Uticaj tumor supresorskih gena TP53 i PTEN na odgovor na različite načine lečenja raka dojke

Rak dojke (RD) je najčešći tip maligniteta i vodeći uzrok smrti od raka kod žena širom sveta. RD je izuzetno heterogena bolest i stoga su neophodni različiti modaliteti lečenja da bi se pokrile ove razlike. Cilj našeg istraživanja je bio da se ispita uticaj inaktivacije TP53 i PTEN tumor supresorskih gena (TSG) na odgovor RD na različite modalitete lečenja, kao i njihova moguća saradnja u tome, na postoperativnim uzorcima RD. Metode. Pacijentkinje su klasifikovane, na osnovu primenjene adjuvantne terapije, u četiri različite grupe: one koje su primale samo hormonsku terapiju (HT), hormonsku terapiju u kombinaciji sa hemoterapijom (HT/CHT), hormonsku terapiju u kombinaciji sa hemoterapijom i biološkom terapijom (HT/CHT/H) i druge sistemske terapije koje isključuju HT. Funkcionalna inaktivacija TP53 i PTEN TSG je proučavana analizom mutacionog statusa, gubitka heterozigotnosti (LOH) i metilacionog statusa. Rezultati. Naši rezultati su pokazali da je TP53 gen izmenjen kod 63 od 90 pacijenata (70%), dok je učestalost promena PTEN gena bila nešto niža, 54 od 90 (60%). Simultana inaktivacija je detektovana u 43 testirana uzorka (48%) sa značajnom povezanošću između dva analizirana TSG-a. Dalje, pokazali smo da status TP53 ima značajan uticaj na odgovor pacijenata na terapiju. Suprotno ovome, nismo pokazali značajnu asocijaciju između mutacionog statusa PTEN-a i različitih modaliteta lečenja. Međutim, utvrđena je značajna povezanost između primenjenih terapija i simultanih inaktivacija ova dva TSG-a (p = 0,00001). Zaključak. Pacijenti sa wtTP53 pokazuju značajno bolji terapijski odgovor bez obzira na vrstu terapije u poređenju sa nosiocima mutiranog TP53 gena.Introduction. Breast cancer (BC) is the most frequent type of malignancy and the leading cause of cancer related death among women worldwide. BC is exceptionally heterogeneous disease and therefore distinct treatment modalities are necessary to address these differences. The aim of our study was to investigate the impact of TP53 and PTEN tumor suppressor genes (TSGs) inactivation on BC response to different treatment modalities and their possible cooperation, on post-operative BC samples. Methods. Patients were classified, based on applied adjuvant therapy, into four distinct groups: those that received hormonal therapy (HT) only, hormonal therapy combined with chemotherapy (HT/CHT), hormonal therapy combined with chemo and biological therapy (HT/CHT/H), and other systemic therapies that exclude HT. Functional inactivation of TP53 and PTEN TSG’s were studied by mutation, loss of heterozygosity (LOH) and hypermethylation analysis. Results. Our results revealed that TP53 gene was altered in 63 out of 90 specimens (70%), while the frequency of PTEN alterations was slightly lower, 54 out of 90 (60%). Simultaneous inactivation was detected in 43 tested samples (48%) with significant association between two analyzed TSGs. Further, we found that TP53 status has significant influence on patients’ therapy response. Contrary to this, no significance was found between mutational status of PTEN and various treatment modalities. However, significant association was found between the type of applied therapy and simultaneous alterations of these two TSGs (p = 0.00001). Conclusion. Patients with wtTP53 show significantly better therapy response regardless of the type of therapy, compared to carriers of altered TPp53 gene

