PIK3CA amplification associates with aggressive phenotype but not markers of AKT-mTOR signaling in endometrial carcinoma

Frederik Holst, Henrica M.J. Werner, Siv Mjøs, Erling A. Hoivik, Kanthida Kusonmano, Elisabeth Wik, Anna Berg, Even Birkeland, William J. Gibson, Mari K. Halle, Jone Trovik, Andrew D. Cherniack, Karl Henning Kalland, Gordon Mills, Christian F. Singer, Camilla Krakstad, Rameen Beroukhim, Helga B. Salvesen

Research output: Contribution to journalArticle

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Abstract

Purpose: Amplification of PIK3CA, encoding the PI3K catalytic subunit alpha, is common in uterine corpus endometrial carcinoma (UCEC) and linked to an aggressive phenotype. However, it is unclear whether PIK3CA amplification acts via PI3K activation. We investigated the association between PIK3CA amplification, markers of PI3K activity, and prognosis in a large cohort of UCEC specimens. Experimental Design: UCECs from 591 clinically annotated patients including 83 tumors with matching metastasis (n ¼ 188) were analyzed by FISH to determine PIK3CA copy-number status. These data were integrated with mRNA and protein expression and clinicopathologic data. Results were verified in The Cancer Genome Atlas dataset. Results: PIK3CA amplifications were associated with disease-specific mortality and with other markers of aggressive disease. PIK3CA amplifications were also associated with other amplifications characteristic of the serous-like somatic copy-number alteration (SCNA)–high subgroup of UCEC. Tumors with PIK3CA amplification also demonstrated an increase in phospho-p70S6K but had decreased levels of activated phospho-AKT1-3 as assessed by Reverse Phase Protein Arrays and an mRNA signature of MTOR inhibition. Conclusions: PIK3CA amplification is a strong prognostic marker and a potential marker for the aggressive SCNA-high subgroup of UCEC. Although PIK3CA amplification associates with some surrogate measures of increased PI3K activity, markers for AKT1-3 and MTOR signaling are decreased, suggesting that this signaling is not a predominant pathway to promote cancer growth of aggressive serous-like UCEC. Moreover, these associations may reflect features of the SCNA-high subgroup of UCEC rather than effects of PIK3CA amplification itself.

Original languageEnglish (US)
Pages (from-to)334-345
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number1
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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Endometrial Neoplasms
Phosphatidylinositol 3-Kinases
Phenotype
Neoplasms
70-kDa Ribosomal Protein S6 Kinases
Protein Array Analysis
Messenger RNA
Atlases
Catalytic Domain
Research Design
Genome
Neoplasm Metastasis
Mortality
Growth
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Holst, F., Werner, H. M. J., Mjøs, S., Hoivik, E. A., Kusonmano, K., Wik, E., ... Salvesen, H. B. (2019). PIK3CA amplification associates with aggressive phenotype but not markers of AKT-mTOR signaling in endometrial carcinoma. Clinical Cancer Research, 25(1), 334-345. https://doi.org/10.1158/1078-0432.CCR-18-0452

PIK3CA amplification associates with aggressive phenotype but not markers of AKT-mTOR signaling in endometrial carcinoma. / Holst, Frederik; Werner, Henrica M.J.; Mjøs, Siv; Hoivik, Erling A.; Kusonmano, Kanthida; Wik, Elisabeth; Berg, Anna; Birkeland, Even; Gibson, William J.; Halle, Mari K.; Trovik, Jone; Cherniack, Andrew D.; Kalland, Karl Henning; Mills, Gordon; Singer, Christian F.; Krakstad, Camilla; Beroukhim, Rameen; Salvesen, Helga B.

In: Clinical Cancer Research, Vol. 25, No. 1, 01.01.2019, p. 334-345.

Research output: Contribution to journalArticle

Holst, F, Werner, HMJ, Mjøs, S, Hoivik, EA, Kusonmano, K, Wik, E, Berg, A, Birkeland, E, Gibson, WJ, Halle, MK, Trovik, J, Cherniack, AD, Kalland, KH, Mills, G, Singer, CF, Krakstad, C, Beroukhim, R & Salvesen, HB 2019, 'PIK3CA amplification associates with aggressive phenotype but not markers of AKT-mTOR signaling in endometrial carcinoma', Clinical Cancer Research, vol. 25, no. 1, pp. 334-345. https://doi.org/10.1158/1078-0432.CCR-18-0452
Holst, Frederik ; Werner, Henrica M.J. ; Mjøs, Siv ; Hoivik, Erling A. ; Kusonmano, Kanthida ; Wik, Elisabeth ; Berg, Anna ; Birkeland, Even ; Gibson, William J. ; Halle, Mari K. ; Trovik, Jone ; Cherniack, Andrew D. ; Kalland, Karl Henning ; Mills, Gordon ; Singer, Christian F. ; Krakstad, Camilla ; Beroukhim, Rameen ; Salvesen, Helga B. / PIK3CA amplification associates with aggressive phenotype but not markers of AKT-mTOR signaling in endometrial carcinoma. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 1. pp. 334-345.
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abstract = "Purpose: Amplification of PIK3CA, encoding the PI3K catalytic subunit alpha, is common in uterine corpus endometrial carcinoma (UCEC) and linked to an aggressive phenotype. However, it is unclear whether PIK3CA amplification acts via PI3K activation. We investigated the association between PIK3CA amplification, markers of PI3K activity, and prognosis in a large cohort of UCEC specimens. Experimental Design: UCECs from 591 clinically annotated patients including 83 tumors with matching metastasis (n ¼ 188) were analyzed by FISH to determine PIK3CA copy-number status. These data were integrated with mRNA and protein expression and clinicopathologic data. Results were verified in The Cancer Genome Atlas dataset. Results: PIK3CA amplifications were associated with disease-specific mortality and with other markers of aggressive disease. PIK3CA amplifications were also associated with other amplifications characteristic of the serous-like somatic copy-number alteration (SCNA)–high subgroup of UCEC. Tumors with PIK3CA amplification also demonstrated an increase in phospho-p70S6K but had decreased levels of activated phospho-AKT1-3 as assessed by Reverse Phase Protein Arrays and an mRNA signature of MTOR inhibition. Conclusions: PIK3CA amplification is a strong prognostic marker and a potential marker for the aggressive SCNA-high subgroup of UCEC. Although PIK3CA amplification associates with some surrogate measures of increased PI3K activity, markers for AKT1-3 and MTOR signaling are decreased, suggesting that this signaling is not a predominant pathway to promote cancer growth of aggressive serous-like UCEC. Moreover, these associations may reflect features of the SCNA-high subgroup of UCEC rather than effects of PIK3CA amplification itself.",
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T1 - PIK3CA amplification associates with aggressive phenotype but not markers of AKT-mTOR signaling in endometrial carcinoma

