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Cold Spring Harb Mol Case Stud. 2016 Nov;2(6):a001263.

Genomic profiling of multiple sequentially acquired tumor metastatic sites from an "exceptional responder" lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response.

Author information

1
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
2
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
3
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
4
Walter Reed National Military Medical Center, Bethesda, Maryland 20889, USA.
5
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
6
Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, Maryland 20848, USA.
7
Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
8
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
9
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C. 20057, USA.

Abstract

We used next-generation sequencing to identify somatic alterations in multiple metastatic sites from an "exceptional responder" lung adenocarcinoma patient during his 7-yr 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 showed increased proliferation, migration, metastasis, and resistance to ERBB2-directed therapy because of L869R mutation and increased migration because of 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 subclone metastasized early from the primary site and evolved independently in lymph nodes.

KEYWORDS:

neoplasm of the lung

PMID:
27900369
PMCID:
PMC5111000
DOI:
10.1101/mcs.a001263
[Indexed for MEDLINE]
Free PMC Article

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