Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Marianthi Georgitsi is active.

Publication


Featured researches published by Marianthi Georgitsi.


Science | 2006

Pituitary adenoma predisposition caused by germline mutations in the AIP gene.

Outi Vierimaa; Marianthi Georgitsi; Rainer Lehtonen; Pia Vahteristo; Antti Kokko; Anniina Raitila; Karoliina Tuppurainen; Tapani Ebeling; Pasi Salmela; Ralf Paschke; Sadi Gundogdu; Ernesto De Menis; Markus J. Mäkinen; Virpi Launonen; Auli Karhu; Lauri A. Aaltonen

Pituitary adenomas are common in the general population, and understanding their molecular basis is of great interest. Combining chip-based technologies with genealogy data, we identified germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in individuals with pituitary adenoma predisposition (PAP). AIP acts in cytoplasmic retention of the latent form of the aryl hydrocarbon receptor and also has other functions. In a population-based series from Northern Finland, two AIP mutations account for 16% of all patients diagnosed with pituitary adenomas secreting growth hormone and for 40% of the subset of patients who were diagnosed when they were younger than 35 years of age. Typically, PAP patients do not display a strong family history of pituitary adenoma; thus, AIP is an example of a low-penetrance tumor susceptibility gene.


The Journal of Clinical Endocrinology and Metabolism | 2010

Clinical characteristics and therapeutic responses in patients with Germ-line AIP mutations and pituitary adenomas : An international collaborative study

Adrian Daly; Maria A. Tichomirowa; Patrick Petrossians; Elina Heliövaara; Marie Lise Jaffrain-Rea; Anne Barlier; Luciana A. Naves; Tapani Ebeling; Auli Karhu; Antti Raappana; Laure Cazabat; Ernesto De Menis; Carmen Fajardo Montañana; Gérald Raverot; Robert J. Weil; Timo Sane; Dominique Maiter; Sebastian Neggers; Maria Yaneva; Antoine Tabarin; Elisa Verrua; Eija Eloranta; Arnaud Murat; Outi Vierimaa; Pasi I. Salmela; Philippe Emy; Rodrigo A. Toledo; María Isabel Sabaté; Chiara Villa; Marc Popelier

CONTEXT AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN This study was an international, multicenter, retrospective case collection/database analysis. SETTING The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.


Proceedings of the National Academy of Sciences of the United States of America | 2007

Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations

Marianthi Georgitsi; Anniina Raitila; Auli Karhu; Karoliina Tuppurainen; Markus J. Mäkinen; Outi Vierimaa; Ralf Paschke; Wolfgang Saeger; Rob B. van der Luijt; Timo Sane; Mercedes Robledo; Ernesto De Menis; Robert J. Weil; Anna Wasik; Grzegorz Zielinski; Olga Lucewicz; Jan Lubinski; Virpi Launonen; Pia Vahteristo; Lauri A. Aaltonen

Pituitary adenomas are common neoplasms of the anterior pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause pituitary adenoma predisposition (PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of pituitary adenomas. To evaluate the role of AIP in pituitary adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected pituitary adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of pituitary adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 adenomas: 12 AIP mutation-positive versus 38 mutation-negative pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.


The Journal of Clinical Endocrinology and Metabolism | 2008

Large Genomic Deletions in AIP in Pituitary Adenoma Predisposition

Marianthi Georgitsi; Elina Heliövaara; Ralf Paschke; Ajith Kumar; Marc Tischkowitz; Outi Vierimaa; Pasi Salmela; Timo Sane; Ernesto De Menis; Salvatore Cannavò; Sadi Gundogdu; Anneke Lucassen; Louise Izatt; Simon Aylwin; Gul Bano; Shirley Hodgson; Christian A. Koch; Auli Karhu; Lauri A. Aaltonen

CONTEXT Germline mutations in AIP have been recently shown to cause pituitary adenoma predisposition (PAP). Subsequently, many intragenic germline mutations have been reported, both in familial and in sporadic settings. OBJECTIVE Our objective was to evaluate the possible contribution of large genomic germline AIP deletions, an important mutation type in tumor predisposition syndromes, in PAP. DESIGN Here, we applied the multiplex ligation-dependent probe amplification assay to examine whether large genomic AIP or MEN1 alterations account for a subset of PAP cases. PATIENTS The study was performed on familial and sporadic pituitary adenoma cases of European origin, which had previously tested negative for germline AIP and MEN1 mutations by sequencing. RESULTS Two of 21 pituitary adenoma families (9.5%) were found to harbor an AIP deletion. No copy number changes were detected among 67 sporadic pituitary adenoma patients. No MEN1 deletions were found. CONCLUSIONS The present study shows that large genomic AIP deletions account for a subset of PAP. Therefore, in suspected PAP cases undergoing counseling and AIP genetic testing, multiplex ligation-dependent probe amplification could be considered if direct sequencing does not identify a mutation.


