Comprehensive molecular profiling of lung adenocarcinoma - PubMed (original) (raw)
. 2014 Jul 31;511(7511):543-50.
doi: 10.1038/nature13385. Epub 2014 Jul 9.
Collaborators
- PMID: 25079552
- PMCID: PMC4231481
- DOI: 10.1038/nature13385
Comprehensive molecular profiling of lung adenocarcinoma
Cancer Genome Atlas Research Network. Nature. 2014.
Erratum in
- Nature. 2014 Oct 9;514(7521):262. Rogers, K [corrected to Rodgers, K]
- Author Correction: Comprehensive molecular profiling of lung adenocarcinoma.
Cancer Genome Atlas Research Network. Cancer Genome Atlas Research Network. Nature. 2018 Jul;559(7715):E12. doi: 10.1038/s41586-018-0228-6. Nature. 2018. PMID: 29925941
Abstract
Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.
Figures
Figure 1. Somatic mutations in lung adenocarcinoma
a, Co-mutation plot from whole exome sequencing of 230 lung adenocarcinomas. Data from TCGA samples were combined with previously published data for statistical analysis. Co-mutation plot for all samples used in the statistical analysis (n =412) can be found in Supplementary Fig. 2. Significant genes with a corrected P value less than 0.025 were identified using the MutSig2CV algorithm and are ranked in order of decreasing prevalence. b, c, The differential patterns of mutation between samples classified as transversion high and transversion low samples (b) or male and female patients (c) are shown for all samples used in the statistical analysis (n =412). Stars indicate statistical significance using the Fisher’s exact test (black stars: q <0.05, grey stars: P <0.05) and are adjacent to the sample set with the higher percentage of mutated samples.
Figure 2. Aberrant RNA transcripts in lung adenocarcinoma associated with somatic DNA translocation or mutation
a, Normalized exon level RNA expression across fusion gene partners. Grey boxes around genes mark the regions that are removed as a consequence of the fusion. Junction points of the fusion events are also listed in Supplementary Table 9. Exon numbers refer to reference transcripts listed in Supplementary Table 9. b, MET exon 14 skipping observed in the presence of exon 14 splice site mutation (ss mut), splice site deletion (ss del) or a Y1003* mutation. A total of 22 samples had insufficient coverage around exon 14 for quantification. The percentage skipping is (total expression minus exon 14 expression)/total expression. c, Significant differences in the frequency of 129 alternative splicing events in mRNA from tumours with U2AF1 S34F tumours compared to U2AF1 WT tumours (q value <0.05). Consistent with the function of U2AF1 in 3′ splice site recognition, most splicing differences involved cassette exon and alternative 3′ splice site events (chi-squared test, P <0.001).
Figure 3. Identification of novel candidate driver genes
a, GISTIC analysis of focal amplifications in oncogene-negative (n =87) and oncogene-positive (n =143) TCGA samples identifies focal gains of MET and ERBB2 that are specific to the oncogene-negative set (purple). b, TP53, KEAP1, NF1 and RIT1 mutations are significantly enriched in samples otherwise lacking oncogene mutations (adjusted P <0.05 by Fisher’s exact test). c, Co-mutation plot of variants of known significance within the RTK/RAS/RAF pathway in lung adenocarcinoma. Not shown are the 63 tumours lacking an identifiable driver lesion. Only canonical driver events, as defined in Supplementary Fig. 9, and proposed driver events, are shown; hence not every alteration found is displayed. d, New candidate driver oncogenes (blue: 13% of cases) and known somatically activated drivers events (red: 63%) that activate the RTK/RAS/RAF pathway can be found in the majority of the 230 lung adenocarcinomas.
Figure 4. Pathway alterations in lung adenocarcinoma
a, Somatic alterations involving key pathway components for RTK signalling, mTOR signalling, oxidative stress response, proliferation and cell cycle progression, nucleosome remodelling, histone methylation, and RNA splicing/processing. b, c, Proteomic analysis by RPPA (n =181) P values by two-sided _t_-test. Box plots represent 5%, 25%, 75%, median, and 95%. PP, proximal proliferative; TRU, terminal respiratory unit; PI, proximal inflammatory. c, mTOR signalling may be activated, by either Akt (for example, via PI(3)K) or inactivation of AMPK (for example, via STK11 loss). Tumours were separated into three main groups: those with PI(3)K-AKT activation, through either PIK3CA activating mutation or unknown mechanism (high p-AKT); those with LKB1-AMPK inactivation, through either STK11 mutation or unknown mechanism with low levels of LKB1 and p-AMPK; and those showing none of the above features.
