Comprehensive molecular profiling of lung adenocarcinoma (original) (raw)

Main

Lung cancer is the most common cause of global cancer-related mortality, leading to over a million deaths each year and adenocarcinoma is its most common histological type. Smoking is the major cause of lung adenocarcinoma but, as smoking rates decrease, proportionally more cases occur in never-smokers (defined as less than 100 cigarettes in a lifetime). Recently, molecularly targeted therapies have dramatically improved treatment for patients whose tumours harbour somatically activated oncogenes such as mutant EGFR1 or translocated ALK, RET, or ROS1 (refs 2, 3, 4). Mutant BRAF and ERBB2 (ref. 5) are also investigational targets. However, most lung adenocarcinomas either lack an identifiable driver oncogene, or harbour mutations in KRAS and are therefore still treated with conventional chemotherapy. Tumour suppressor gene abnormalities, such as those in TP53 (ref. 6), STK11 (ref. 7), CDKN2A8, KEAP1 (ref. 9), and SMARCA4 (ref. 10) are also common but are not currently clinically actionable. Finally, lung adenocarcinoma shows high rates of somatic mutation and genomic rearrangement, challenging identification of all but the most frequent driver gene alterations because of a large burden of passenger events per tumour genome11,12,13. Our efforts focused on comprehensive, multiplatform analysis of lung adenocarcinoma, with attention towards pathobiology and clinically actionable events.

Clinical samples and histopathologic data

We analysed tumour and matched normal material from 230 previously untreated lung adenocarcinoma patients who provided informed consent (Supplementary Table 1). All major histologic types of lung adenocarcinoma were represented: 5% lepidic, 33% acinar, 9% papillary, 14% micropapillary, 25% solid, 4% invasive mucinous, 0.4% colloid and 8% unclassifiable adenocarcinoma (Supplementary Fig. 1)14. Median follow-up was 19 months, and 163 patients were alive at the time of last follow-up. Eighty-one percent of patients reported past or present smoking. Supplementary Table 2 summarizes demographics. DNA, RNA and protein were extracted from specimens and quality-control assessments were performed as described previously15. Supplementary Table 3 summarizes molecular estimates of tumour cellularity16.

Somatically acquired DNA alterations

We performed whole-exome sequencing (WES) on tumour and germline DNA, with a mean coverage of 97.6× and 95.8×, respectively, as performed previously17. The mean somatic mutation rate across the TCGA cohort was 8.87 mutations per megabase (Mb) of DNA (range: 0.5–48, median: 5.78). The non-synonymous mutation rate was 6.86 per Mb. MutSig2CV18 identified significantly mutated genes among our 230 cases along with 182 similarly-sequenced, previously reported lung adenocarcinomas12. Analysis of these 412 tumour/normal pairs highlighted 18 statistically significant mutated genes (Fig. 1a shows co-mutation plot of TCGA samples (n = 230), Supplementary Fig. 2 shows co-mutation plot of all samples used in the statistical analysis (n = 412) and Supplementary Table 4 contains complete MutSig2CV results, which also appear on the TCGA Data Portal along with many associated data files (https://tcga-data.nci.nih.gov/docs/publications/luad_2014/). TP53 was commonly mutated (46%). Mutations in KRAS (33%) were mutually exclusive with those in EGFR (14%). BRAF was also commonly mutated (10%), as were PIK3CA (7%), MET (7%) and the small GTPase gene, RIT1 (2%). Mutations in tumour suppressor genes including STK11 (17%), KEAP1 (17%), NF1 (11%), RB1 (4%) and CDKN2A (4%) were observed. Mutations in chromatin modifying genes SETD2 (9%), ARID1A (7%) and SMARCA4 (6%) and the RNA splicing genes RBM10 (8%) and U2AF1 (3%) were also common. Recurrent mutations in the MGA gene (which encodes a Max-interacting protein on the MYC pathway19) occurred in 8% of samples. Loss-of-function (frameshift and nonsense) mutations in MGA were mutually exclusive with focal MYC amplification (Fisher’s exact test P = 0.04), suggesting a hitherto unappreciated potential mechanism of MYC pathway activation. Coding single nucleotide variants and indel variants were verified by resequencing at a rate of 99% and 100%, respectively (Supplementary Fig. 3a, Supplementary Table 5). Tumour purity was not associated with the presence of false negatives identified in the validation data (P = 0.31; Supplementary Fig. 3b).

