Genomic landscape of allelic imbalance in premalignant atypical adenomatous hyperplasias of the lungResearch in context
Smruthy Sivakumar,
F. Anthony San Lucas,
Yasminka A. Jakubek,
Tina L. McDowell,
Wenhua Lang,
Noah Kallsen,
Shanna Peyton,
Gareth E. Davies,
Junya Fukuoka,
Yasushi Yatabe,
Jianjun Zhang,
P. Andrew Futreal,
Jerry Fowler,
Junya Fujimoto,
Erik A. Ehli,
Ernest T. Hawk,
Ignacio I. Wistuba,
Humam Kadara,
Paul Scheet
Affiliations
Smruthy Sivakumar
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
F. Anthony San Lucas
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Yasminka A. Jakubek
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Tina L. McDowell
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Wenhua Lang
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Noah Kallsen
Avera Institute for Human Genetics, Sioux Falls, SD, USA
Shanna Peyton
Avera Institute for Human Genetics, Sioux Falls, SD, USA
Gareth E. Davies
Avera Institute for Human Genetics, Sioux Falls, SD, USA
Junya Fukuoka
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Yasushi Yatabe
Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
Jianjun Zhang
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
P. Andrew Futreal
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Jerry Fowler
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Junya Fujimoto
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Erik A. Ehli
Avera Institute for Human Genetics, Sioux Falls, SD, USA
Ernest T. Hawk
Division of Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Ignacio I. Wistuba
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Humam Kadara
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Corresponding author.
Paul Scheet
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Correspondence to: P. Scheet, Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Background: Genomic investigation of atypical adenomatous hyperplasia (AAH), the only known precursor lesion to lung adenocarcinomas (LUAD), presents challenges due to the low mutant cell fractions. This necessitates sensitive methods for detection of chromosomal aberrations to better study the role of critical alterations in early lung cancer pathogenesis and the progression from AAH to LUAD. Methods: We applied a sensitive haplotype-based statistical technique to detect chromosomal alterations leading to allelic imbalance (AI) from genotype array profiling of 48 matched normal lung parenchyma, AAH and tumor tissues from 16 stage-I LUAD patients. To gain insights into shared developmental trajectories among tissues, we performed phylogenetic analyses and integrated our results with point mutation data, highlighting significantly-mutated driver genes in LUAD pathogenesis. Findings: AI was detected in nine AAHs (56%). Six cases exhibited recurrent loss of 17p. AI and the enrichment of 17p events were predominantly identified in patients with smoking history. Among the nine AAH tissues with detected AI, seven exhibited evidence for shared chromosomal aberrations with matched LUAD specimens, including losses harboring tumor suppressors on 17p, 8p, 9p, 9q, 19p, and gains encompassing oncogenes on 8q, 12p and 1q. Interpretation: Chromosomal aberrations, particularly 17p loss, appear to play critical roles early in AAH pathogenesis. Genomic instability in AAH, as well as truncal chromosomal aberrations shared with LUAD, provide evidence for mutation accumulation and are suggestive of a cancerized field contributing to the clonal selection and expansion of these premalignant lesions. Fund: Supported in part by Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150079 (PS and HK), NIH grant R01HG005859 (PS) and The University of Texas MD Anderson Cancer Center Core Support Grant. Keywords: Atypical adenomatous hyperplasia, Lung adenocarcinoma, Preneoplasia, Pathogenesis, Allelic imbalance, Chromosomal instability