Figure 5. Integrative analysis
a–c, Integrating unsupervised analyses of 230 lung adenocarcinomas reveals significant interactions between molecular subtypes. Tumours are displayed as columns, grouped by mRNA expression subtypes (a), DNA methylation subtypes (b), and integrated subtypes by iCluster analysis (c). All displayed features are significantly associated with subtypes depicted. The CIMP phenotype is defined by the most variable CpG island and promoter probes.
Similar articles
- Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study.
Shi J, Hua X, Zhu B, Ravichandran S, Wang M, Nguyen C, Brodie SA, Palleschi A, Alloisio M, Pariscenti G, Jones K, Zhou W, Bouk AJ, Boland J, Hicks B, Risch A, Bennett H, Luke BT, Song L, Duan J, Liu P, Kohno T, Chen Q, Meerzaman D, Marconett C, Laird-Offringa I, Mills I, Caporaso NE, Gail MH, Pesatori AC, Consonni D, Bertazzi PA, Chanock SJ, Landi MT. Shi J, et al. PLoS Med. 2016 Dec 6;13(12):e1002162. doi: 10.1371/journal.pmed.1002162. eCollection 2016 Dec. PLoS Med. 2016. PMID: 27923066 Free PMC article. - MET exon 14 skipping mutation in triple-negative pulmonary adenocarcinomas and pleomorphic carcinomas: An analysis of intratumoral MET status heterogeneity and clinicopathological characteristics.
Kwon D, Koh J, Kim S, Go H, Kim YA, Keam B, Kim TM, Kim DW, Jeon YK, Chung DH. Kwon D, et al. Lung Cancer. 2017 Apr;106:131-137. doi: 10.1016/j.lungcan.2017.02.008. Epub 2017 Feb 16. Lung Cancer. 2017. PMID: 28285687 - Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing.
Zhao J, Sun Y, Huang Y, Song F, Huang Z, Bao Y, Zuo J, Saffen D, Shao Z, Liu W, Wang Y. Zhao J, et al. Sci Rep. 2017 Jan 16;7:40488. doi: 10.1038/srep40488. Sci Rep. 2017. PMID: 28091594 Free PMC article. - Gene aberrations for precision medicine against lung adenocarcinoma.
Saito M, Shiraishi K, Kunitoh H, Takenoshita S, Yokota J, Kohno T. Saito M, et al. Cancer Sci. 2016 Jun;107(6):713-20. doi: 10.1111/cas.12941. Epub 2016 May 25. Cancer Sci. 2016. PMID: 27027665 Free PMC article. Review. - [Advances on driver oncogenes of lung adenocarcinoma].
Wang J, Zhang Z, Zhang S. Wang J, et al. Zhongguo Fei Ai Za Zhi. 2013 Feb;16(2):91-6. doi: 10.3779/j.issn.1009-3419.2013.02.06. Zhongguo Fei Ai Za Zhi. 2013. PMID: 23425901 Free PMC article. Review. Chinese.
Cited by
- LungHist700: A dataset of histological images for deep learning in pulmonary pathology.
Diosdado J, Gilabert P, Seguí S, Borrego H. Diosdado J, et al. Sci Data. 2024 Oct 5;11(1):1088. doi: 10.1038/s41597-024-03944-3. Sci Data. 2024. PMID: 39368979 Free PMC article. - Performance of somatic structural variant calling in lung cancer using Oxford Nanopore sequencing technology.
Liu L, Zhang J, Wood S, Newell F, Leonard C, Koufariotis LT, Nones K, Dalley AJ, Chittoory H, Bashirzadeh F, Son JH, Steinfort D, Williamson JP, Bint M, Pahoff C, Nguyen PT, Twaddell S, Arnold D, Grainge C, Simpson PT, Fielding D, Waddell N, Pearson JV. Liu L, et al. BMC Genomics. 2024 Sep 30;25(1):898. doi: 10.1186/s12864-024-10792-3. BMC Genomics. 2024. PMID: 39350042 Free PMC article. - RNA sequencing identifies lung cancer lineage and facilitates drug repositioning.
