Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma.

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is activated in multiple cancers including ovarian carcinoma (OC). However, the relative contribution of the single components within the PI3K pathway to AKT activation in OC is still unclear. We examined 98 tumor samples from Italian OC patients...

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Autores principales:	Carmela De Marco, Nicola Rinaldo, Paola Bruni, Carmine Malzoni, Fulvio Zullo, Fernanda Fabiani, Simona Losito, Marianna Scrima, Federica Zito Marino, Renato Franco, Alfina Quintiero, Valter Agosti, Giuseppe Viglietto
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b8cea4f6b7944fc39c67c5c7718c6df6
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spelling	oai:doaj.org-article:b8cea4f6b7944fc39c67c5c7718c6df62021-11-18T07:58:23ZMultiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma.1932-620310.1371/journal.pone.0055362https://doaj.org/article/b8cea4f6b7944fc39c67c5c7718c6df62013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23408974/?tool=EBIhttps://doaj.org/toc/1932-6203The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is activated in multiple cancers including ovarian carcinoma (OC). However, the relative contribution of the single components within the PI3K pathway to AKT activation in OC is still unclear. We examined 98 tumor samples from Italian OC patients for alterations in the members of the PI3K pathway. We report that AKT is significantly hyperactive in OC compared to normal tissue (n = 93; p<0.0001) and that AKT activation is preferentially observed in the elderly (>58 years old; n = 93; p<0.05). The most frequent alteration is the overexpression of the p110α catalytic subunit of PI3K (63/93, ∼68%); less frequent alterations comprise the loss of PTEN (24/89, 27%) and the overexpression of AKT1 (18/96, 19%) or AKT2 (11/88,12.5%). Mutations in the PIK3CA or KRAS genes were detected at lower frequency (12% and 10%, respectively) whereas mutations in AKT1 or AKT2 genes were absent. Although many tumors presented a single lesion (28/93, of which 23 overexpressed PIK3CA, 1 overexpressed AKT and 4 had lost PTEN), many OC (35/93) presented multiple alterations within the PI3K pathway. Apparently, aberrant PI3K signalling was mediated by activation of the canonical downstream AKT-dependent mTOR/S6K1/4EBP1 pathway and by regulation of expression of oncogenic transcription factors that include HMGA1, JUN-B, FOS and MYC but not by AKT-independent activation of SGK3. FISH analysis indicated that gene amplification of PIK3CA, AKT1 and AKT2 (but not of PI3KR1) and the loss of PTEN are common and may account for changes in the expression of the corresponding proteins. In conclusion, our results indicate that p110α overexpression represents the most frequent alteration within the PI3K/AKT pathway in OC. However, p110α overexpression may not be sufficient to activate AKT signalling and drive ovarian tumorigenesis since many tumors overexpressing PI3K presented at least one additional alteration.Carmela De MarcoNicola RinaldoPaola BruniCarmine MalzoniFulvio ZulloFulvio ZulloFernanda FabianiSimona LositoMarianna ScrimaFederica Zito MarinoRenato FrancoAlfina QuintieroValter AgostiGiuseppe VigliettoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 2, p e55362 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Carmela De Marco Nicola Rinaldo Paola Bruni Carmine Malzoni Fulvio Zullo Fulvio Zullo Fernanda Fabiani Simona Losito Marianna Scrima Federica Zito Marino Renato Franco Alfina Quintiero Valter Agosti Giuseppe Viglietto Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma.
description	The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is activated in multiple cancers including ovarian carcinoma (OC). However, the relative contribution of the single components within the PI3K pathway to AKT activation in OC is still unclear. We examined 98 tumor samples from Italian OC patients for alterations in the members of the PI3K pathway. We report that AKT is significantly hyperactive in OC compared to normal tissue (n = 93; p<0.0001) and that AKT activation is preferentially observed in the elderly (>58 years old; n = 93; p<0.05). The most frequent alteration is the overexpression of the p110α catalytic subunit of PI3K (63/93, ∼68%); less frequent alterations comprise the loss of PTEN (24/89, 27%) and the overexpression of AKT1 (18/96, 19%) or AKT2 (11/88,12.5%). Mutations in the PIK3CA or KRAS genes were detected at lower frequency (12% and 10%, respectively) whereas mutations in AKT1 or AKT2 genes were absent. Although many tumors presented a single lesion (28/93, of which 23 overexpressed PIK3CA, 1 overexpressed AKT and 4 had lost PTEN), many OC (35/93) presented multiple alterations within the PI3K pathway. Apparently, aberrant PI3K signalling was mediated by activation of the canonical downstream AKT-dependent mTOR/S6K1/4EBP1 pathway and by regulation of expression of oncogenic transcription factors that include HMGA1, JUN-B, FOS and MYC but not by AKT-independent activation of SGK3. FISH analysis indicated that gene amplification of PIK3CA, AKT1 and AKT2 (but not of PI3KR1) and the loss of PTEN are common and may account for changes in the expression of the corresponding proteins. In conclusion, our results indicate that p110α overexpression represents the most frequent alteration within the PI3K/AKT pathway in OC. However, p110α overexpression may not be sufficient to activate AKT signalling and drive ovarian tumorigenesis since many tumors overexpressing PI3K presented at least one additional alteration.
format	article
author	Carmela De Marco Nicola Rinaldo Paola Bruni Carmine Malzoni Fulvio Zullo Fulvio Zullo Fernanda Fabiani Simona Losito Marianna Scrima Federica Zito Marino Renato Franco Alfina Quintiero Valter Agosti Giuseppe Viglietto
author_facet	Carmela De Marco Nicola Rinaldo Paola Bruni Carmine Malzoni Fulvio Zullo Fulvio Zullo Fernanda Fabiani Simona Losito Marianna Scrima Federica Zito Marino Renato Franco Alfina Quintiero Valter Agosti Giuseppe Viglietto
author_sort	Carmela De Marco
title	Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma.
title_short	Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma.
title_full	Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma.
title_fullStr	Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma.
title_full_unstemmed	Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma.
title_sort	multiple genetic alterations within the pi3k pathway are responsible for akt activation in patients with ovarian carcinoma.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/b8cea4f6b7944fc39c67c5c7718c6df6
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Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma.

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