Genomic landscape of allelic imbalance in premalignant atypical adenomatous hyperplasias of the lung.
Adenocarcinoma
/ genetics
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 Neoplasms
/ genetics
Male
Middle Aged
Models, Statistical
Mutation
Neoplasm Staging
Phylogeny
Polymorphism, Single Nucleotide
Precancerous Conditions
/ genetics
Young Adult
Allelic imbalance
Atypical adenomatous hyperplasia
Chromosomal instability
Lung adenocarcinoma
Pathogenesis
Preneoplasia
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Apr 2019
Apr 2019
Historique:
received:
12
10
2018
revised:
28
02
2019
accepted:
07
03
2019
pubmed:
25
3
2019
medline:
21
8
2019
entrez:
26
3
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
RESULTS
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
CONCLUSIONS
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.
Identifiants
pubmed: 30905849
pii: S2352-3964(19)30160-4
doi: 10.1016/j.ebiom.2019.03.020
pmc: PMC6491940
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
296-303Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
Références
Nat Genet. 1999 May;22(1):106-9
pubmed: 10319873
Clin Cancer Res. 2000 Feb;6(2):357-62
pubmed: 10690511
Am J Gastroenterol. 2001 Oct;96(10):2839-48
pubmed: 11693316
Am J Pathol. 2001 Nov;159(5):1941-8
pubmed: 11696455
Oncogene. 2002 Oct 7;21(45):6877-83
pubmed: 12362270
J Gastroenterol Hepatol. 2003 Jun;18(6):683-9
pubmed: 12753151
Nature. 2007 Dec 6;450(7171):893-8
pubmed: 17982442
Annu Rev Pathol. 2006;1:331-48
pubmed: 18039118
N Engl J Med. 2008 Sep 25;359(13):1367-80
pubmed: 18815398
Cancer Prev Res (Phila). 2008 Nov;1(6):413-23
pubmed: 19138988
Nat Rev Mol Cell Biol. 2010 Mar;11(3):220-8
pubmed: 20177397
Virchows Arch. 2011 May;458(5):561-9
pubmed: 21279520
Oral Oncol. 2011 Oct;47(10):956-60
pubmed: 21880540
BMC Cancer. 2012 Jun 12;12:235
pubmed: 22691236
Genome Res. 2013 Jan;23(1):152-8
pubmed: 23028187
Science. 2013 Mar 29;339(6127):1546-58
pubmed: 23539594
Oral Oncol. 2013 Dec;49(12):1121-8
pubmed: 24075955
Nature. 2014 Jul 31;511(7511):543-50
pubmed: 25079552
Science. 2014 Oct 10;346(6206):251-6
pubmed: 25301630
J Thorac Oncol. 2015 Sep;10(9):1243-1260
pubmed: 26291008
Nat Commun. 2015 Sep 16;6:8258
pubmed: 26374070
Cancer Prev Res (Phila). 2016 Jul;9(7):518-27
pubmed: 27006378
Cancer Cell. 2016 May 9;29(5):737-750
pubmed: 27165745
Cancer Res. 2016 Jul 1;76(13):3676-83
pubmed: 27216194
Cancer Prev Res (Phila). 2016 Jun;9(6):417-27
pubmed: 27221540
Sci Rep. 2016 Aug 22;6:31628
pubmed: 27545006
Cancer Res. 2017 Nov 15;77(22):6119-6130
pubmed: 28951454
Nat Commun. 2018 Jan 15;9(1):216
pubmed: 29335443
Bioinformatics. 2018 Nov 21;:null
pubmed: 30462146
Curr Opin Syst Biol. 2017 Apr;2:1-8
pubmed: 30603736
Hiroshima J Med Sci. 1998 Mar;47(1):17-25
pubmed: 9583279