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Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study
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نویسنده
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shi j. ,hua x. ,zhu b. ,ravichandran s. ,wang m. ,nguyen c. ,brodie s.a. ,palleschi a. ,alloisio m. ,pariscenti g. ,jones k. ,zhou w. ,bouk a.j. ,boland j. ,hicks b. ,risch a. ,bennett h. ,luke b.t. ,song l. ,duan j. ,liu p. ,kohno t. ,chen q. ,meerzaman d. ,marconett c. ,laird-offringa i. ,mills i. ,caporaso n.e. ,gail m.h. ,pesatori a.c. ,consonni d. ,bertazzi p.a. ,chanock s.j. ,landi m.t.
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منبع
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plos medicine - 2016 - دوره : 13 - شماره : 12
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چکیده
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Background: lung adenocarcinoma (luad) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. we aimed to characterize the genomic landscape of luad and identify mutation signatures associated with tumor progression. methods and findings: we performed an integrative genomic analysis,incorporating whole exome sequencing (wes),determination of dna copy number and dna methylation,and transcriptome sequencing for 101 luad samples from the environment and genetics in lung cancer etiology (eagle) study. we detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. we performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. we also tested the association between mutation signatures and clinical outcomes,including distant metastasis,survival,and tumor grade. we identified and replicated two novel candidate driver genes,pou class 4 homeobox 2 (pou4f2) (mutated in 9 [8.9%] samples) and zkscan1 (mutated in 6 [5.9%] samples),and characterized their major deleterious mutations. zkscan1 was part of a mutually exclusive gene set that included the rtk/ras/raf pathway genes braf,egfr,kras,met,and nf1,indicating an important driver role for this gene. moreover,we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. in the tumor evolution analysis,four driver genes had a significantly lower fraction of subclonal mutations (fsm),including tp53 (p = 0.007),keap1 (p = 0.012),stk11 (p = 0.0076),and egfr (p = 0.0078),suggesting a tumor initiation role for these genes. subclonal mutations were significantly enriched in apobec-related signatures (p < 2.5×10−50). the total number of somatic mutations (p = 0.0039) and the fraction of transitions (p = 5.5×10−4) were associated with increased risk of distant metastasis. our study’s limitations include a small number of luad patients for subgroup analyses and a single-sample design for investigation of subclonality. conclusions: these data provide a genomic characterization of luad pathogenesis and progression. the distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures,and may serve as a foundation for more effective treatments for this lethal disease. luad’s high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes. © 2016 public library of science. all rights reserved.
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آدرس
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division of cancer epidemiology and genetics,national cancer institute,bethesda,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md, United States, advanced biomedical computing center,frederick national laboratory for cancer research,leidos biomedical research inc.,frederick,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md,united states,cancer genomics research laboratory,frederick national laboratory for cancer research,leidos biomedical research inc.,frederick,md, United States, center for biomedical informatics and information technology,national cancer institute,bethesda,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md,united states,cancer genomics research laboratory,frederick national laboratory for cancer research,leidos biomedical research inc.,frederick,md, United States, division of thoracic surgery,fondazione irccs ca’ granda—ospedale maggiore policlinico,milan, Italy, division of thoracic surgery,istituto clinico humanitas,rozzano,milan, Italy, thoracic surgery unit,community hospital,brescia, Italy, division of cancer epidemiology and genetics,national cancer institute,bethesda,md,united states,cancer genomics research laboratory,frederick national laboratory for cancer research,leidos biomedical research inc.,frederick,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md,united states,cancer genomics research laboratory,frederick national laboratory for cancer research,leidos biomedical research inc.,frederick,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md,united states,cancer genomics research laboratory,frederick national laboratory for cancer research,leidos biomedical research inc.,frederick,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md,united states,cancer genomics research laboratory,frederick national laboratory for cancer research,leidos biomedical research inc.,frederick,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md,united states,cancer genomics research laboratory,frederick national laboratory for cancer research,leidos biomedical research inc.,frederick,md, United States, information management services,inc.,rockville,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md, United States, advanced biomedical computing center,frederick national laboratory for cancer research,leidos biomedical research inc.,frederick,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md,united states,cancer genomics research laboratory,frederick national laboratory for cancer research,leidos biomedical research inc.,frederick,md, United States, center for psychiatric genetics,department of psychiatry and behavioral sciences,north shore university health system research institute,university of chicago pritzker school of medicine,evanston,il, United States, department of physiology & cancer center,medical college of wisconsin,milwaukee,wi, United States, division of genome biology,national cancer center research institute,tokyo, Japan, center for biomedical informatics and information technology,national cancer institute,bethesda,md, United States, center for biomedical informatics and information technology,national cancer institute,bethesda,md, United States, departments of surgery and of biochemistry and molecular biology,norris comprehensive cancer center,keck school of medicine,university of southern california,los angeles,ca, United States, departments of surgery and of biochemistry and molecular biology,norris comprehensive cancer center,keck school of medicine,university of southern california,los angeles,ca, United States, prostate cancer uk/movember centre of excellence for prostate cancer research,centre for cancer research and cell biology,queen’s university,belfast, United Kingdom, division of cancer epidemiology and genetics,national cancer institute,bethesda,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md, United States, epidemiology unit,fondazione irccs ca’ granda—ospedale maggiore policlinico,milan,italy,department of clinical sciences and community health,universita’ degli studi di milano,milan, Italy, epidemiology unit,fondazione irccs ca’ granda—ospedale maggiore policlinico,milan, Italy, epidemiology unit,fondazione irccs ca’ granda—ospedale maggiore policlinico,milan,italy,department of clinical sciences and community health,universita’ degli studi di milano,milan, Italy, division of cancer epidemiology and genetics,national cancer institute,bethesda,md, United States, division of cancer epidemiology and genetics,national cancer institute,bethesda,md, United States
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Authors
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