Figure 1: Somatic mutations in lung adenocarcinoma.

figure 1

a, Co-mutation plot from whole exome sequencing of 230 lung adenocarcinomas. Data from TCGA samples were combined with previously published data12 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.

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Past or present smoking associated with cytosine to adenine (C >A) nucleotide transversions as previously described both in individual genes and genome-wide12,13. C > A nucleotide transversion fraction showed two peaks; this fraction correlated with total mutation count (_R_2 = 0.30) and inversely correlated with cytosine to thymine (C > T) transition frequency (_R_2 = 0.75) (Supplementary Fig. 4). We classified each sample (Supplementary Methods) into one of two groups named transversion-high (TH, n = 269), and transversion-low (TL, n = 144). The transversion-high group was strongly associated with past or present smoking (P < 2.2 × 10−16), consistent with previous reports13. The transversion-high and transversion-low patient cohorts harboured different gene mutations. Whereas KRAS mutations were significantly enriched in the transversion-high cohort (P = 2.1 × 10−13), EGFR mutations were significantly enriched in the transversion-low group (P = 3.3 × 10−6). PIK3CA and RB1 mutations were likewise enriched in transversion-low tumours (P < 0.05). Additionally, the transversion-low tumours were specifically enriched for in-frame insertions in EGFR and ERBB2 (ref. 5) and for frameshift indels in RB1 (Fig. 1b). RB1 is commonly mutated in small-cell lung carcinoma (SCLC). We found RB1 mutations in transversion-low adenocarcinomas were enriched for frameshift indels versus single nucleotide substitutions compared to SCLC (P < 0.05)20,21 suggesting a mutational mechanism in transversion-low adenocarcinoma that is probably distinct from smoking in SCLC.

Gender is correlated with mutation patterns in lung adenocarcinoma22. Only a fraction of significantly mutated genes from the complete set reported in this study (Fig. 1a) were enriched in men or women (Fig. 1c). EGFR mutations were enriched in tumours from the female cohort (P = 0.03) whereas loss-of-function mutations within RBM10, an RNA-binding protein located on the X chromosome23 were enriched in tumours from men (P = 0.002). When examining the transversion-high group, 16 out of 21 RBM10 mutations were observed in males (P = 0.003, Fisher’s exact test).

Somatic copy number alterations were very similar to those previously reported for lung adenocarcinoma24 (Supplementary Fig. 5, Supplementary Table 6). Significant amplifications included NKX2-1, TERT, MDM2, KRAS, EGFR, MET, CCNE1, CCND1, TERC and MECOM (Supplementary Table 6), as previously described24, 8q24 near MYC, and a novel peak containing CCND3 (Supplementary Table 6). The CDKN2A locus was the most significant deletion (Supplementary Table 6). Supplementary Table 7 summarizes molecular and clinical characteristics by sample. Low-pass whole-genome sequencing on a subset (n = 93) of the samples revealed an average of 36 gene–gene and gene–inter-gene rearrangements per tumour. Chromothripsis25 occurred in six of the 93 samples (6%) (Supplementary Fig. 6, Supplementary Table 8). Low-pass whole genome sequencing-detected rearrangements appear in Supplementary Table 9.

