Research Papers:

Modulation of proliferation factors in lung adenocarcinoma with an analysis of the transcriptional consequences of genomic EGFR activation

Melanie Haas Kucherlapati _

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Oncotarget. 2019; 10:6913-6933. https://doi.org/10.18632/oncotarget.27316

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Melanie Haas Kucherlapati1,2

1 Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

2 Department of Medicine, Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

Correspondence to:

Melanie Haas Kucherlapati,email: [email protected]

Keywords: proliferation; mutation; transcription; EGFR; lung adenocarcinoma

Received: August 03, 2019     Accepted: October 26, 2019     Published: December 10, 2019


Genes of the pre-replication, pre-initiation and replisome complexes duplicate the genome from many sites once in a normal cell cycle. This study examines complex components in lung adenocarcinoma (LUAD) closely, correlating changes in the genome and transcriptome with proliferation and overall survival. Molecular subtypes (The Cancer Genome Atlas (TCGA), 2014) based on copy number, DNA methylation, and mRNA expression had variable proliferation levels, the highest correlating with decreased survival. A pattern of increased expression typified by POLE2 and POLQ was found for multiple replication factors over thirty-seven tumor types. EGFR altered cases unanticipatedly inversely correlated with proliferation factor expression in LUAD, Colon adenocarcinoma, and Cancer Cell Line Encyclopedia cell lines, but not in glioblastoma or breast cancer. Activation mutations did not uniformly correlate with proliferation, most cases were pre-metastatic. A gene expression profile was identified, and pathway involvement considered. Significantly, results suggest EGFR over expression and activation are early alterations that likely stall the replication complex through PCNA phosphorylation creating replication stress responsible for DNA damage response and further mutation, but does not promote increased proliferation itself. An argument is presented that the mechanism driving lethality in this tumor cohort could differ from over proliferation seen in other LUAD.

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