TP53 and c-myc Co-alterations: A hallmark of oral cancer progression

Background: Head and neck squamous cell carcinoma, including oral cancer, is the sixth most common cancer worldwide. Despite advances in surgery and treatment, the 5-year survival rate has not improved significantly. Therefore, reliable molecular markers for oral cancer progression are badly needed. Methods: We conducted a copy number analysis to estimate amplification status of c-myc, cycD1 and EGFR oncogenes, mutational PCR-SSCP analysis to determine activation of H-ras oncogene and inactivation of TP53 tumour suppressor gene and methylation specific PCR analysis to evaluate hypermethylation of p16 and MGMT genes. Results: c-myc oncogene was amplified in 56.7%, cycDI in 20% and EGFR in 16.7% of Oral Squamous Cell Carcinoma (OSCC) cases while H-ras was activated in 33.3% of samples. Amplification of c-myc was significantly associated with the tumour grade 2. Interestingly, EGFR and H-ras alterations were mutually exclusive. p16 and MGMT were inactivated by hypermethylation in 30% and 13.3% of cases. Co-alteration of cycDI and p16 were not observed in any of the analyzed samples. TP53 was inactivated in 56.7% of samples and was significantly associated with progression of OSCC, grade 2 and stage 2. Moreover, TP53 and c-myc oncogene were simultaneously altered in grade 2 OSCC. Conclusions: The most promising marker of OSCC progression remains the TP53 tumour suppressor, which is the most frequently mutated gene in oral cancers. Since there is synergism between TP53 and c-myc, it seems that co-alteration of these two genes could be also a good marker of OSCC progression from grade1 to grade 2 tumours.Uvod: Skvamocelularni karcinomi glave i vrata (HNSCC) uključujući i skvamocelularni karcinom usne duplje (OSCC) ubrajaju se u šest najčešćih tipova humanih maligniteta. Uprkos značajnim napredcima u hirurškom i terapijskom tretmanu, stopa petogodišnjeg preživljavanja kod ovog tipa maligniteta nije značajnije popravljena. Upravo zato, definisanje pouzdanih molekularnih markera progresije kod OSSC predstavlja apsolutni prioritetet. Metode: Amplifikacioni status c-myc, cycD1 i EGFR gena određen je pomoću eseja za detekciju broja genskih kopija, aktivacija H-ras onkogena i inaktivacija TP53 tumor supresora određena je PCR-SSCP mutacionom analizom, a hipermetilacija promotora p16 i MGMT gena je ispitana metil specifičnim PCR-om (MSP). Rezultati: Amplifikacija c-myc onkogena detektovana je kod 56,7%, cycD1 onkogena kod 20%, a EGFR onkogena kod 16,7% analiziranih oralnih skvamocelularnih carcinoma. Istovremeno, mutaciona aktivacija H-ras onkogena detektovana je kod 33,3% ispitanih uzoraka. Amplifikovani c-myc, statistički značajno korelira sa gradusom 2 OSCC. Posebno intrigantan je bio nalaz po kom se onkogene aktivacije u EGFR i H-ras genu međusobno isključuju. Hipermetilacija promotora p16 gena detektovana je kod 30%, a MGMT kod 13,3% analiziranih uzoraka. Ko-alteracije cycDI i p16 gena nisu zapažene ni u jednom od analiziranih uzoraka. Inaktivacija TP53 gena detektovana je kod 56,7% uzoraka i utvrđeno je da statistički značajno korelira sa gradusom 2 i statusom 2 OSCC. Pored ovoga, utvrđeno je da statistički značajan broj uzoraka gradusa 2, sa aktiviranim TP53 genom ima istovremeno aktiviran i c-myc onkogen. Zaključak: TP53, najčešće mutirani gen u oralnim karcinomima, ostaje za sada i najpouzdaniji marker progresije kod OSCC. Obzirom na detektovani sinergizam između TP53 i c-myc gena, možemo reći da su istovremene promene u ova dva gena još pouzdaniji pokazatelj progresije OSSC iz gradusa 1 u gradus 2.Projekat ministarstva br. III 41031 i br. ON17304

Role of PTEN, PI3K, and mTOR in Triple-Negative Breast Cancer.

Breast cancer is the most commonly occurring malignancy and the leading cause of cancer-related death in women. Triple-negative breast cancer (TNBC) is the most aggressive subtype and is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival. The aim of this study was to investigate the PI3K/PTEN/Akt/mTOR pathway as one of the most frequently deregulated pathways in cancer. We aimed to explore the impact of PI3K and mTOR oncogenes as well as the PTEN tumor suppressor on TNBC clinical behavior, prognosis, and multidrug resistance (MDR), using immunohistochemistry and copy number analysis by quantitative real-time PCR. Our results revealed that loss of PTEN and high expression of PI3K and mTOR proteins are associated with poor outcome of TNBC patients. PTEN deletions appeared as a major cause of reduced or absent PTEN expression in TNBC. Importantly, homozygous deletions of PTEN (and not hemizygous deletions) are a potential molecular marker of metastasis formation and good predictors of TNBC outcome. In conclusion, we believe that concurrent examination of PTEN/PI3K/mTOR protein expression may be more useful in predicting TNBC clinical course than the analysis of single protein expression. Specifically, our results showed that PTEN-reduced/PI3K-high/mTOR-high expression constitutes a 'high risk' profile of TNBC

