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Protein expression and gene amplification of human epidermal growth factor receptor 2 (HER2) with lung adenocarcinoma

dc.contributor.advisorEri, Živka
dc.contributor.advisorVučković, Ljiljana
dc.contributor.otherPanjković, Milana
dc.contributor.otherKnežević-Ušaj, Slavica
dc.contributor.otherGolubović, Mileta
dc.contributor.otherZarić, Bojan
dc.contributor.otherTadić-Latinović, Ljiljana
dc.creatorMiladinović, Mirjana
dc.date.accessioned2019-01-25T16:10:46Z
dc.date.available2019-01-25T16:10:46Z
dc.date.available2020-07-03T13:27:48Z
dc.date.issued2019-01-11
dc.identifier.urihttps://www.cris.uns.ac.rs/DownloadFileServlet/Disertacija153857244485237.pdf?controlNumber=(BISIS)107833&fileName=153857244485237.pdf&id=12081&source=NaRDuS&language=srsr
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/10697
dc.identifier.urihttps://www.cris.uns.ac.rs/record.jsf?recordId=107833&source=NaRDuS&language=srsr
dc.identifier.urihttps://www.cris.uns.ac.rs/DownloadFileServlet/IzvestajKomisije153857245488474.pdf?controlNumber=(BISIS)107833&fileName=153857245488474.pdf&id=12082&source=NaRDuS&language=srsr
dc.identifier.urinull/DownloadFileServlet/IzvestajKomisije153857245488474.pdf?controlNumber=(BISIS)107833&fileName=153857245488474.pdf&id=12082
dc.description.abstractReceptor humanog epidermalnog faktora rasta 2 (HER2) pripada porodici receptora protein-tirozin kinaze čija je aktivacija povezana sa proliferacijom malignih ćelija, inhibicijom apoptoze, tumorskom angiogenezom i sposobnosti invazije i metastaziranja. Povećana proteinska ekspresija HER2 receptora može nastati kao posledica amplifikacije gena i/ili transkripcijskih promena. Ekspresija HER2 receptora u humanim tumorima povezuje se sa agresivnijim ponašanjem i lošijom prognozom. Učestalost povećane proteinske ekspresije HER2 receptora u nesitnoćelijskim karcinomima pluća (NSCLC) je najviše zastupljena u adenokarcinomu u odnosu na druge histološke tipove. Identifikacija HER2 pozitivnih NSCLC omogućava određivanje grupe pacijenata koji bi bili kandidati za specifičnu terapiju. Problem predstavlja izbor metode detekcije HER2 receptora i nepostojanje utvrđenog protokola za očitavanje rezultata kao što postoji kod karcinoma dojke i želuca. Osnovni ciljevi ove doktorske disertacije su bili: da se odredi učestalost povećane proteinske ekspresije HER2 receptora u adenokarcinomu pluća; da se uporede rezultati povećane proteinske ekspresije HER2 receptora dobijene korišćenjem HER2 antitela „Hercep Test Dako“ i „Ventana anti-HER2/neu (4B5)“ antitela; da se uporedi prisustvo amplifikacije HER2 gena pomoću in situ hibridizacije (ISH) (Dual IHC HER2 kit;Ventana Medical Systems) retestiranjem uzoraka kod kojih je povećana proteinska ekspresija HER2 receptora ocenjena sa 2+ i 3+ dobijena „Hercep Test Dako“ sa prisustnom amplifikacijom HER2 gena na uzorcima koji su pomoću „Ventana anti-HER2/neu (4B5)“ ocenjeni sa 2+ i 3+; da se uporedi učestalost povećane proteinske ekspresije HER2 receptora i prisustva HER2 genske amplifikacije kod različitih histoloških podtipova adenokarcinoma pluća; da se utvrdi da li je povećana proteinska ekspresija HER2 receptora u adenokarcinomu pluća i/ili prisustvo genske amplifikacije povezano sa demografskim (starost i pol pacijenta) parametrima, pušačkim statusom, pojavom metastaza u regionalnim limfnim čvorovima i udaljenim organima, infiltracijom pleure i okolnih struktura, odnosno stadijumom bolesti. Povećana proteinska ekspresija HER2 receptora u adenokarcinomu pluća iznosi 7,4% za Hercep Test Dako i 2,7% za Ventana anti-HER2/neu (4B5) antitelo. Kod pozitivne ekspresije slažu se u 2%, dok se kod negativne ekspresije slažu u 91,9% slučajeva, što je ukupno 93,9%. Učestalost amplifikacije HER2 gena kod adenokarcinoma pluća je 17,6%, od toga je kod 2,7% slučajeva prisutna high grade amplifikacija. Postoji statistički značajna povezanost između povećane proteinske ekspresije HER2 receptora dobijene upotrebom HercepTest Dako i Ventana anti-HER2/neu (4B5) antitela i amplifikacije HER2 gena. Amplifikacija HER2 gena prisutna je kod 90,9% pacijenata sa povećanom proteinskom ekspresijom HER2 receptora koja se dobije upotrebom HercepTest Dako i kod 75% upotrebom Ventana anti-HER2/neu (4B5) antitela. Povećana proteinska ekspresija HER2 receptora dobijena pomoću HercepTest Dako i Ventana anti-HER2/neu (4B5) antitela je najčešća kod solidnog predominantnog tipa adenokarcinoma u patološkom T2a deskriptoru i IB stadijumu i acinarnog predominantnog tipa adenokarcinoma u patološkom T1b deskriptoru i IA stadijumu. Amplifikacija HER2 gena je najčešća kod solidnog a zatim kod acinarnog i papilarnog predominantnog tipa adenokarcinoma. Povećana proteinska ekspresija HER2 receptora dobijena pomoću HercepTest Dako i Ventana anti-HER2/neu (4B5) antitela i amplifikacija HER2 gena se najčešće javljaju kod muškaraca, pušača, u starosnoj dobi od 61-70 godina, tumora veličine 31-50 mm, N0 i M0 statusu bolesti, bez prisustva tumorske infiltracije pleure i okolnih struktura.sr