Clinical Endocrinology | 2008

Aryl hydrocarbon receptor interacting protein (AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas

Marianthi Georgitsi; Ernesto De Menis; Salvatore Cannavò; Markus J. Mäkinen; Karoliina Tuppurainen; Paolo Pauletto; Lorenzo Curtò; Robert J. Weil; Ralf Paschke; Grzegorz Zielinski; Anna Wasik; Jan Lubinski; Pia Vahteristo; Auli Karhu; Lauri A. Aaltonen

Objective  Pituitary adenomas occur rarely in childhood and adolescence. Pituitary adenoma predisposition (PAP) has been recently associated with germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. The aim of the study was to examine the proportion of germline AIP mutations in apparently sporadic paediatric pituitary adenomas.


American Journal of Pathology | 2010

Mice with Inactivation of Aryl Hydrocarbon Receptor Interacting Protein (Aip) Display Complete Penetrance of Pituitary Adenomas with aberrant ARNT Expression

Anniina Raitila; Heli J. Lehtonen; Johanna Arola; Elina Heliövaara; Manuel Ahlsten; Marianthi Georgitsi; Anu Jalanko; Anders Paetau; Lauri A. Aaltonen; Auli Karhu

Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been shown to predispose to pituitary adenoma predisposition, a condition characterized by growth hormone (GH)-secreting pituitary tumors. To study AIP-mediated tumorigenesis, we generated an Aip mouse model. Heterozygous mice developed normally but were prone to pituitary adenomas, in particular to those secreting GH. A complete loss of AIP was detected in these lesions, and full penetrance was reached at the age of 15 months. No excess of any other tumor type was found. Ki-67 analysis indicated that Aip-deficient tumors have higher proliferation rates compared with Aip-proficient tumors, suggesting a more aggressive disease. Similar to human AIP-deficient pituitary adenomas, immunohistochemical studies showed that expression of aryl hydrocarbon receptor nuclear translocator 1 or 2 (ARNT or ARNT2) protein was lost in the mouse tumors, suggesting that mechanisms of AIP-related tumorigenesis involve aberrant ARNT function. The Aip(+/-) mouse appears to be an excellent model for the respective human disease phenotype. This model constitutes a tool to further study AIP-associated pituitary tumorigenesis and may be potentially valuable in efforts to develop therapeutic strategies to treat pituitary adenomas.


Endocrine-related Cancer | 2007

No evidence of somatic aryl hydrocarbon receptor interacting protein mutations in sporadic endocrine neoplasia

Anniina Raitila; Marianthi Georgitsi; Auli Karhu; Karoliina Tuppurainen; Markus J. Mäkinen; K Birkenkamp-Demtröder; K Salmenkivi; T F Ørntoft; Johanna Arola; Virpi Launonen; Pia Vahteristo; Lauri A. Aaltonen

Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently observed in patients with pituitary adenoma predisposition (PAP). Though AIP mutation-positive individuals with prolactin-, mixed growth hormone/prolactin-, and ACTH-producing pituitary adenomas as well as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age. Pituitary adenomas are also component tumors of some familial endocrine neoplasia syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Genes underlying MEN1 and CNC are rarely mutated in sporadic pituitary adenomas, but more often in other lesions contributing to these two syndromes. Thus far, the occurrence of somatic AIP mutations has not been studied in endocrine tumors other than pituitary adenomas. Here, we have analyzed 32 pituitary adenomas and 79 other tumors of the endocrine system for somatic AIP mutations by direct sequencing. No somatic mutations were identified. However, two out of nine patients with prolactin-producing adenoma were shown to harbor a Finnish founder mutation (Q14X) with a complete loss of the wild-type allele in the tumors. These results are in agreement with previous studies in that prolactin-producing adenomas are component tumors in PAP. The data also support the previous finding that somatic AIP mutations are not common in pituitary adenomas and suggest that such mutations are rare in other endocrine tumors as well.


European Journal of Endocrinology | 2009

Aggressive pituitary adenomas occurring in young patients in a large Polynesian kindred with a germline R271W mutation in the AIP gene

Juliet Jennings; Marianthi Georgitsi; Ian Holdaway; Adrian Daly; Maria A. Tichomirowa; Albert Beckers; Lauri A. Aaltonen; Auli Karhu; Fergus J. Cameron