Molekularnobiološke osobine oralnih skvamocelularnih karcinoma

Oral squamous cell carcinomas (OSCCs) are associated with poor prognosis, and despite advances in therapy approaches, no major improvement in survival has been achieved in the recent years. Efforts are now directed toward finding new biological markers that could predict tumor behavior more accurately. OSCCs, as the majority of malignant tumors, arise from progressive accumulation of genetic and epigenetic lesions, transforming normal cells into malignant. In this paper, an analysis of current studies directed to understanding the underlying mechanisms of OSCC pathogenesis was presented. The emphasis was put on mutational analysis of cancer genes, as well as on the role of viral infections and methylation processes in OSCC. Finally, an overview of studies that tried to determine the possibility for developing OSCC was given.Oralne skvamocelularne karcinome (OSCK) odlikuje uglavnom loša prognoza i, uprkos pomacima u terapijskim postupcima, poslednjih godina nije ostvaren napredak u preživljavanju osoba s ovim tumorom. Velike nade se polažu u molekularnu medicinu i pronalaženje novih bioloških markera pomoću kojih bi preciznije nego što to dopuštaju klinički i histopatološki parametri moglo da se predvidi ponašanje tumora. OSCK, kao i većina drugih malignih oboljenja, rezultat su postupne akumulacije raznovrsnih genetičkih i epigenetičkih promena u ćelijama, koje od normalnih postaju neoplastične. U ovom radu dat je presek nekih od pravaca istraživanja na polju molekularne biologije oralnih karcinoma, s osvrtom na studije koje se bave ispitivanjem somatskih mutacija u kancerskim genima, učešćem onkogenih virusa u patogenezi i značaju procesa metilacije za OSCK. Takođe su pomenute studije posvećene utvrđivanju eventualnog postojanja predispozicije za razvoj OSCK

Moleculobiological characteristics of oral squamous cell carcinomas

Oral squamous cell carcinomas (OSCCs) are associated with poor prognosis, and despite advances in therapy approaches, no major improvement in survival has been achieved in the recent years. Efforts are now directed toward finding new biological markers that could predict tumor behavior more accurately. OSCCs, as the majority of malignant tumors, arise from progressive accumulation of genetic and epigenetic lesions, transforming normal cells into malignant. In this paper, an analysis of current studies directed to understanding the underlying mechanisms of OSCC pathogenesis was presented. The emphasis was put on mutational analysis of cancer genes, as well as on the role of viral infections and methylation processes in OSCC. Finally, an overview of studies that tried to determine the possibility for developing OSCC was given.Oralne skvamocelularne karcinome (OSCK) odlikuje uglavnom loša prognoza i, uprkos pomacima u terapijskim postupcima, poslednjih godina nije ostvaren napredak u preživljavanju osoba s ovim tumorom. Velike nade se polažu u molekularnu medicinu i pronalaženje novih bioloških markera pomoću kojih bi preciznije nego što to dopuštaju klinički i histopatološki parametri moglo da se predvidi ponašanje tumora. OSCK, kao i većina drugih malignih oboljenja, rezultat su postupne akumulacije raznovrsnih genetičkih i epigenetičkih promena u ćelijama, koje od normalnih postaju neoplastične. U ovom radu dat je presek nekih od pravaca istraživanja na polju molekularne biologije oralnih karcinoma, s osvrtom na studije koje se bave ispitivanjem somatskih mutacija u kancerskim genima, učešćem onkogenih virusa u patogenezi i značaju procesa metilacije za OSCK. Takođe su pomenute studije posvećene utvrđivanju eventualnog postojanja predispozicije za razvoj OSCK.Projekat ministarstva br. 17507

