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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish
Pages (from-to)296-303
Number of pages8
JournalEBioMedicine
Volume42
DOIs
StatePublished - Apr 2019

Bibliographical note

Publisher Copyright:
© 2019

Keywords

  • Allelic imbalance
  • Atypical adenomatous hyperplasia
  • Chromosomal instability
  • Lung adenocarcinoma
  • Pathogenesis
  • Preneoplasia

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

Fingerprint

Dive into the research topics of 'Genomic landscape of allelic imbalance in premalignant atypical adenomatous hyperplasias of the lung'. Together they form a unique fingerprint.

Cite this