Apr 20, 2020

SMARCA4 supports the oncogenic landscape of KRAS-driven lung tumors

BioRxiv : the Preprint Server for Biology
Eric Collisson

Abstract

Cancer resequencing studies identify recurrent mutations in the switch/sucrose non-fermentable (SWI/SNF) complex at an unexpectedly high frequency across many cancer types. Some SWI/SNF mutations appear to be loss-of-function events, implying that the intact SWI/SNF complex is tumor suppressive. We examined the distribution and function of SMARCA4 mutations, the most frequently mutated SWI/SNF complex gene in lung adenocarcinoma, using human cancers, cell lines and mouse model systems. We found that lung adenocarcinomas harboring activated oncogenes have fewer deleterious mutations in SMARCA4 and express higher levels of the mRNA than cancers without activated oncogenes, indicating distinct dependencies on SMARCA4 in these two settings. Surprisingly, intact Smarca4 promoted the growth and tumorgenicity of KrasG12D-driven mouse lung tumors and human cells. Mechanistically, we found that Smarca4 supports the oncogenic transcriptional/signaling landscape of KrasG12D-driven mouse lung cancer. This dependency on the chromatin maintenance machinery in established cancer cells support treatments directed towards pathogenic SWI/SNF complexes in lung adenocarcinoma and other malignancies.

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Mentioned in this Paper

Human Papillomavirus
Genome
Trees (plant)
Class 1
Somatic Mutation
Neoplasms
Whole Exome Sequencing
Sequencing
Major Histocompatibility Complex
Neck

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