Genomic instability as a prognostic marker in malignant brain cancer

Introduction: Glioblastoma and Astrocytoma are diff use malignant brain tumors and characterized as the most aggressive and invasive brain cancers. Glioblastoma IDH wild-type is a primary brain tumour that develops de novo, and Astrocytoma IDH mutant is a secondary tumour which arises by progression from lower tumour grades. They are characterized by poor survival, resistance to therapy and poor prognosis which develops as a consequence of genomic instability. Genomic instability also contributes to tumour heterogeneity and provides the genomic diversity necessary for selecƟ on. Materials and methods: 31 paƟ ents with Glioblastoma IDH wild-type and Astrocytoma IDH mutant, grade 3 and 4, were analysed for the presence of genomic instability using AP-PCR, DNA profi ling method. Comparing DNA profi les between tumour Ɵ ssue and normal Ɵ ssue (blood) of the same paƟ ent, we detected qualitaƟ ve and quanƟ taƟ ve changes. QualitaƟ ve changes are detected as the presence and absence of bands and are the manifestaƟ on of microsatellite instability (MIN). QuanƟ taƟ ve changes are the representaƟ on of chromosomal instability (CIN) and are detected as diff erences in the intensity of bands. Survival analyses were performed using Kaplan & Maier test for survival data in relaƟ on to diff erent histological tumour type and genomic instability. StaƟ sƟ cal diff erences were considered signifi cant for p≤ 0,05. Results: PaƟ ents with Glioblastoma IDH wild-type have signifi cantly shorter survival compared to other histological types (p=0,025). For each histological type that we analysed and each type of instability MIN, CIN and total genomic instability, two groups of paƟ ents were made – those with high and low instability. PaƟ ents with Glioblastoma IDH wild-type that have low total genomic instability have signifi cantly shorter survival (p=0,045) compared to other analysed types of brain cancer. PaƟ ents with Astrocytoma IDH mutant grade 4 who have high total genomic instability and high CIN have signifi cantly shorter survival (p=0,018, p=0,007 respecƞ ully). Conclusion: PaƟ ents with Glioblastoma IDH wild-type have shorter survival which makes this tumour the most aggressive and malignat of all analysed tumours. Our results show that low genomic instability in Glioblastoma IDH wild-type and high genomic instability lead by high CIN in Astrocytoma IDH mutant, gradus 4 contribute to shorter survival, which makes genomic instability a potential good prognostic markerThe first number of Oncology Insights includes Proceedings book of The Sixth Congress of the Serbian Association for Cancer Research with international participation (Oct 2-4, 2023, Belgrade

Moleculobiological characteristics of oral squamous cell carcinomas

Oral squamous cell carcinomas (OSCCs) are associated with poor prognosis, and despite advances in therapy approaches, no major improvement in survival has been achieved in the recent years. Efforts are now directed toward finding new biological markers that could predict tumor behavior more accurately. OSCCs, as the majority of malignant tumors, arise from progressive accumulation of genetic and epigenetic lesions, transforming normal cells into malignant. In this paper, an analysis of current studies directed to understanding the underlying mechanisms of OSCC pathogenesis was presented. The emphasis was put on mutational analysis of cancer genes, as well as on the role of viral infections and methylation processes in OSCC. Finally, an overview of studies that tried to determine the possibility for developing OSCC was given.Oralne skvamocelularne karcinome (OSCK) odlikuje uglavnom loša prognoza i, uprkos pomacima u terapijskim postupcima, poslednjih godina nije ostvaren napredak u preživljavanju osoba s ovim tumorom. Velike nade se polažu u molekularnu medicinu i pronalaženje novih bioloških markera pomoću kojih bi preciznije nego što to dopuštaju klinički i histopatološki parametri moglo da se predvidi ponašanje tumora. OSCK, kao i većina drugih malignih oboljenja, rezultat su postupne akumulacije raznovrsnih genetičkih i epigenetičkih promena u ćelijama, koje od normalnih postaju neoplastične. U ovom radu dat je presek nekih od pravaca istraživanja na polju molekularne biologije oralnih karcinoma, s osvrtom na studije koje se bave ispitivanjem somatskih mutacija u kancerskim genima, učešćem onkogenih virusa u patogenezi i značaju procesa metilacije za OSCK. Takođe su pomenute studije posvećene utvrđivanju eventualnog postojanja predispozicije za razvoj OSCK.Projekat ministarstva br. 17507

