Alternate molecular genetic pathways in ovarian carcinomas of common histological types

Willner, Julia B.; Wurz, Kaitlyn; Allison, Kimberly H.; Galic, Vijaya; Garcia, Rochelle L.; Goff, Barbara A.; Swisher, Elizabeth M.

doi:10.1016/j.humpath.2006.10.007

Cited by 109 publications

(77 citation statements)

References 25 publications

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“…Our findings provide further evidence that endometrial adenocarcinomas with mutations in the kinase domain (exon 20) or the PIK3CA mRNA overexpression are associated with adverse prognostic parameters. Although similar findings have been reported in high-grade ovarian carcinomas, 25 reports have been contradictory regarding the prognostic significance of the PIK3CA helical and kinase domain mutations in breast carcinomas. [26][27][28][29] However, it has been reported that chickens injected with exon 20 PIK3CA mutants developed larger tumors than those injected with exon 9 PIK3CA mutants.…”

Section: Discussionsupporting

confidence: 62%

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

et al. 2009

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The status of p53 and the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) signaling pathway was investigated in 132 endometrial carcinomas, including endometrioid endometrial carcinomas, non-endometrioid endometrial carcinomas, and mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas. Results were compared with the clinicopathologic parameters associated with prognosis, patients' follow-up, and other genetic alterations found frequently in these tumors. Molecular genetic differences between low-grade and high-grade endometrioid adenocarcinomas were encountered; ie, PIK3CA mutations were detected in 26 and 34% of cases, respectively. We found p53 alterations in only 17% of high-grade endometrioid adenocarcinomas. In contrast, non-endometrioid adenocarcinomas had a higher frequency of p53 alterations (54%), PIK3CA mRNA overexpression (45%), and exon 20 PIK3CA mutations (21%). In the mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas, the most frequent alterations were p53 (50%) and PIK3CA (44%) mutations, followed by PTEN mutations (38%). In some cases, p53 and PIK3CA alterations coexisted, but they rarely coexisted with the PTEN mutations. Our findings suggest that the PIK3CA mutations are frequent events in endometrial carcinomas of any histological type. However, location of the PIK3CA mutations, either in exon 9 or exon 20, varies significantly according to the histologic grade and type of carcinoma. Carcinomas with exon 20 PIK3CA mutations or PIK3CA mRNA overexpression were often high-grade carcinomas associated with myometrial invasion; in contrast, tumors that carried exon 9 mutations were more likely to be low-grade carcinomas. The Kaplan-Meier analysis suggested that p53 alterations (strong immunoexpression or mutations) conferred a worse prognosis (P ¼ 0.000). Although alterations in the PI3K-AKT signaling pathway alone did not influence overall survival, patients with deregulated PI3K-AKT pathway (PIK3CA and/or PTEN alterations) and p53 alterations had shorter survival (P ¼ 0.000) than patients with only p53 alterations. Such a relationship was lost when we considered exon 9 PIK3CA mutations. Our results contribute to further characterize the molecular genetic model for endometrial carcinogenesis.

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Section: Discussionsupporting

confidence: 62%

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

et al. 2009

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“…Solid tümörlerin moleküler temellerinin anlaşılması, biyolojik terapotik ajanlara yanıtın öngörülmesi ve anlaşılması açı-sından giderek artan bir önem kazanmaktadır (25). Tümörün metastatik potansiyelinin ve uzun dönem biyolojik davranışının doğru öngörülmesi, jinekolojik malignitelerde de önemli bir terapotik ve prognostik amaçtır.…”

Section: Discussionunclassified

“…Konvansiyonel yüksek dereceli seröz karsinomda, TP53 mutasyonlarının, karsinogenezin erken döneminde gerçekleştiği dü-şünülmektedir (25). Bu konuda, Lee ve arkadaşlarının çalışma-larında, TP53 ekspresyonunun, yüksek tümör derecesi ve seröz subtiple anlamlı derecede ilişkili olduğu gösterilmiştir (4).…”

Section: Overin Yüzey Epitelinde Tp53 Ekspresyonuunclassified

“…Shimizu ve arkadaşları da, berrak hücreli over karsinomu olgularında (n=13) TP53 gen mutasyonu saptamamışlardır (27). Willner ve arkadaşları-nın çalışmalarında ise, seröz karsinoma benzer şekilde, yüksek dereceli endometrioid karsinomda ve berrak hücreli karsinomda da yüksek oranda TP53 mutasyonu saptanmıştır (25). Ça-lışmamızda yer alan dört berrak hücreli tümörün ise, üçünde TP53 aşırı-ekspresyonu saptandı.…”