Description of aberrant RNA transcripts

Gene fusions, splice site mutations or mutations in genes encoding splicing factors promote or sustain the malignant phenotype by generating aberrant RNA transcripts. Combining DNA with mRNA sequencing enabled us to catalogue aberrant RNA transcripts and, in many cases, to identify the DNA-encoded mechanism for the aberration. Seventy-five per cent of somatic mutations identified by WES were present in the RNA transcriptome when the locus in question was expressed (minimum 5×) (Supplementary Fig. 7a) similar to prior analyses15. Previously identified fusions involving ALK (3/230 cases), ROS1 (4/230) and RET (2/230) (Fig. 2a, Supplementary Table 10), all occurred in transversion-low tumours (P = 1.85 × 10−4, Fisher’s exact test).

Figure 2: Aberrant RNA transcripts in lung adenocarcinoma associated with somatic DNA translocation or mutation.

figure 2

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).

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MET activation can occur by exon 14 skipping, which results in a stabilized protein26. Ten tumours had somatic MET DNA alterations with MET exon 14 skipping in RNA. In nine of these samples, a 5′ or 3′ splice site mutation or deletion was identified27. MET exon 14 skipping was also found in the setting of a MET Y1003* stop codon mutation (Fig. 2b, Supplementary Fig. 8a). The codon affected by the Y1003* mutation is predicted to disrupt multiple splicing enhancer sequences, but the mechanism of skipping remains unknown in this case.

S34F mutations in U2AF1 have recently been reported in lung adenocarcinoma12 but their contribution to oncogenesis remains unknown. Eight samples harboured _U2AF1_S34F. We identified 129 splicing events strongly associated with _U2AF1_S34F mutation, consistent with the role of U2AF1 in 3′-splice site selection28. Cassette exons and alternative 3′ splice sites were most commonly affected (Fig. 2c, Supplementary Table 11)29. Among these events, alternative splicing of the CTNNB1 proto-oncogene was strongly associated with U2AF1 mutations (Supplementary Fig. 8b). Thus, concurrent analysis of DNA and RNA enabled delineation of both cis and trans mechanisms governing RNA processing in lung adenocarcinoma.

Candidate driver genes

The receptor tyrosine kinase (RTK)/RAS/RAF pathway is frequently mutated in lung adenocarcinoma. Striking therapeutic responses are often achieved when mutant pathway components are successfully inhibited. Sixty-two per cent (143/230) of tumours harboured known activating mutations in known driver oncogenes, as defined by others30. Cancer-associated mutations in KRAS (32%, n = 74), EGFR (11%, n = 26) and BRAF (7%, n = 16) were common. Additional, previously uncharacterized KRAS, EGFR and BRAF mutations were observed, but were not classified as driver oncogenes for the purposes of our analyses (see Supplementary Fig. 9a for depiction of all mutations of known and unknown significance); explaining the differing mutation frequencies in each gene between this analysis and the overall mutational analysis described above. We also identified known activating ERBB2 in-frame insertion and point mutations (n = 5)6, as well as mutations in MAP2K1 (n = 2), NRAS and HRAS (n = 1 each). RNA sequencing revealed the aforementioned MET exon 14 skipping (n = 10) and fusions involving ROS1 (n = 4), ALK (n = 3) and RET (n = 2). We considered these tumours collectively as oncogene-positive, as they harboured a known activating RTK/RAS/RAF pathway somatic event. DNA amplification events were not considered to be driver events before the comparisons described below.

We sought to nominate previously unrecognized genomic events that might activate this critical pathway in the 38% of samples without a RTK/RAS/RAF oncogene mutation. Tumour cellularity did not differ between oncogene-negative and oncogene-positive samples (Supplementary Fig. 9b). Analysis of copy number alterations using GISTIC31 identified unique focal ERBB2 and MET amplifications in the oncogene-negative subset (Fig. 3a, Supplementary Table 6); amplifications in other wild-type proto-oncogenes, including KRAS and EGFR, were not significantly different between the two groups.

Figure 3: Identification of novel candidate driver genes.

figure 3

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.