TP53 and c-myc Co-alterations: A hallmark of oral cancer progression

Background: Head and neck squamous cell carcinoma, including oral cancer, is the sixth most common cancer worldwide. Despite advances in surgery and treatment, the 5-year survival rate has not improved significantly. Therefore, reliable molecular markers for oral cancer progression are badly needed. Methods: We conducted a copy number analysis to estimate amplification status of c-myc, cycD1 and EGFR oncogenes, mutational PCR-SSCP analysis to determine activation of H-ras oncogene and inactivation of TP53 tumour suppressor gene and methylation specific PCR analysis to evaluate hypermethylation of p16 and MGMT genes. Results: c-myc oncogene was amplified in 56.7%, cycDI in 20% and EGFR in 16.7% of Oral Squamous Cell Carcinoma (OSCC) cases while H-ras was activated in 33.3% of samples. Amplification of c-myc was significantly associated with the tumour grade 2. Interestingly, EGFR and H-ras alterations were mutually exclusive. p16 and MGMT were inactivated by hypermethylation in 30% and 13.3% of cases. Co-alteration of cycDI and p16 were not observed in any of the analyzed samples. TP53 was inactivated in 56.7% of samples and was significantly associated with progression of OSCC, grade 2 and stage 2. Moreover, TP53 and c-myc oncogene were simultaneously altered in grade 2 OSCC. Conclusions: The most promising marker of OSCC progression remains the TP53 tumour suppressor, which is the most frequently mutated gene in oral cancers. Since there is synergism between TP53 and c-myc, it seems that co-alteration of these two genes could be also a good marker of OSCC progression from grade1 to grade 2 tumours.Uvod: Skvamocelularni karcinomi glave i vrata (HNSCC) uključujući i skvamocelularni karcinom usne duplje (OSCC) ubrajaju se u šest najčešćih tipova humanih maligniteta. Uprkos značajnim napredcima u hirurškom i terapijskom tretmanu, stopa petogodišnjeg preživljavanja kod ovog tipa maligniteta nije značajnije popravljena. Upravo zato, definisanje pouzdanih molekularnih markera progresije kod OSSC predstavlja apsolutni prioritetet. Metode: Amplifikacioni status c-myc, cycD1 i EGFR gena određen je pomoću eseja za detekciju broja genskih kopija, aktivacija H-ras onkogena i inaktivacija TP53 tumor supresora određena je PCR-SSCP mutacionom analizom, a hipermetilacija promotora p16 i MGMT gena je ispitana metil specifičnim PCR-om (MSP). Rezultati: Amplifikacija c-myc onkogena detektovana je kod 56,7%, cycD1 onkogena kod 20%, a EGFR onkogena kod 16,7% analiziranih oralnih skvamocelularnih carcinoma. Istovremeno, mutaciona aktivacija H-ras onkogena detektovana je kod 33,3% ispitanih uzoraka. Amplifikovani c-myc, statistički značajno korelira sa gradusom 2 OSCC. Posebno intrigantan je bio nalaz po kom se onkogene aktivacije u EGFR i H-ras genu međusobno isključuju. Hipermetilacija promotora p16 gena detektovana je kod 30%, a MGMT kod 13,3% analiziranih uzoraka. Ko-alteracije cycDI i p16 gena nisu zapažene ni u jednom od analiziranih uzoraka. Inaktivacija TP53 gena detektovana je kod 56,7% uzoraka i utvrđeno je da statistički značajno korelira sa gradusom 2 i statusom 2 OSCC. Pored ovoga, utvrđeno je da statistički značajan broj uzoraka gradusa 2, sa aktiviranim TP53 genom ima istovremeno aktiviran i c-myc onkogen. Zaključak: TP53, najčešće mutirani gen u oralnim karcinomima, ostaje za sada i najpouzdaniji marker progresije kod OSCC. Obzirom na detektovani sinergizam između TP53 i c-myc gena, možemo reći da su istovremene promene u ova dva gena još pouzdaniji pokazatelj progresije OSSC iz gradusa 1 u gradus 2.Projekat ministarstva br. III 41031 i br. ON17304

TP53 AND C-MYC CO-ALTERATIONS - A HALLMARK OF ORAL CANCER PROGRESSION

Background: Head and neck squamous cell carcinoma, including oral cancer, is the sixth most common cancer worldwide. Despite advances in surgery and treatment, the 5-year survival rate has not improved significantly. There fore, reliable molecular markers for oral cancer progression are badly needed. Methods: We conducted a copy number analysis to estimate amplification status of c-myc, cycD1 and EGFR oncogenes, mutational PCR-SSCP analysis to determine activation of H-ras oncogene and inactivation of TP53 tumour suppressor gene and methylation specific PCR analysis to evaluate hypermethylation of p16 and MGMT genes. Results: c-myc oncogene was amplified in 56.7%, cycD1 in 20% and EGFR in 16.7% of Oral Squamous Cell Carcinoma (OSCC) cases while H-ras was activated in 33.3% of samples. Amplification of c-myc was significantly associated with the tumour grade 2. Interestingly, EGFR and H-ras alterations were mutually exclusive. p16 and MGMT were inactivated by hypermethylation in 30% and 13.3% of cases. Co-alteration of cycD1 and p16 were not observed in any of the analyzed samples. TP53 was inactivated in 56.7% of samples and was significantly associated with progression of OSCC, grade 2 and stage 2. Moreover, TP53 and c-myc oncogene were simultaneously altered in grade 2 OSCC. Conclusions: The most promising marker of OSCC progression remains the TP53 tumour suppressor, which is the most frequently mutated gene in oral cancers. Since there is synergism between TP53 and c-myc, it seems that co-alteration of these two genes could be also a good marker of OSCC progression from grade1 to grade 2 tumours

