Genomic landscape of allelic imbalance in premalignant atypical adenomatous hyperplasias of the lung

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

doi:10.1016/j.ebiom.2019.03.020

Genomic landscape of allelic imbalance in premalignant atypical adenomatous hyperplasias of the lung

EBioMedicine. 2019 Apr:42:296-303. doi: 10.1016/j.ebiom.2019.03.020. Epub 2019 Mar 21.

Authors

Smruthy Sivakumar¹, F Anthony San Lucas², Yasminka A Jakubek², Tina L McDowell³, Wenhua Lang³, Noah Kallsen⁴, Shanna Peyton⁴, Gareth E Davies⁴, Junya Fukuoka⁵, Yasushi Yatabe⁶, Jianjun Zhang⁷, P Andrew Futreal⁸, Jerry Fowler², Junya Fujimoto³, Erik A Ehli⁴, Ernest T Hawk⁹, Ignacio I Wistuba³, Humam Kadara¹⁰, Paul Scheet¹¹

Affiliations

¹ 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.
² Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Avera Institute for Human Genetics, Sioux Falls, SD, USA.
⁵ Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
⁶ Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.
⁷ 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.
⁸ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Division of Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: hkadara@mdanderson.org.
¹¹ 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. Electronic address: pscheet@alum.wustl.edu.

Abstract

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: Allelic imbalance; Atypical adenomatous hyperplasia; Chromosomal instability; Lung adenocarcinoma; Pathogenesis; Preneoplasia.

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / pathology
Adult
Aged
Aged, 80 and over
Alleles
Allelic Imbalance
Cell Transformation, Neoplastic / genetics*
Chromosomal Instability
Disease Progression
Female
Genetic Heterogeneity
Genome-Wide Association Study
Haplotypes
Humans
Hyperplasia
Lung / metabolism*
Lung / pathology*
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Male
Middle Aged
Models, Statistical
Mutation
Neoplasm Staging
Phylogeny
Polymorphism, Single Nucleotide
Precancerous Conditions / genetics*
Young Adult

Grants and funding

P30 CA016672/CA/NCI NIH HHS/United States