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We next analysed WES data independently in the oncogene-negative and oncogene-positive subsets. We found that TP53, KEAP1, NF1 and RIT1 mutations were significantly enriched in oncogene-negative tumours (P < 0.01; Fig. 3b, Supplementary Table 12). NF1 mutations have previously been reported in lung adenocarcinoma11, but this is the first study, to our knowledge, capable of identifying all classes of loss-of-function NF1 defects and to statistically demonstrate that NF1 mutations, as well as KEAP1 and TP53 mutations are enriched in the oncogene-negative subset of lung adenocarcinomas (Fig. 3c). All RIT1 mutations occurred in the oncogene-negative subset and clustered around residue Q79 (homologous to Q61 in the switch II region of RAS genes). These mutations transform NIH3T3 cells and activate MAPK and PI(3)K signalling[32](/articles/nature13385#ref-CR32 "Berger, A. H. et al. Oncogenic RIT1 mutations in lung adenocarcinoma. Oncogene http://dx.doi.org/10.1038/onc.2013.581

             (2014)"), supporting a driver role for mutant _RIT1_ in 2% of lung adenocarcinomas. This analysis increases the rate at which putative somatic lung adenocarcinoma driver events can be identified within the RTK/RAS/RAF pathway to 76% ([Fig. 3d](/articles/nature13385#Fig3)).

Recurrent alterations in key pathways

Recurrent aberrations in multiple key pathways and processes characterize lung adenocarcinoma (Fig. 4a). Among these were RTK/RAS/RAF pathway activation (76% of cases), PI(3)K-mTOR pathway activation (25%), p53 pathway alteration (63%), alteration of cell cycle regulators (64%, Supplementary Fig. 10), alteration of oxidative stress pathways (22%, Supplementary Fig. 11), and mutation of various chromatin and RNA splicing factors (49%).

Figure 4: Pathway alterations in lung adenocarcinoma.

figure 4

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.

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We then examined the phenotypic sequelae of some key genomic events in the tumours in which they occurred. Reverse-phase protein arrays provided proteomic and phosphoproteomic phenotypic evidence of pathway activity. Antibodies on this platform are listed in Supplementary Table 13. This analysis suggested that DNA sequencing did not identify all samples with phosphoprotein evidence of activation of a given signalling pathway. For example, whereas _KRAS_-mutant lung adenocarcinomas had higher levels of phosphorylated MAPK than KRAS wild-type tumours had on average, many KRAS wild-type tumours displayed significant MAPK pathway activation (Fig. 4b, Supplementary Fig. 10). The multiple mechanisms by which lung adenocarcinomas achieve MAPK activation suggest additional, still undetected RTK/RAS/RAF pathway alterations. Similarly, we found significant activation of mTOR and its effectors (p70S6kinase, S6, 4E-BP1) in a substantial fraction of the tumours (Fig. 4c). Analysis of mutations in PIK3CA and STK11, STK11 protein levels, and AMPK and AKT phosphorylation33 led to the identification of three major mTOR patterns in lung adenocarcinoma: (1) tumours with minimal or basal mTOR pathway activation, (2) tumours showing higher mTOR activity accompanied by either _STK11_-inactivating mutation or combined low STK11 expression and low AMPK activation and (3) tumours showing high mTOR activity accompanied by either phosphorylated AKT activation, PIK3CA mutation, or both. As with MAPK, many tumours lack an obvious underlying genomic alteration to explain their apparent mTOR activation.

