Profil ekspresji genów w gwiaździakach włosowatokomórkowych wieku dziecięcego w odniesieniu do lokalizacji, obrazu radiologiczno‑morfologicznego i przebiegu klinicznego choroby

• Authors: Magdalena Zakrzewska

Title variants

EN

Gene expression profiles of pilocytic astrocytoma in relation to the location, radiological features and clinical course of the disease

• Languages of publication: PL

Abstracts

PL

Gwiaździak włosowatokomórkowy (pilocytic astrocytoma, PA) jest najczęstszym nowotworem mózgu występującym u dzieci, u których stanowi około 30% wszystkich nowotworów ośrodkowego układu nerwowego. Biologia molekularna tego nowotworu, pomimo jego częstego występowania w populacji dziecięcej, nie została dotąd wystarczająco poznana, a ewentualnego związku pomiędzy obecnością zaburzeń molekularnych a parametrami klinicznymi nie zdefiniowano na poziomie pozwalającym wykorzystać wyniki badań genetycznych w sferze działań klinicznych. Celem projektu było ustalenie profili ekspresji genów różnicujących gwiaździaka włosowatokomórkowego wieku dziecięcego w zależności od jego umiejscowienia, obrazu radiologiczno‑morfologicznego oraz przebiegu klinicznego choroby. Do badań zakwalifikowano nowotworowy materiał tkankowy pochodzący od 86 dzieci (55 chłopców, 31 dziewcząt) w wieku od 1 do 17 lat (mediana 7 lat). Wszystkie przypadki zostały zdiagnozowane w Zakładzie Patologii Molekularnej i Neuropatologii Uniwersytetu Medycznego w Łodzi w oparciu o kryteria bieżącej klasyfikacji nowotworów ośrodkowego układu nerwowego według WHO. Badania mające na celu identyfikację istotnych biologicznie odchyleń w ekspresji genów przeprowadzono przy użyciu mikromacierzy wysokiej gęstości Human Genome U133 Plus 2.0 (Affymetrix) w 50 przypadkach gwiaździaków włosowatokomórkowych. Badana grupa była zróżnicowana pod względem lokalizacji (28 nowotworów móżdżku i komory IV, 11 nowotworów dróg wzrokowych i podwzgórza, 9 nowotworów półkul mózgu, 2 nowotwory pnia mózgu), obrazu radiologiczno‑morfologicznego (27 nowotworów litych, 10 nowotworów torbielowatych, w których wzmocnieniu kontrastowemu ulegały ściana torbieli i guzek przyścienny, 8 nowotworów torbielowatych z guzkiem przyściennym, w których wzmocnieniu kontrastowemu ulegał tylko guzek przyścienny, 5 nowotworów z obecnymi cechami martwicy centralnej) i przebiegu klinicznego choroby (5 przypadków z cechami klinicznymi progresji choroby po resekcji subtotalnej, 2 przypadki rozwijające się w przebiegu neurofibromatozy typu 1.). Po normalizacji wyników przy użyciu algorytmu GC‑RMA przeprowadzono analizy bioinformatyczne wykorzystujące przede wszystkim pakiet Bioconductor. Wyselekcjonowano 862 geny różnicujące gwiaździaki włosowatokomórkowe pod względem umiejscowienia anatomicznego i wykazano obecność istotnej zależności statystycznej pomiędzy profilem ekspresji genów w odniesieniu do lokalizacji zmiany (p=0,001). Na podstawie uzyskanych wyników dokonano wyboru genów będących markerami molekularnymi dla nowotworów rozwijających się w poszczególnych lokalizacjach (IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1, SIX1). Nie wykazano możliwości zróżnicowania badanej grupy w zależności od obrazu radiologiczno‑morfologicznego. Geny najlepiej różnicujące badaną grupę cechowały się małą amplitudą zmian i brakiem znamienności statystycznej (p=0,88). Podobnie progresja choroby nie była związana z profilem ekspresji genów (p=0,83). Walidację uzyskanych wyników przeprowadzono w oparciu o QRT‑PCR. Przeprowadzone analizy pozwoliły stwierdzić, że gwiaździakiwłosowatokomórkowe w zależności od lokalizacji anatomicznej posiadają charakterystyczny profil ekspresji genów, sugerujący ich różne pochodzenie. Z kolei obraz radiologiczno‑morfologiczny oraz przebieg kliniczny choroby nie mają związku z całkowitym profilem ekspresji genów.

EN

Pilocytic astrocytoma (PA) is the most common type of brain tumour in paediatric population connected with favourable prognosis although in numbered cases recurrence or dissemination could be observed. PA accounts for 30% of all brain tumours occurring in children. The tumours affect various anatomical structures and show different radiological appearance. Genetics of this tumour as well as the plausible correlations between molecular profile and clinical course of the disease and/or radiological features are still undefined. The purpose of our research was the identification of gene expression profiles related to localization and radiological features of pilocytic astrocytomas and clinical course of the disease. Eighty six children with PAs, operated on in the Department of Neurosurgery, Polish Mother’s Memorial Hospital Research Institute, were included in this study. The group was comprised of 55 males and 31 females. The mean age of patients at the time of diagnosis was 7 years (ranging from 1 to 17 years). All specimens were diagnosed at the Department of Molecular Pathology and Neuropathology Medical University of Lodz, according to the WHO criteria. The analysis was done by high density oligonucleotide microarrays (GeneChip Human Genome U133 Plus 2.0) in 50 snap‑frozen tissue samples diversified in terms of localization (28 cerebellar tumours, 11 optic tracts and hypothalamic tumours, 9 hemispheric tumours, 2 brain stem tumours), radiological appearance (27 solid or mainly solid tumours, 10 cystic tumours where the mural nodule and the cyst wall were enhanced, 8 cystic tumours where only the mural nodule was enhanced, 5 largely necrotic tumours) and clinical course (5 cases of progressive disease after subtotal resection, 2 cases connected with neurofibromatosis type 1). Bioinformatic analyses with using Bioconductor packages were done after normalization of data with using GC‑RMA algorithm. Gene expression profile of pilocytic astrocytomas highly depends on the tumour localization. This correlation reach statistical significance (p=0.001). Eight hundred sixty‑two probesets differentiated tumours of different localization with high significance of global test. Most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes. Analysis of the genes differentiating between radiological features showed much weaker transcriptome differences, with the borderline significance in the global test of association (p=0.88). No genes showed significant association with the tendency to progression in univariate analysis (p=0.83). The results of microarray analysis were confirmed by QRT‑PCR. In the conclusion we showed that gene expression profile in pilocytic astrocytomas is connected with tumour localization and such relationship suggest different origin of PA arising within various anatomical brain structures. Morphological and radiological features as well as clinical course of disease seem not to be associated with different gene expression pattern.

Keywords

EN

children; dzieci; gene expression profiling; gwiaździak włosowatokomórkowy; location; lokalizacja; obraz radiologiczny; outcome; pilocytic astrocytoma; profil ekspresji genów; przebiegchoroby; radiology

Discipline

• MEDICINE: MEDICINE

• Publisher: Medical Communications
• Journal: Aktualności Neurologiczne
• Year: 2011
• Volume: 11
• Issue: 3
• Pages: 135-198

Contributors

author

Magdalena Zakrzewska

• Zakład Patologii Molekularnej i Neuropatologii, Uniwersytet Medyczny w Łodzi

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