Zeng L, Zhang L, Li L, Liao X, Yin C, Zhang L, Chen X, Sun J. Zeng L, et al. PeerJ. 2024 Sep 24;12:e18159. doi: 10.7717/peerj.18159. eCollection 2024. PeerJ. 2024. PMID: 39346064 Free PMC article. - Tenascin-C in the early lung cancer tumor microenvironment promotes progression through integrin αvβ1 and FAK.
Samson SC, Rojas A, Zitnay RG, Carney KR, Hettinga W, Schaelling MC, Sicard D, Zhang W, Gilbert-Ross M, Dy GK, Cavnar MJ, Furqan M, Browning RF Jr, Naqash AR, Schneider BP, Tarhini A, Tschumperlin DJ, Venosa A, Marcus AI, Emerson LL, Spike BT, Knudsen BS, Mendoza MC. Samson SC, et al. bioRxiv [Preprint]. 2024 Sep 21:2024.09.17.613509. doi: 10.1101/2024.09.17.613509. bioRxiv. 2024. PMID: 39345541 Free PMC article. Preprint. - Therapeutic modulation of ROCK overcomes metabolic adaptation of cancer cells to OXPHOS inhibition and drives synergistic anti-tumor activity.
Blazanin N, Liang X, Mahmud I, Kim E, Martinez S, Tan L, Chan W, Anvar NE, Ha MJ, Qudratullah M, Minelli R, Peoples M, Lorenzi P, Hart T, Lissanu Y. Blazanin N, et al. bioRxiv [Preprint]. 2024 Sep 20:2024.09.16.613317. doi: 10.1101/2024.09.16.613317. bioRxiv. 2024. PMID: 39345502 Free PMC article. Preprint.
References
- Paez JG, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500. - PubMed
- Stephens P, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature. 2004;431:525–526. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- U24 CA143882/CA/NCI NIH HHS/United States
- U24 CA143866/CA/NCI NIH HHS/United States
- U24 CA126551/CA/NCI NIH HHS/United States
- HHMI/Howard Hughes Medical Institute/United States
- U24 CA143843/CA/NCI NIH HHS/United States
- U24 CA126543/CA/NCI NIH HHS/United States
- U54 HG003079/HG/NHGRI NIH HHS/United States
- U24 CA143883/CA/NCI NIH HHS/United States
- U24 CA143867/CA/NCI NIH HHS/United States
- U24 CA126546/CA/NCI NIH HHS/United States
- UL1 TR000005/TR/NCATS NIH HHS/United States
- P30 CA016672/CA/NCI NIH HHS/United States
- U54 HG003067/HG/NHGRI NIH HHS/United States
- U24 CA143835/CA/NCI NIH HHS/United States
- K08 CA137153/CA/NCI NIH HHS/United States
- P30 CA006973/CA/NCI NIH HHS/United States
- U24 CA143845/CA/NCI NIH HHS/United States
- U24 CA143799/CA/NCI NIH HHS/United States
- T32 GM007753/GM/NIGMS NIH HHS/United States
- U54 HG003273/HG/NHGRI NIH HHS/United States
- P30 CA008748/CA/NCI NIH HHS/United States
- U24 CA144025/CA/NCI NIH HHS/United States
- U24 CA126554/CA/NCI NIH HHS/United States
- U24 CA180951/CA/NCI NIH HHS/United States
- U24 CA143840/CA/NCI NIH HHS/United States
- U24 CA126561/CA/NCI NIH HHS/United States
- U24 CA137153/CA/NCI NIH HHS/United States
- U24 CA143858/CA/NCI NIH HHS/United States
- P30 CA177558/CA/NCI NIH HHS/United States
- R01 HG006272/HG/NHGRI NIH HHS/United States
- U24 CA143848/CA/NCI NIH HHS/United States
- U24 CA126563/CA/NCI NIH HHS/United States
- U24 CA126544/CA/NCI NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous