implicates the CD gene, or another gene in that interval, in follicular Thyroid tumorigenesis. However, this does not explain the lack of LOH in follicular carcinomas. Taken together, it may instead be evidence against a stepwise progression from atypical Adenomas to carcinomas. Alternatively, sporadic Thyroid Adenoma formation may be independent of that locus, but loss of this region could prevent carcinoma formation, thus implying that the CD gene may be an oncogene or growth promoter.
Vasily Vasko - One of the best experts on this subject based on the ideXlab platform.
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genetic alterations and their relationship in the phosphatidylinositol 3 kinase akt pathway in Thyroid cancer
Clinical Cancer Research, 2007Co-Authors: Peng Hou, Yangang Wang, Stephen Condouris, Dingxie Liu, Yuan Shan, Kimberley Studeman, Ariel Trink, Adel K Elnaggar, Giovanni Tallini, Vasily VaskoAbstract:Purpose: To investigate the overall occurrence and relationship of genetic alterations in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in Thyroid tumors and explore the scope of this pathway as a therapeutic target for Thyroid cancer. Experimental Design: We examined collectively the major genetic alterations and their relationship in this pathway, including PIK3CA copy number gain and mutation, Ras mutation, and PTEN mutation, in a large series of primary Thyroid tumors. Results: Occurrence of any of these genetic alterations was found in 25 of 81 (31%) benign Thyroid Adenoma (BTA), 47 of 86 (55%) follicular Thyroid cancer (FTC), 21 of 86 (24%) papillary Thyroid cancer (PTC), and 29 of 50 (58%) anaplastic Thyroid cancer (ATC), with FTC and ATC most frequently harboring these genetic alterations. PIK3CA copy gain was associated with increased PIK3CA protein expression. A mutual exclusivity among these genetic alterations was seen in BTA, FTC, and PTC, suggesting an independent role of each of them through the PI3K/Akt pathway in the tumorigenesis of the differentiated Thyroid tumors. However, coexistence of these genetic alterations was increasingly seen with progression from differentiated tumor to undifferentiated ATC. Their coexistence with BRAF mutation was also frequent in PTC and ATC. Conclusions: The data provide strong genetic implication that aberrant activation of PI3K/Akt pathway plays an extensive role in Thyroid tumorigenesis, particularly in FTC and ATC, and promotes progression of BTA to FTC and to ATC as the genetic alterations of this pathway accumulate. Progression of PTC to ATC may be facilitated by coexistence of PI3K/Akt pathway–related genetic alterations and BRAF mutation. The PI3K/Akt pathway may thus be a major therapeutic target in Thyroid cancers.
Stephen Condouris - One of the best experts on this subject based on the ideXlab platform.
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high prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol 3 kinase akt pathway in Thyroid tumors
The Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Yangang Wang, Hongyu Yu, Wei Wang, Meiju Ji, Shihua Zhao, Stephen Condouris, Michael Mingzhao XingAbstract:Context: Genetic alterations in the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and their role in Thyroid tumor pathogenesis in Chinese people remain undefined. Objective: The objective of the study was to examine the major genetic alterations and their relationship in the PI3K/Akt pathway in differentiated Thyroid tumors in a Chinese cohort. Design: We used real-time quantitative PCR for the analysis of PIK3CA copy gain and direct DNA sequencing for the detection of PIK3CA, RAS, and PTEN mutations on genomic DNA isolated from 234 Thyroid tumors, including 31 follicular Thyroid cancer (FTC), 141 papillary Thyroid cancer (PTC), and 62 follicular Thyroid Adenoma (FTA). Results: We found PIK3CA copy gain (defined as four or more copies) in nine of 31 FTC (29%), 20 of 141 PTC (14%), and five of 62 FTA (8%); PIK3CA gene mutations in four of 31 FTC (13%), one of 141 PTC (1%), and none of 62 FTA (0%); Ras mutations in three of 31 FTC (10%) and none of the 141 PTC and 62 FTA; and PTEN mutations in two of 31 ...
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genetic alterations and their relationship in the phosphatidylinositol 3 kinase akt pathway in Thyroid cancer
Clinical Cancer Research, 2007Co-Authors: Peng Hou, Yangang Wang, Stephen Condouris, Dingxie Liu, Yuan Shan, Kimberley Studeman, Ariel Trink, Adel K Elnaggar, Giovanni Tallini, Vasily VaskoAbstract:Purpose: To investigate the overall occurrence and relationship of genetic alterations in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in Thyroid tumors and explore the scope of this pathway as a therapeutic target for Thyroid cancer. Experimental Design: We examined collectively the major genetic alterations and their relationship in this pathway, including PIK3CA copy number gain and mutation, Ras mutation, and PTEN mutation, in a large series of primary Thyroid tumors. Results: Occurrence of any of these genetic alterations was found in 25 of 81 (31%) benign Thyroid Adenoma (BTA), 47 of 86 (55%) follicular Thyroid cancer (FTC), 21 of 86 (24%) papillary Thyroid cancer (PTC), and 29 of 50 (58%) anaplastic Thyroid cancer (ATC), with FTC and ATC most frequently harboring these genetic alterations. PIK3CA copy gain was associated with increased PIK3CA protein expression. A mutual exclusivity among these genetic alterations was seen in BTA, FTC, and PTC, suggesting an independent role of each of them through the PI3K/Akt pathway in the tumorigenesis of the differentiated Thyroid tumors. However, coexistence of these genetic alterations was increasingly seen with progression from differentiated tumor to undifferentiated ATC. Their coexistence with BRAF mutation was also frequent in PTC and ATC. Conclusions: The data provide strong genetic implication that aberrant activation of PI3K/Akt pathway plays an extensive role in Thyroid tumorigenesis, particularly in FTC and ATC, and promotes progression of BTA to FTC and to ATC as the genetic alterations of this pathway accumulate. Progression of PTC to ATC may be facilitated by coexistence of PI3K/Akt pathway–related genetic alterations and BRAF mutation. The PI3K/Akt pathway may thus be a major therapeutic target in Thyroid cancers.