Clonal X-inactivation analysis of human tumours using the human androgen receptor gene (HUMARA) polymorphism: a non-radioactive and semiquantitative strategy applicable to fresh and archival tissue

Kopp, Peter; Jaggi, Rolf; Tobler, Andreas; Borisch, Bettina; Oestreicher, M; Sabacan, Leah; Jameson, J. Larry; Fey, Martin F.

doi:10.1006/mcpr.1997.0099

Cited by 45 publications

(31 citation statements)

References 18 publications

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“…MC clonality was further assayed on gDNA from 26 of 46 female patients by the human-androgen receptor (HUMARA) X-chromosome inactivation test. 43 …”

Section: Dna Extraction and Molecular Studiesmentioning

confidence: 99%

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

Garcia-Montero¹,

Jara‐Acevedo

Álvarez‐Twose

et al. 2016

Blood

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Key Points• Acquisition of the KIT D816V mutation in an early pluripotent progenitor cell confers ISM cases a greater risk for disease progression.• Despite the early acquisition of the KIT mutation, onset of clinical symptoms of ISM is often delayed to middle adulthood.Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indolent systemic mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSCmutated patients had multilineage KIT mutation (100% vs 30%, P 5 .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P 5 .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P 5 .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P 5 .04), and a shorter progression-free survival (P £ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome. (Blood. 2016;127(6):761-768)

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“…MC clonality was further assayed on gDNA from 26 of 46 female patients by the human-androgen receptor (HUMARA) X-chromosome inactivation test. 43 …”

Section: Dna Extraction and Molecular Studiesmentioning

confidence: 99%

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

Garcia-Montero¹,

Jara‐Acevedo

Álvarez‐Twose

et al. 2016

Blood

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“…Allele intensity was calculated as described by Kopp et al (14). A corrected ratio ((digested allele 1/allele 2)/(non-digested allele 1/allele 2)) value equal to or higher than three was chosen as the cut-off value for clonality, indicating that one of the parental alleles represented 75% or more of the alleles present in the sample (14).…”

Section: Clonality (Ar) Assaymentioning

confidence: 99%

Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain

Palos-Paz

Perez-Guerra²,

Cameselle-Teijeiro³

et al. 2008

European Journal of Endocrinology

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Objective: Toxic thyroid adenoma (TA) is a common cause of hyperthyroidism. Mutations in the TSH receptor (TSHR) gene, and less frequently in the adenylate cyclase-stimulating G alpha protein (GNAS) gene, are well established causes of TA in Europe. However, genetic causes of TA remain unknown in a small percentage of cases. We report the first study to investigate mutations in TSHR, GNAS, protein kinase, cAMP-dependent, regulatory, type I alpha (PRKAR1A) and RAS genes, in a large series of TA from Galicia, an iodine-deficient region in NW Spain. Design and methods: Eighty-five TA samples were obtained surgically from 77 hyperthyroid patients, operated on for treatment of non-autoimmune toxic nodular goitre. After DNA extraction, all coding exons of TSHR, GNAS and PRKAR1A genes, and exons 2 and 3 of HRAS, KRAS and NRAS were amplified by PCR and sequenced. Previously unreported mutants were cloned in expression vectors and their basal constitutive activities were determined by quantification of cAMP response element (CRE)-luciferase activity in CO7 cells transfected with wild-type and mutant plasmids. Results: TSHR gene mutations were found in 52 (61.2%) samples, GNAS gene mutations in 4 (4.71%) samples and no PRKAR1A or RAS mutations were found. Only three previously unreported mutations were found, two affecting the TSHR, A623F and I635V, and one affecting the G-protein a-subunit (Gsa), L203P. All mutant proteins showed higher CRE-luciferase activity than their wild-type counterparts. Conclusions: TA in a hyperthyroid population living in Galicia, a Spanish iodine-deficient region, harbours elevated frequencies of TSHR and GNAS mutations activating the cAMP pathway. However, the genetic cause of TA was undetermined in 34% of the TA samples.European Journal of Endocrinology 159 623-631

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“…The non-random inactivation of the female X-chromosome is a sign of monoclonal neoplastic proliferation (not a sign of malignancy), and its occurrence was also subject to investigation during the demonstration of the clonal nature of aggressive fibromatoses (8,40,45). A nonrandom X inactivation pattern was found in 72% of patients with sporadic desmoids, with a lesion clonality ratio ranging between 1.3 and 18.7 (40,45).…”

Section: The Neoplastic Nature Of Desmoidsmentioning

confidence: 99%

“…A nonrandom X inactivation pattern was found in 72% of patients with sporadic desmoids, with a lesion clonality ratio ranging between 1.3 and 18.7 (40,45). Evidence of malignancy has also been sought by assessing expression of tumor markers in desmoid tissue.…”

Section: The Neoplastic Nature Of Desmoidsmentioning

confidence: 99%

“…Evidence of malignancy has also been sought by assessing expression of tumor markers in desmoid tissue. In comparison to other malignancies, desmoids were found with a relatively low expression of metastasis promoting extracellular matrix proteins such as osteopontin and osteonectin, suggested to be the reason for the inability to disseminate (39,45). Other common malignant tumor markers as Ki-67, pRB or Bcl-2 have not been observed to be upregulated in desmoid tissue (39,43,(46)(47)(48).…”

Section: The Neoplastic Nature Of Desmoidsmentioning

confidence: 99%

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Diagnosis and multidisciplinary treatment of sporadical desmoid tumors

Mátrai¹

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Clonal X-inactivation analysis of human tumours using the human androgen receptor gene (HUMARA) polymorphism: a non-radioactive and semiquantitative strategy applicable to fresh and archival tissue

Cited by 45 publications

References 18 publications

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain

Diagnosis and multidisciplinary treatment of sporadical desmoid tumors

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