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Cancer Res. 2017 Nov 15;77(22):6119-6130. doi: 10.1158/0008-5472.CAN-17-1605. Epub 2017 Sep 26.

Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma.

Author information

1
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas.
3
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
7
Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.
8
Division of Pulmonology and Critical Care Medicine, University of California Los Angeles, Los Angeles, California.
9
School of Medicine, Boston University, Boston, Massachusetts.
10
Division of Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
11
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. pscheet@alum.wustl.edu hk94@aub.edu.lb.
12
Department of Biochemistry and Molecular Genetics, The American University of Beirut, Beirut, Lebanon.

Abstract

There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF-mutant cases. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF-mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB) and elevated protumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. Cancer Res; 77(22); 6119-30. ©2017 AACR.

PMID:
28951454
PMCID:
PMC5774855
DOI:
10.1158/0008-5472.CAN-17-1605
[Indexed for MEDLINE]
Free PMC Article

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