ΕΡΕΥΝΑ - ΚΑΙΝΟΤΟΜΙΑ

Παράλληλα με τις υπηρεσίες που προσφέρει, η BioGenomica αναπτύσσει ερευνητική δραστηριότητα που εστιάζεται στα εξής:

	Συμμετοχή σε εθνικές και ευρωπαϊκές μελέτες με στόχο τον εντοπισμό νέων γονιδίων ή μεταλλάξεων που σχετίζονται με την εκδήλωση κληρονομικών ασθενειών. (Πρόγραμμα συνεργασίας με το Ε.Κ.Ε.Φ.Ε. "Δημόκριτος" και άλλα ερευνητικά εργαστήρια και κλινικές στην Ελλάδα και την Ευρώπη).
	Συμμετοχή σε βιοχημικές και βιοφυσικές μελέτες με στόχο τον χαρακτηρισμό σημειακών παθογόνων μεταλλάξεων σε σχέση με τη λειτουργία της ανθρώπινης πρωτεΐνης BRCA1 (Πρόγραμμα συνεργασίας με Ε.Κ.Ε.Φ.Ε "Δημόκριτος").
	Συμμετοχή στην ανάπτυξη καινοτόμων αισθητήρων νανομηχανικής τεχνολογίας για την ακριβή και ταχεία ανίχνευση γενετικών μεταλλάξεων σε βιολογικά υλικά.
	Ευρωπαϊκό Πρόγραμμα NEMOSLAB.
	Ερευνητικές Μελέτες Νέων Παθογόνων Μεταλλάξεων.
	Ευρωπαϊκο πρόγραμμα PYTHIA.

Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast / ovarian cancer patients.

Irene Konstantopoulou, Theodore Rampias, Angela Ladopoulou,George Koutsodontis, Sophia Armaou, Theodore Anagnostopoulos, George Nikolopoulos, Smaragda Kamakari, George Nounesis, Antonis Stylianakis, Charisios Karanikiotis, Evangelia Razis, Helen Gogas, Antonios Keramopoulos, Vassiliki Gaki, Christos Markopoulos, Dimosthenis Skarlos, Nikos Pandis, Thalia Bei, Iordanis Arzimanoglou, George Fountzilas and Drakoulis Yannoukakos.

127 Greek breast/ovarian cancer families were screened for germline BRCA1/2 mutations by dHPLC followed by direct sequencing. Our results indicated 16 and 5 breast / ovarian cancer families bearing deleterious mutations in the BRCA1 and BRCA2 genes, respectively. Two novel BRCA2 germline mutations (G4X and 3783del10) are reported here for the first time. Subsequent compilation of our present findings with previously reported mutation data reveals that in a total of 287 Greek breast / ovarian cancer families, 46 and 13 carry a deleterious mutation in BRCA1 and BRCA2, respectively. It should be noted that two BRCA1 mutations, 5382insC and G1738R, both located in exon 20, account for 46% of the families found to carry a mutation. Based on our mutation analysis results, we propose here a hierarchical, cost-effective BRCA1/2 mutation screening protocol for individuals of Greek ethnic origin. The suggested protocol can impact on the clinical management of breast-ovarian cancer families on a national healthcare system level.

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G1738R is a BRCA1 founder mutation in Greek breast/ovarian cancer patients: evaluation of its pathogenicity and inferences on its genealogical history.

Theodore Anagnostopoulos, Maroulio Pertesi, Irene Konstantopoulou, Sofia Armaou1, Smaragda Kamakari, George Nasioulas, Athanassios Athanasiou, Alex Dobrovic, Mary-Anne Young, David Goldgar, George Fountzilas and Drakoulis Yannoukakos.

We have performed screening in 287 breast / ovarian cancer families in Greece which has revealed that ~12% (8/65) of all index patients-carriers of a deleterious mutation in BRCA1 and BRCA2 genes, contain the base substitution G to A at position 5331 of BRCA1 gene.

This generates the amino acid change G1738R for which based on a combination of genetic, in silico and histopathological analysis there are strong suggestions that it is a causative mutation. In this paper, we present further evidence suggesting the pathogenicity of this variant. Forty breast / ovarian cancer patients were reported in 11 Greek families: the above eight living in Greece, two living in Australia and one in USA, all containing G1738R. Twenty of these patients were screened and were all found to be carriers of the same base substitution. In addition, we have detected the same base change in five breast / ovarian cancer patients after screening 475 unselected patient samples with no apparent family history. The mean age of onset for all the above patients was 39.4 and 53.6 years for breast and ovarian cancer cases, respectively. A multi-factorial likelihood model for classification of unclassified variants in BRCA1 and BRCA2 developed previously was applied on G1738R and the odds of it being a deleterious mutation was estimated to be 11470:1. In order to explain the prevalence of this mutation mainly in the Greek population, its genealogical history was examined. DNA samples were collected from 11 carrier families living in Greece, Australia and USA. Screening of eight intragenic SNPs, three intragenic and seven extragenic microsatellite markers and comparison with control individuals, suggested a common origin for the mutation while the time to its most recent common ancestor was estimated to be 11 generations (about 275 years assuming a generational interval of 25 years) with a 1-lod support interval of 4-24 generations (100-600 years). Considering the large degree of genetic heterogeneity in the Greek population, the identification of a frequent founder mutation greatly facilitates genetic screening.

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A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening.

Philippos Kaldrymides, Nikolaos Mytakidis, Theodore Anagnostopoulos, Manolis Vassiliou, Athanasia Tertipi, Maria Zahariou, Theodoros Rampias Giorgos Koutsodontis, Irene Konstantopoulou, Angela Ladopoulou, Thalia Bei and Drakoulis Yannoukakos.

Familial medullary thyroid carcinoma (FMTC) is caused by germ-line mutations in the RET proto-oncogene. These mutations concern mainly cysteine residues in exons 10 and 11, whereas noncysteine mutations in exons 13-16 are rare. Mutations in other exons have been reported only in isolated families. In this study we have analysed the RET gene in two FMTC families negative for mutations in the above exons. DESIGN: We have analysed exons 7-19 and 21 in one index patient from each family using DNA sequencing. PATIENTS: Twenty-eight subjects from both families were clinically assessed and subsequently molecularly analysed for the presence of RET gene mutations. RESULTS: We have found the mutation c.1597G-->T (Gly533Cys) in two Greek families with FMTC. The mutation was detected in all seven MTC patients of both families as well as in 13 asymptomatic relatives in the heterozygote state, although one of the patients was also a homozygote due to consanguinity. The mutation shows a wide clinical heterogeneity, as there are carrier patients with age of diagnosis ranging from 23 to 88 years. CONCLUSIONS: It is likely that this mutation causes FMTC, as no other mutation was found in the RET gene, the mutation co-segregates with FMTC, and family members without the mutation are clinically unaffected. As the same point mutation was previously found in a large Brazilian family, it may be present in other populations as well. Therefore, exon 8 of RET should be screened in FMTC families with no identified common RET mutations. Read the entire article