Amplification of cycline D1, c-myc and EGFR oncogenes in tumour samples of breast cancer patients

Background: Breast cancer is the most common form of cancer in women. It arises from multiple genetic changes in oncogenes and tumor suppressor genes. Among so far studied oncogenes relatively few, including epdermal growth factor receptor (EGfR), cyclinD1 (CCNDİ)and c-myc, have been found to play an important role in progression of this type of human malignancy. The aim of this study was to examine the prognostic potential of CCND1, c-myc and EGFR amplification and their possible cooperation in breast carcinogenesis. Methods: Copy number analyses of CCND1 and c-myc genes were done by TaqMan based quantitative real time PCR. Amplification status of EGFR was determined by differential Pcr. Results: Amplification of CCND1, c-myc and EGFR oncogene has been found in 20.4%, 26.5% and 26.5% of breast cancer cases, respectively. Analysis showed that amplification of CCND1 oncogene was significantly associated with the stage II of disease while amplification of EGFR gene was significantly associated with overexpression of HER-2/neu. Tumour stage and expression of HER-2/neu appeared to be significant predictors of patient's outcome. Stage I patients lived significantly longer then stage III patients (p=0.04) while patients with HER-2/neu overexpression had worse prognoses and lived significantly shorter (p=0.001). Finally, survival of patients who underwent hormone therapy only was significantly longer (p=0.001) then survival of the rest of patients. Conclusions: Amplification of CCND1 or EGFR oncogene is associated with the progression of breast cancer and bad prognosis. No co-ordination in amplification of CCND1, c-myc and EGFR oncogenes were established in this cohort of breast cancer patients.Uvod: Kancer dojke je najčešći tip maligniteta koji se javljaju kod žena. Tumori dojke nastaju kao rezultat akumulacije genetičkih promena kako u onkogenima tako i u tumor supresorskim genima. Među mnogim onkogenima čija je uloga u genezi tumora dojke ispitivana do danas, samo se neki smatraju značajnim za razviće ovih karcinoma. U tu se grupu svakako ubrajaju receptor za epidermalni factor rasta (EGFR), c-myc i ciklinD1 (CCND1). Cilj rada je bio utvrditi prognostički značaj amplifikacije CCND1, c-myc i EGFR onkogena u razviću tumora dojke kao i eventualne međusobne koalteracije ovih gena. Metode: Amplifikacioni status CCND1 i c-myc gena određen je kvantitativnim PCR-om u realnom vremenu, a amplifikacioni status EGFR onkogena je definisan diferencijalnim PCR-om. Rezultati: Amplifikacija CCND1 gena detektovana je kod 20.4%, a c-myc i EGFR onkogena kod 26.5% ispitanih uzoraka. Analize su pokazale da je amplifikacija CCND1 onkogena statistički značajno povezana sa stadijumom II tumora dojke kao i da amplifikacija EGFR-a značajno korelira sa povećanom ekspresijom HER2/neu. Analize kliničkih i histopatoloških parametara su jasno pokazale da stadijum tumora i nivo ekspresije HER2/neu gena predstavljaju značajne pokazatelje daljeg toka bolesti, odnosno sudbine pacijenta. Utvrđeno je da pacijentkinje sa tumorima dojke stadijuma I žive značajno duže od onih sa tumorom stadijuma III (p= 0.04) kao i da pacijentkinje sa HER2/neu pozitivnim statusom imaju goru prognozu i žive značajno krace (p=0.001). Na kraju, studija je pokazala da pacijentkinje podvrgnute samo hormonskoj terapiji imaju najbolju prognozu i žive značajno duže od ostalih (p=0.001). Zaključak: Amplifikacija CCND1 i EGFR onkogena je povezana sa lošom prognozom i progresijom karcinoma dojke. U ispitivanom tumorskom uzorku nisu detektovane nikakve koalteracije CCND1, c-myc i EGFR onkogena.Projekat ministarstva br. III 41031 i br. ON17304