dc.description.abstractHuman epidermal growth factor 2 (HER2) is a member of the epidermal growth factor family having tyrosine kinase activity, which is directly linked to malignant cells proliferation, apoptosis inhibition, tumor angiogenesis and ability for invasion and metastasis. Increased protein expression of HER2 receptors can be the consequence of gene amplification and/or transcription changes. Expression of HER2 receptors in human tumors is associated with more aggressive behavior and worse prognosis. Incidence of increased protein expression of HER2 receptors in non-small-cell lung carcinoma (NSCLS) is mainly represented in adenocarcinoma, in comparison with other histological types. Identification of HER2 positive NSCLC enables determination of a group of patients who would be candidates for specific therapy. The problem occurs in choosing the method of detection of HER2 receptors and non-existence of determined protocol for reading the results, as the one ones which exist for breast and gastric carcinoma. The main objectives of this PhD dissertation were: to determine the incidence of increased protein expression of HER2 receptors in lung adenocarcinoma; to compare the results of the increased protein expression of HER2 receptors obtained by using HER2 antibodies "HercepTest Dako" and "Ventana anti-HER2/neu (4B5)" antibodies; to compare the presence of HER2 gene amplification by in situ hybridization (ISH) (Dual IHC HER2 kit: Ventana Medical Systems) by retesting the samples in which the increased protein expression of HER2 receptors was graded with 2+ and 3+, obtained by "HercepTest Dako" with present gene HER2 amplification on samples obtained by "Ventana anti-HER2/neu (4B5) and graded with 2+ and 3+; to compare the incidence of increased protein expression of HER2 receptors and presence of HER2 gene amplification in different histological subtypes of lung adenocarcinoma; to determine if the increased protein expression of HER2 receptors in lung adenocarcinoma and/or presence of gene amplification is related to demographic (age and sex of the patient) parameters, smoking status, appearance of metastases in regional lymphatic nodes, distant organs, infiltration of pleura and surrounding structures, and stage of the disease. Increased protein expression of HER2 in lung adenocarcinoma is 7.4% for HercepTest Dako and 2.7% for Ventana anti-HER2/neu (4B5) antibody. In positive expression they are correlated in 2%, while in negative expression they are correlated in 91.9% cases, which is overall 93.9%. The incidence of HER2 gene amplification in lung adenocarcinoma is 17.6%, from that in 2.7% of the cases high grade amplification is present. There is a statistically significant correlation between increased protein expression of HER2 receptors obtained by use of HercepTest Dako and Ventana anti-HER2 /neu (4B5) antibody and amplification of HER2 genes. Amplification of HER2 genes is present in 90.9% of patients with increased protein expression of HER2 receptors, which is obtained by using HercepTest Dako and in 75% patients by using Ventana anti-HER2/neu (4B5) antibody. Increased protein expression of HER2 receptors obtained by HercepTest Dako and Ventana anti-Her2/neu (4B5) antibody is most common in solid predominant type of adenocarcinoma in pathological T2a descriptor and IB stadium and acinar predominant type of adenocarcinoma in pathological T1b descriptor and IA stadium. Amplification of HER2 genes is most common in solid, and then in acinar and papillary predominant type of adenocarcinoma. Increased protein expression of HER2 receptors obtained by HercepTest Dako and Ventana anti-HER2/neu (4B5) antibody and amplification of HER2 genes most commonly occurs in men, smokers, at the age of 61-70 years, tumor size 31-50 mm, NO and MO disease status, without presence of tumor infiltration of pleura and surrounding structures.en
dc.languagesr (latin script)
dc.publisherУниверзитет у Новом Саду, Медицински факултетsr
dc.rightsopenAccessen
dc.sourceУниверзитет у Новом Садуsr
dc.subjectadenokarcinomsr
dc.subjectAdenocarcinomaen
dc.subjectErbB-2en
dc.subjectLung Neoplasmsen
dc.subjectReceptoren
dc.subjectneoplazme plućasr
dc.subjectreceptor humanog epidermalnog faktora rasta 2sr
dc.subjectimunohistohemijasr
dc.subjectgenska amplifikacijasr
dc.subjecthistološki tipovi neoplazmisr
dc.subjectpolni faktorisr
dc.subjectstarosni faktorisr
dc.subjectpušenjesr
dc.subjectstadijum neoplazmisr
dc.subjectImmunohistochemistryen
dc.subjectGene Amplificationen
dc.subjectNeoplasms by Histologic Typeen
dc.subjectSex Factorsen
dc.subjectAge Factorsen
dc.subjectSmokingen
dc.subjectNeoplasm Stagingen
dc.titleProteinska ekspresija i genska amplifikacija receptora humanog epidermalnog faktora rasta 2 ( HER2) kod adenokarcinoma plućasr
dc.title.alternativeProtein expression and gene amplification of human epidermal growth factor receptor 2 (HER2) with lung adenocarcinomaen
dc.typedoctoralThesissr
dc.rights.licenseBY-NC-ND
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/35216/IzvestajKomisije.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/35215/Disertacija.pdf


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