Abstract
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.
Highlights
It is well established that cancer is the result of accumulated genetic changes to tumor suppressor genes or oncogenes, and that these changes lead to uncontrolled cellular proliferation
The status of forty genes known to be involved in cellular proliferation was examined for genomic mutations and changes in expression over the lung adenocarcinoma (LUAD) tumor cohort (Figure 1) (Table 1)
This study shows expression of pre-replication and pre-initiation complex and replisome components vary between LUAD subtypes reported by The Cancer Genome Atlas (TCGA) [2, 3]
Summary
It is well established that cancer is the result of accumulated genetic changes to tumor suppressor genes or oncogenes, and that these changes lead to uncontrolled cellular proliferation. This feature is important clinically, and many well established chemotherapeutic agents are designed to directly or indirectly inhibit DNA synthesis. Cisplatin and carboplatin are two examples, often used in neoadjuvant and adjuvant chemotherapy regimens when treating patients with lung adenocarcinoma (LUAD). These reagents crosslink purine bases in DNA preventing replication and repair and promoting cell death. Targeted therapies are available for several molecular classes of LUAD including EGFR mutation positive, ALK rearrangement positive, ROS1 rearrangement positive, BRAF V600E mutation positive, NTRK gene fusion positive, as well as anti-PD-L1 therapy [1]
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