Section: Overin Yüzey Epitelinde Tp53 Ekspresyonuunclassified

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Tp53 Expression And Ki-67 Proliferation Index In Surface Epithelial Tumors Of The Ovary And Their Relationship With The Histopathological Prognostic Parameters

Özkara¹,

Filinte²

2010

TUTFD

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ÖZETAmaç: Malign, "borderline" ve benign epitelyal over tümörlerinde TP53 ve Ki-67 ekspresyonlarını; karsinomlarda histopatolojik parametrelerle iliş-kisini; farklı özelliklerdeki olgu gruplarında TP53 ve Ki-67 ekspresyonlarını araştırmak; overde karsinogenezi tartışmak. Gereç ve Yöntemler:Yüz'ü malign, 27'si "borderline" ve 31'i benign, toplam 158 epitelyal over tümörü ve 42 non-tümöral over dokusunda standart immunohistokimya tekniği kullanıldı.Bulgular: TP53 aşırı-ekspresyonu, "borderline" tümörlere (%40.7) kıyasla malignlerde (%61.0); 50 yaş üstündeki; yüksek dereceli, az/indiferansiye ve seröz; solid yapılanmalı seröz, yüksek pleomorfizm dereceli seröz ve non-seröz, yüksek mitotik indeksli non-seröz subtiplerde; lenf nodu tutulumu gösteren, ileri evredeki karsinomlarda daha yüksekti (p<0.05). Ortalama Ki-67 indeksleri, malignlerde %41.3, "borderline" tümörlerde %17.2 olup; fark anlamlıydı. Karsinomların Ki-67 indeksleri, dereceleri yükseldik-çe artarken; lenf nodu tutulumlu olgularda azalma gösterdi. Karsinomların farklı subtiplerinin, derecelerine, lenf nodu tutulumları ve evrelerine göre, TP53 ekspresyonları ve Ki-67 indeksleriyle ilişkilerinde farklılıklar saptandı.Sonuç: TP53 aşırı-ekspresyonunun, malign ve "borderline" over tümör-lerinin gelişimindeki rolünü desteklemektedir. Karsinomlarda, TP53 ekspresyonunun derecesi, yaş, histopatolojik subtip, derece, pleomorfizm, yapılanma özelliği, mitotik aktivite, lenf nodu tutulumu ve evre ile ilişkili olarak farklılık; Ki-67 proliferasyon indeksi ile de korelasyon göstermekte-dir. Malign epitelyal over tümörlerinin bu biyolojik parametrelere göre de ayrılması, gelecekte daha olguya özgün tedavi protokollerinin belirlenmesinde, özellikle erken evrede önemli olabilir. Material and Methods: Standard immunohistochemistry was performed in 100 malignant, 27 borderline and 31 benign tumors and 42 non-tumoral ovarian epithelia.Results: TP53 overexpression was higher in malignant (61.0%) than in borderline tumors (40.7%); in malignant cases above 50 years-of-age, with high grade and in undifferentiated and serous subtypes. Carcinomas with solid architecture in serous, high mitosis in non-serous and high pleomorphism in both subtypes; lymph node involvement, and advanced stage also showed higher expressions of TP53 (p<0.05). The mean Ki-67 index was 41.3% in malignant and 17.2% in borderline tumors. Ki-67 index tended to increase with increasing grade, and decrease with lymph node involvement. The coexpression of proteins according to grade, lymph node involvement and stage in different subtypes, showed significant differences and correlations.Conclusion: Our findings support the role of TP53 overexpression in development of "borderline" and malignant epithelial ovarian tumors. The degree of TP53 expression differed in terms of histopathological parameters; and was correlated with Ki-67 index. Especially in early stages, these biological factors could provide additional information to stratify patients for case specific therapies.

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“…Pathway activation through PIK3CA can occur through either amplification or activating mutation of the catalytic subunit. Mutations of PIK3CA are typically associated with endometrioid and clear cell subtypes and are associated with lower tumor stage and grade (Campbell et al 2004, Kolasa et al 2009, Willner et al 2007. Amplifications, on the other hand, have been detected in all histological subtypes, though there was an association with poorer differentiation.…”

Section: Pik3ca and Akt2mentioning

confidence: 99%

Gene Amplification in Ovarian Carcinomas: Lessons from Selected Amplified Gene Families

Gaillard¹

2012

Ovarian Cancer - Basic Science Perspective

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Alternate molecular genetic pathways in ovarian carcinomas of common histological types

Cited by 109 publications

References 25 publications

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

Tp53 Expression And Ki-67 Proliferation Index In Surface Epithelial Tumors Of The Ovary And Their Relationship With The Histopathological Prognostic Parameters

Gene Amplification in Ovarian Carcinomas: Lessons from Selected Amplified Gene Families

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