Molecular subtypes of lung adenocarcinoma

Broad transcriptional and epigenetic profiling can reveal downstream consequences of driver mutations, provide clinically relevant classification and offer insight into tumours lacking clear drivers. Prior unsupervised analyses of lung adenocarcinoma gene expression have used varying nomenclature for transcriptional subtypes of the disease34,35,36,37. To coordinate naming of the transcriptional subtypes with the histopathological38, anatomic and mutational classifications of lung adenocarcinoma, we propose an updated nomenclature: the terminal respiratory unit (TRU, formerly bronchioid), the proximal-inflammatory (PI, formerly squamoid), and the proximal-proliferative (PP, formerly magnoid)39 transcriptional subtypes (Fig. 5a). Previously reported associations of expression signatures with pathways and clinical outcomes34,36,39 were observed (Supplementary Fig. 7b) and integration with multi-analyte data revealed statistically significant genomic alterations associated with these transcriptional subtypes. The PP subtype was enriched for mutation of KRAS, along with inactivation of the STK11 tumour suppressor gene by chromosomal loss, inactivating mutation, and reduced gene expression. In contrast, the PI subtype was characterized by solid histopathology and co-mutation of NF1 and TP53. Finally, the TRU subtype harboured the majority of the _EGFR_-mutated tumours as well as the kinase fusion expressing tumours. TRU subtype membership was prognostically favourable, as seen previously34 (Supplementary Fig. 7c). Finally, the subtypes exhibited different mutation rates, transition frequencies, genomic ploidy profiles, patterns of large-scale aberration, and differed in their association with smoking history (Fig. 5a). Unsupervised clustering of miRNA sequencing-derived or reverse phase protein array (RPPA)-derived data also revealed significant heterogeneity, partially overlapping with the mRNA-based subtypes, as demonstrated in Supplementary Figs 12 and 13.

Figure 5: Integrative analysis.

figure 5

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.

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Mutations in chromatin-modifying genes (for example, SMARCA4, ARID1A and SETD2) suggest a major role for chromatin maintenance in lung adenocarcinoma. To examine chromatin states in an unbiased manner, we selected the most variable DNA methylation-specific probes in CpG island promoter regions and clustered them by methylation intensity (Supplementary Table 14). This analysis divided samples into two distinct subsets: a significantly altered CpG island methylator phenotype-high (CIMP-H(igh)) cluster and a more normal-like CIMP-L(ow) group, with a third set of samples occupying an intermediate level of methylation at CIMP sites (Fig. 5b). Our results confirm a prior report40 and provide additional insights into this epigenetic program. CIMP-H tumours often showed DNA hypermethylation of several key genes: CDKN2A, GATA2, GATA4, GATA5, HIC1, HOXA9, HOXD13, RASSF1, SFRP1, SOX17 and WIF1 among others (Supplementary Fig. 14). WNT pathway genes are significantly over-represented in this list (P value = 0.0015) suggesting that this is a key pathway with an important driving role within this subtype. MYC overexpression was significantly associated with the CIMP-H phenotype as well (P = 0.003).

Although we did not find significant correlations between global DNA methylation patterns and individual mutations in chromatin remodelling genes, there was an intriguing association between SETD2 mutation and CDKN2A methylation. Tumours with low CDKN2A expression due to methylation (rather than due to mutation or deletion) had lower ploidy, fewer overall mutations (Fig. 5c) and were significantly enriched for SETD2 mutation, suggesting an important role for this chromatin-modifying gene in the development of certain tumours.

Integrative clustering41 of copy number, DNA methylation and mRNA expression data found six clusters (Fig. 5c). Tumour ploidy and mutation rate are higher in clusters 1–3 than in clusters 4–6. Clusters 1–3 frequently harbour TP53 mutations and are enriched for the two proximal transcriptional subtypes. Fisher’s combined probability tests revealed significant copy number associated gene expression changes on 3q in cluster one, 8q in cluster two, and chromosome 7 and 15q in cluster three (Supplementary Fig. 15). The low ploidy and low mutation rate clusters four and five contain many TRU samples, whereas tumours in cluster 6 have comparatively lower tumour cellularity, and few other distinguishing molecular features. Significant copy number-associated gene expression changes are observed on 6q in cluster four and 19p in cluster five. The CIMP-H tumours divided into a high ploidy, high mutation rate, proximal-inflammatory CIMP-H group (cluster 3) and a low ploidy, low mutation rate, TRU-associated CIMP-H group (cluster 4), suggesting that the CIMP phenotype in lung adenocarcinoma can occur in markedly different genomic and transcriptional contexts. Furthermore, cluster four is enriched for CDKN2A methylation and SETD2 mutations, suggesting an interaction between somatic mutation of SETD2 and deregulated chromatin maintenance in this subtype. Finally, cluster membership was significantly associated with mutations in TP53, EGFR and STK11 (Supplementary Fig. 15, Supplementary Table 6).