OBJECTIVE Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) were recently shown to confer a pituitary adenoma predisposition in patients with familial isolated pituitary adenomas (FIPA). We report a large Samoan FIPA kindred from Australia/New Zealand with an R271W mutation that was associated with aggressive pituitary tumors. DESIGN AND METHODS Case series with germline screening of AIP and haplotype analyses among R271W families. RESULTS This previously unreported kindred consisted of three affected individuals that either presented with or had first symptoms of a pituitary macroadenoma in late childhood or adolescence. The index case, a 15-year-old male with incipient gigantism and his maternal aunt, had somatotropinomas, and the maternal uncle of the index case had a prolactinoma. All tumors were large (15, 40, and 60 mm maximum diameter) and two required transcranial surgery and radiotherapy. All three affected subjects and ten other unaffected relatives were found to be positive for a germline R271W AIP mutation. Comparison of the single nucleotide polymorphism patterns among this family and two previously reported European FIPA families with the same R271W mutation demonstrated no common ancestry. CONCLUSIONS This kindred exemplifies the aggressive features of pituitary adenomas associated with AIP mutations, while genetic analyses among three R271W FIPA families indicate that R271W represents a mutational hotspot that should be studied further in functional studies.


Journal of Endocrinological Investigation | 2009

Mutation analysis of MEN1, HRPT2, CASR, CDKN1B, and AIP genes in primary hyperparathyroidism patients with features of genetic predisposition.

Outi Vierimaa; A. Villablanca; A. Alimov; Marianthi Georgitsi; Anniina Raitila; Pia Vahteristo; C. Larsson; A. Ruokonen; E. Eloranta; Tapani Ebeling; J. Ignatius; Lauri A. Aaltonen; J. Leisti; Pasi Salmela

Objective: Primary hyperparathyroidism (PHPT), a common endocrine condition, is usually caused by sporadically occurring parathyroid adenoma. A subset of patients carry germline mutations in genes such as MEN1 (multiple endocrine neoplasia type 1), HRPT2 (hyperparathyroidism 2), and CASR (calcium-sensing receptor) predisposing to syndromic forms of PHPT or familial isolated hyperparathyroidism (FIHP). Recently, germline mutations in two novel genes AIP (aryl hydrocarbon receptor-interacting protein) and CDKN1B (cyclin-dependent kinase inhibitor 1B) have been found to be associated with endocrine tumors. The purpose of this study was to evaluate the role of MEN1, HRPT2, CASR, AIP, and CDKN1B genes in PHPT patients with clinical features suggestive of genetic predisposition. Patients and design: Medical records of patients treated for PHPT from 1974 to 2001 at Oulu University Hospital were reviewed. Patients with multiglandular or recurrent/persistent disease, other MEN1-related manifestations, aged 40 yr or younger at onset or with a family history of PHPT/MEN1-related tumor were invited to the study. Twenty patients with previously diagnosed MEN1 were excluded. Participants were interviewed and blood samples obtained for biochemical screening and mutation analysis of MEN1, HRPT2, CASR, AIP, and CDKN1B. Results: Of the 56 invited patients, 29 took part in the study. One patient was found to carry the c. 1356_1367del12 MEN1 founder mutation. Mutations in other genes were not detected. Conclusions: Apart from MEN1, mutations in other genes predisposing to PHPT seem to be rare or non-existing in Northern Finnish PHPT patients. No evidence was found for a role of AIP or CDKN1B in PHPT predisposition.


Journal of Endocrinological Investigation | 2009

Aryl hydrocarbon receptor interacting protein mutations seem not to associate with familial non-medullary thyroid cancer

Anniina Raitila; Marianthi Georgitsi; Elena Bonora; Manuela Vargiolu; Karoliina Tuppurainen; Markus J. Mäkinen; Outi Vierimaa; Pasi Salmela; Virpi Launonen; Pia Vahteristo; Lauri A. Aaltonen; Giovanni Romeo; Auli Karhu

Background: Over 95% of all thyroid malignancies are non-medullary thyroid carcinomas (NMTC). Familial NMTC are more aggressive and mortality is higher as compared with sporadic carcinomas. Known genetic factors do not explain all familial NMTC. Recently, thyroid disorders have been observed in families with germline mutations in aryl hydrocarbon receptor interacting protein (AIP) but, due to frequent occurrence of these conditions in the population, the significance of this co-occurrence is not clear. Aim, subjects and methods: To examine whether AIP is involved in familial NMTC, we performed AIP mutation screening in 93 familial NMTC cases. In addition, the AIP status was studied in one follicular thyroid adenoma patient with a known AIP mutation from an additional cohort. Results: No potentially pathogenic changes were identified, but two likely rare polymorphisms were detected. AIP mutation-positive patient’s follicular thyroid adenoma showed no loss of heterozygosity or lack of immunohistochemical AIP staining. Conclusion: Our study indicates that germline AIP mutations are rare or do not exist in familial NMTC.

Collaboration


Dive into the Marianthi Georgitsi's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar

Auli Karhu

University of Helsinki

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Outi Vierimaa

Oulu University Hospital

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Timo Sane

University of Helsinki

View shared research outputs
Researchain Logo
Decentralizing Knowledge