Browsing by Author "Loughrey, Paul Benjamin (56993777000)"

In the original publication of this article, upper and lower part of Table 2 was incorrectly formatted. The incorrect and correct version of Table 2 are shown in this correction article. The original article has been corrected. Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper table) and in the entire cohort (lower table) Hypermethylated and positive enriched in PC pval padj NES size KEGG cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG focal adhesion 7.16E-05 0.0015 1.44 191 KEGG adherens junction 8.97E-05 0.0017 1.64 67 KEGG calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG gap junction 0.0063 0.036 1.40 83 KEGG axon guidance 1.60E-06 0.00028 1.53 122 KEGG calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG leukocyte transendothelial migration 0.011 0.10 1.28 108 Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper part of the table) and in the entire cohort (lower part of the table) Hypermethylated and positive enriched in PC pval padj NES size KEGG Cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG Axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG Pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG Neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG Focal adhesion 7.16E-05 0.0015 1.44 191 KEGG Adherens junction 8.97E-05 0.0017 1.64 67 KEGG Calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG Leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG Gap junction 0.0063 0.036 1.40 83 Hypermethylated and positive enriched in PC pval padj NES size KEGG Axon guidance 1.60E-06 0.00028 1.53 122 KEGG Calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG Neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG Regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG Cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG Leukocyte transendothelial migration 0.011 0.10 1.28 108 © The Author(s) 2024.

In the original publication of this article, upper and lower part of Table 2 was incorrectly formatted. The incorrect and correct version of Table 2 are shown in this correction article. The original article has been corrected. Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper table) and in the entire cohort (lower table) Hypermethylated and positive enriched in PC pval padj NES size KEGG cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG focal adhesion 7.16E-05 0.0015 1.44 191 KEGG adherens junction 8.97E-05 0.0017 1.64 67 KEGG calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG gap junction 0.0063 0.036 1.40 83 KEGG axon guidance 1.60E-06 0.00028 1.53 122 KEGG calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG leukocyte transendothelial migration 0.011 0.10 1.28 108 Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper part of the table) and in the entire cohort (lower part of the table) Hypermethylated and positive enriched in PC pval padj NES size KEGG Cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG Axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG Pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG Neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG Focal adhesion 7.16E-05 0.0015 1.44 191 KEGG Adherens junction 8.97E-05 0.0017 1.64 67 KEGG Calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG Leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG Gap junction 0.0063 0.036 1.40 83 Hypermethylated and positive enriched in PC pval padj NES size KEGG Axon guidance 1.60E-06 0.00028 1.53 122 KEGG Calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG Neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG Regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG Cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG Leukocyte transendothelial migration 0.011 0.10 1.28 108 © The Author(s) 2024.

Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0–2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors. © The Author(s) 2024.

Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0–2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors. © The Author(s) 2024.

Objective: Heterozygous germline loss-of-function variants in AIP are associated with young-onset growth hormone and/or prolactin-secreting pituitary tumours. However, the pathogenic role of the c.911G > A; p.(Arg304Gln) (R304Q) AIP variant has been controversial. Recent data from public exome/genome databases show this variant is not infrequent. The objective of this work was to reassess the pathogenicity of R304Q based on clinical, genomic, and functional assay data. Design: Data were collected on published R304Q pituitary neuroendocrine tumour cases and from International Familial Isolated Pituitary Adenoma Consortium R304Q cases (n = 38, R304Q cohort). Clinical features, population cohort frequency, computational analyses, prediction models, presence of loss-of-heterozygosity, and in vitro/in vivo functional studies were assessed and compared with data from pathogenic/likely pathogenic AIP variant patients (AIPmut cohort, n = 184). Results: Of 38 R304Q patients, 61% (23/38) had growth hormone excess, in contrast to 80% of AIPmut cohort (147/184, P < .001). R304Q cohort was older at disease onset and diagnosis than the AIPmut cohort (median [quartiles] onset: 25 y [16-35] vs 16 y [14-23], P < .001; median [quartiles] diagnosis: 36 y [24-44] vs 21 y [15-29], P < .001). R304Q is present in gnomADv2.1 (0.31%) and UK Biobank (0.16%), including three persons with homozygous R304Q. No loss-of-heterozygosity was detected in four R304Q pituitary neuroendocrine tumour samples. In silico predictions and experimental data were conflicting. Conclusions: Evidence suggests that R304Q is not pathogenic for pituitary neuroendocrine tumour. We recommend changing this variant classification to likely benign and do not recommend pre-symptomatic genetic testing of family members or follow-up of already identified unaffected individuals with the R304Q variant. © The Author(s) 2025. Published by Oxford University Press on behalf of European Society of Endocrinology.

Objective: Heterozygous germline loss-of-function variants in AIP are associated with young-onset growth hormone and/or prolactin-secreting pituitary tumours. However, the pathogenic role of the c.911G > A; p.(Arg304Gln) (R304Q) AIP variant has been controversial. Recent data from public exome/genome databases show this variant is not infrequent. The objective of this work was to reassess the pathogenicity of R304Q based on clinical, genomic, and functional assay data. Design: Data were collected on published R304Q pituitary neuroendocrine tumour cases and from International Familial Isolated Pituitary Adenoma Consortium R304Q cases (n = 38, R304Q cohort). Clinical features, population cohort frequency, computational analyses, prediction models, presence of loss-of-heterozygosity, and in vitro/in vivo functional studies were assessed and compared with data from pathogenic/likely pathogenic AIP variant patients (AIPmut cohort, n = 184). Results: Of 38 R304Q patients, 61% (23/38) had growth hormone excess, in contrast to 80% of AIPmut cohort (147/184, P < .001). R304Q cohort was older at disease onset and diagnosis than the AIPmut cohort (median [quartiles] onset: 25 y [16-35] vs 16 y [14-23], P < .001; median [quartiles] diagnosis: 36 y [24-44] vs 21 y [15-29], P < .001). R304Q is present in gnomADv2.1 (0.31%) and UK Biobank (0.16%), including three persons with homozygous R304Q. No loss-of-heterozygosity was detected in four R304Q pituitary neuroendocrine tumour samples. In silico predictions and experimental data were conflicting. Conclusions: Evidence suggests that R304Q is not pathogenic for pituitary neuroendocrine tumour. We recommend changing this variant classification to likely benign and do not recommend pre-symptomatic genetic testing of family members or follow-up of already identified unaffected individuals with the R304Q variant. © The Author(s) 2025. Published by Oxford University Press on behalf of European Society of Endocrinology.