Conclusions

We assessed the mutation profiles, structural rearrangements, copy number alterations, DNA methylation, mRNA, miRNA and protein expression of 230 lung adenocarcinomas. In recent years, the treatment of lung adenocarcinoma has been advanced by the development of multiple therapies targeted against alterations in the RTK/RAS/RAF pathway. We nominate amplifications in MET and ERBB2 as well as mutations of NF1 and RIT1 as driver events specifically in otherwise oncogene-negative lung adenocarcinomas. This analysis increases the fraction of lung adenocarcinoma cases with somatic evidence of RTK/RAS/RAF activation from 62% to 76%. While all lung adenocarcinomas may activate this pathway by some mechanism, only a subset show tonic pathway activation at the protein level, suggesting both diversity between tumours with seemingly similar activating events and as yet undescribed mechanisms of pathway activation. Therefore, the current study expands the range of possible targetable alterations within the RTK/RAS/RAF pathway in general and suggests increased implementation of MET and ERBB2/HER2 inhibitors in particular. Our discovery of inactivating mutations of MGA further underscores the importance of the MYC pathway in lung adenocarcinoma.

This study further implicates both chromatin modifications and splicing alterations in lung adenocarcinoma through the integration of DNA, transcriptome and methylome analysis. We identified alternative splicing due to both splicing factor mutations in trans and mutation of splice sites in cis, the latter leading to activation of the MET gene by exon 14 skipping. Cluster analysis separated tumours based on single-gene driver events as well as large-scale aberrations, emphasizing lung adenocarcinoma’s molecular heterogeneity and combinatorial alterations, including the identification of coincident SETD2 mutations and CDKN2A methylation in a subset of CIMP-H tumours, providing evidence of a somatic event associated with a genome-wide methylation phenotype. These studies provide new knowledge by illuminating modes of genomic alteration, highlighting previously unappreciated altered genes, and enabling further refinement in sub-classification for the improved personalization of treatment for this deadly disease.

Methods Summary

All specimens were obtained from patients with appropriate consent from the relevant institutional review board. DNA and RNA were collected from samples using the Allprep kit (Qiagen). We used standard approaches for capture and sequencing of exomes from tumour DNA and normal DNA15 and whole-genome shotgun sequencing. Significantly mutated genes were identified by comparing them with expectation models based on the exact measured rates of specific sequence lesions42. GISTIC analysis of the circular-binary-segmented Affymetrix SNP 6.0 copy number data was used to identify recurrent amplification and deletion peaks31. Consensus clustering approaches were used to analyse mRNA, miRNA and methylation subtypes using previous approaches15. The publication web page is (https://tcga-data.nci.nih.gov/docs/publications/luad_2014/). Sequence files are in CGHub (https://cghub.ucsc.edu/).

Change history

In Supplementary Table 7 of this Article, the iCLUSTER output column contained incorrect cluster labels. This table has been corrected online. Corrected online 08 October 2014 - The surname of author Kristen Rodgers was misspelled 'Rogers'. This has been corrected online

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Acknowledgements

This study was supported by NIH grants: U24 CA126561, U24 CA126551, U24 CA126554, U24 CA126543, U24 CA126546, U24 CA137153, U24 CA126563, U24 CA126544, U24 CA143845, U24 CA143858, U24 CA144025, U24 CA143882, U24 CA143866, U24 CA143867, U24 CA143848, U24 CA143840, U24 CA143835, U24 CA143799, U24 CA143883, U24 CA143843, U54 HG003067, U54 HG003079 and U54 HG003273. We thank K. Guebert and L. Gaffney for assistance and C. Gunter for review.