AU - Holst, Frederik

AU - Werner, Henrica M.J.

AU - Mjøs, Siv

AU - Hoivik, Erling A.

AU - Kusonmano, Kanthida

AU - Wik, Elisabeth

AU - Berg, Anna

AU - Birkeland, Even

AU - Gibson, William J.

AU - Halle, Mari K.

AU - Trovik, Jone

AU - Cherniack, Andrew D.

AU - Kalland, Karl Henning

AU - Mills, Gordon

AU - Singer, Christian F.

AU - Krakstad, Camilla

AU - Beroukhim, Rameen

AU - Salvesen, Helga B.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: Amplification of PIK3CA, encoding the PI3K catalytic subunit alpha, is common in uterine corpus endometrial carcinoma (UCEC) and linked to an aggressive phenotype. However, it is unclear whether PIK3CA amplification acts via PI3K activation. We investigated the association between PIK3CA amplification, markers of PI3K activity, and prognosis in a large cohort of UCEC specimens. Experimental Design: UCECs from 591 clinically annotated patients including 83 tumors with matching metastasis (n ¼ 188) were analyzed by FISH to determine PIK3CA copy-number status. These data were integrated with mRNA and protein expression and clinicopathologic data. Results were verified in The Cancer Genome Atlas dataset. Results: PIK3CA amplifications were associated with disease-specific mortality and with other markers of aggressive disease. PIK3CA amplifications were also associated with other amplifications characteristic of the serous-like somatic copy-number alteration (SCNA)–high subgroup of UCEC. Tumors with PIK3CA amplification also demonstrated an increase in phospho-p70S6K but had decreased levels of activated phospho-AKT1-3 as assessed by Reverse Phase Protein Arrays and an mRNA signature of MTOR inhibition. Conclusions: PIK3CA amplification is a strong prognostic marker and a potential marker for the aggressive SCNA-high subgroup of UCEC. Although PIK3CA amplification associates with some surrogate measures of increased PI3K activity, markers for AKT1-3 and MTOR signaling are decreased, suggesting that this signaling is not a predominant pathway to promote cancer growth of aggressive serous-like UCEC. Moreover, these associations may reflect features of the SCNA-high subgroup of UCEC rather than effects of PIK3CA amplification itself.

AB - Purpose: Amplification of PIK3CA, encoding the PI3K catalytic subunit alpha, is common in uterine corpus endometrial carcinoma (UCEC) and linked to an aggressive phenotype. However, it is unclear whether PIK3CA amplification acts via PI3K activation. We investigated the association between PIK3CA amplification, markers of PI3K activity, and prognosis in a large cohort of UCEC specimens. Experimental Design: UCECs from 591 clinically annotated patients including 83 tumors with matching metastasis (n ¼ 188) were analyzed by FISH to determine PIK3CA copy-number status. These data were integrated with mRNA and protein expression and clinicopathologic data. Results were verified in The Cancer Genome Atlas dataset. Results: PIK3CA amplifications were associated with disease-specific mortality and with other markers of aggressive disease. PIK3CA amplifications were also associated with other amplifications characteristic of the serous-like somatic copy-number alteration (SCNA)–high subgroup of UCEC. Tumors with PIK3CA amplification also demonstrated an increase in phospho-p70S6K but had decreased levels of activated phospho-AKT1-3 as assessed by Reverse Phase Protein Arrays and an mRNA signature of MTOR inhibition. Conclusions: PIK3CA amplification is a strong prognostic marker and a potential marker for the aggressive SCNA-high subgroup of UCEC. Although PIK3CA amplification associates with some surrogate measures of increased PI3K activity, markers for AKT1-3 and MTOR signaling are decreased, suggesting that this signaling is not a predominant pathway to promote cancer growth of aggressive serous-like UCEC. Moreover, these associations may reflect features of the SCNA-high subgroup of UCEC rather than effects of PIK3CA amplification itself.

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