Intratumor heterogeneity of ALK-rearrangements and homogeneity of EGFR-mutations in mixed lung adenocarcinoma

Federica Zito Marino, Giuseppina Liguori, Gabriella Aquino, Elvira La Mantia, Silvano Bosari, Stefano Ferrero, Lorenzo Rosso, Gabriella Gaudioso, Nicla De Rosa, Marianna Scrima, Nicola Martucci, Antonello La Rocca, Nicola Normanno, Alessandro Morabito, Gaetano Rocco, Gerardo Botti, Renato Franco

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Abstract

Background Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be 'major', characterized by a single tumor showing two different histologic types, and 'minor', due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas. Methods 590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR. Results 10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components. Conclusion Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes.

Original languageEnglish
Article numbere0139264
JournalPLoS One
Volume10
Issue number9
DOIs
Publication statusPublished - Sep 30 2015

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adenocarcinoma
Tumors
Adenosquamous Carcinoma
Adenocarcinoma
lungs
carcinoma
mutation
Mutation
neoplasms
Neoplasms
Non-Small Cell Lung Carcinoma
Cells
lung neoplasms
Growth
reverse transcriptase polymerase chain reaction
Adenocarcinoma of lung
cells
Polymerase Chain Reaction
therapeutics
Proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

@article{b0cb354ae379493185c9b71110e5cd16,
title = "Intratumor heterogeneity of ALK-rearrangements and homogeneity of EGFR-mutations in mixed lung adenocarcinoma",
abstract = "Background Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be 'major', characterized by a single tumor showing two different histologic types, and 'minor', due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas. Methods 590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR. Results 10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components. Conclusion Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes.",
author = "Marino, {Federica Zito} and Giuseppina Liguori and Gabriella Aquino and Mantia, {Elvira La} and Silvano Bosari and Stefano Ferrero and Lorenzo Rosso and Gabriella Gaudioso and {De Rosa}, Nicla and Marianna Scrima and Nicola Martucci and Rocca, {Antonello La} and Nicola Normanno and Alessandro Morabito and Gaetano Rocco and Gerardo Botti and Renato Franco",
year = "2015",
month = "9",
day = "30",
doi = "10.1371/journal.pone.0139264",
language = "English",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
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TY - JOUR

T1 - Intratumor heterogeneity of ALK-rearrangements and homogeneity of EGFR-mutations in mixed lung adenocarcinoma

AU - Marino, Federica Zito

AU - Liguori, Giuseppina

AU - Aquino, Gabriella

AU - Mantia, Elvira La

AU - Bosari, Silvano

AU - Ferrero, Stefano

AU - Rosso, Lorenzo

AU - Gaudioso, Gabriella

AU - De Rosa, Nicla

AU - Scrima, Marianna

AU - Martucci, Nicola

AU - Rocca, Antonello La

AU - Normanno, Nicola

AU - Morabito, Alessandro

AU - Rocco, Gaetano

AU - Botti, Gerardo

AU - Franco, Renato

PY - 2015/9/30

Y1 - 2015/9/30

N2 - Background Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be 'major', characterized by a single tumor showing two different histologic types, and 'minor', due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas. Methods 590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR. Results 10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components. Conclusion Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes.

AB - Background Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be 'major', characterized by a single tumor showing two different histologic types, and 'minor', due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas. Methods 590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR. Results 10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components. Conclusion Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes.

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U2 - 10.1371/journal.pone.0139264

DO - 10.1371/journal.pone.0139264

M3 - Article

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

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