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Genetic Analysis to Interrogate Tumor Heterogeneity in Lung Adenocarcinoma

ABSTRACT:

We employed next-generation sequencing to identify somatic alterations in multiple metastatic sites from an "exceptional responder" lung adenocarcinoma patient during his seven year course of ERBB2-directed therapies. The degree of heterogeneity was unprecedented, with ~1% similarity between somatic alterations of the lung and lymph nodes. One novel translocation, PLAG1-ACTA2, present in both sites, up-regulated ACTA2 expression. ERBB2, the predominant driver oncogene, was amplified in both sites, more pronounced in the lung, and harbored an L869R mutation in the lymph node. Functional studies demonstrated increased proliferation, migration, metastasis, and resistance to ERBB2-directed therapy due to L869R mutation and increased migration due to ACTA2 overexpression. Within the lung, a nonfunctional CDK12, due to a novel G879V mutation, correlated with down-regulation of DNA damage response genes, causing genomic instability, and sensitivity to chemotherapy. We propose a model whereby a sub-clone metastasized early from the primary site and evolved independently in lymph nodes.

PROVIDER: phs001159 | dbGaP |

SECONDARY ACCESSION(S): PRJNA326708PRJNA326709

REPOSITORIES: dbGaP

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			Action	DRS
	GapExchange_phs001159.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs001159.LungAdenocarcinomaTumorHeterogeneity.v1.p1.MULTI.pdf	Pdf
	manifest_phs001159.LungAdenocarcinomaTumorHeterogeneity.v1.p1.c2.HMB-IRB-PUB.pdf	Pdf
	datadict_v2.xsl	Other

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