Author information

Authors and Affiliations

  1. University of California San Francisco, San Francisco, 94158, California, USA
    Eric A. Collisson & Barry S. Taylor
  2. The Eli and Edythe L. Broad Institute, Cambridge, 02142, Massachusetts, USA
    Joshua D. Campbell, Angela N. Brooks, Alice H. Berger, Juliann Chmielecki, Gad Getz, Peter S. Hammerman, Bryan Hernandez, Carrie Sougnez, Andrew D. Cherniack, Mara Rosenberg, Matthew Meyerson, Mara Rosenberg, Stacey B. Gabriel, Kristian Cibulskis, Carrie Sougnez, Jaegil Kim, Chip Stewart, Lee Lichtenstein, Eric S. Lander, Michael S. Lawrence, Gad Getz, Joshua D. Campbell, Angela N. Brooks, Juliann Chmielecki, Marcin Imielinski, Robert C. Onofrio, Travis Zack, Carrie Sougnez, Elena Helman, Chandra Sekhar Pedamallu, Jill Mesirov, Andrew D. Cherniack, Gordon Saksena, Steven E. Schumacher, Scott L. Carter, Bryan Hernandez, Levi Garraway, Rameen Beroukhim, Stacey B. Gabriel, Gad Getz, Matthew Meyerson, Mara Rosenberg, Juok Cho, Daniel DiCara, David Heiman, Pei Lin, William Mallard, Douglas Voet, Hailei Zhang, Lihua Zou, Michael S. Noble, Michael S. Lawrence, Gordon Saksena, Nils Gehlenborg, Helga Thorvaldsdottir, Jill Mesirov, Marc-Danie Nazaire, Jim Robinson & Gad Getz
  3. Dana Farber Cancer Institute, Boston, 02115, Massachusetts, USA
    Angela N. Brooks, Matthew Meyerson, Angela N. Brooks, Levi Garraway, Rameen Beroukhim & Matthew Meyerson
  4. Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USA
    William Lee, Marc Ladanyi, Nikolaus Schultz, Ronglai Shen, William D. Travis, William Lee, B. Arman Aksoy, Giovanni Ciriello, Gideon Dresdner, Jianjiong Gao, Benjamin Gross, Venkatraman E. Seshan, Marc Ladanyi, Boris Reva, Rileen Sinha, S. Onur Sumer, Nils Weinhold, Nikolaus Schultz, Ronglai Shen, Chris Sander, William D. Travis, Natasha Rekhtman, Maureen Zakowski, Valerie W. Rusch, William D. Travis & Natasha Rekhtman
  5. University of Michigan, Ann Arbor, Michigan 48109, USA.,
    David G. Beer
  6. Johns Hopkins University, Baltimore, 21287, Maryland, USA
    Leslie Cope, Ludmila Danilova, James G. Herman, Stephen B. Baylin, Leslie Cope, Ludmila Danilova, Stephen B. Baylin, Peter Illei, Edward Gabrielson, James Shin, Beverly Lee, Kristen Rodgers, Dante Trusty, Malcolm V. Brock & Peter Illei
  7. Baylor College of Medicine, Houston, 77030, Texas, USA
    Chad J. Creighton, Chad J. Creighton & David Wheeler
  8. Washington University, St. Louis, 63108, Missouri, USA
    Li Ding, Ramaswamy Govindan, Cyriac Kandoth, Robert Fulton, Lucinda L. Fulton, Michael D. McLellan, Richard K. Wilson, Kai Ye, Catrina C. Fronick, Christopher A. Maher, Christopher A. Miller, Michael C. Wendl, Christopher Cabanski, Li Ding, Elaine Mardis, Ramaswamy Govindan, Mark A. Watson, Sandra McDonald & Bryan Meyers
  9. Harvard Medical School, Boston, 02115, Massachusetts, USA
    Gad Getz, Raju Kucherlapati, Angela Hadjipanayis, Gad Getz, Marcin Imielinski, Eran Hodis, Levi Garraway, Rameen Beroukhim, Gad Getz, Matthew Meyerson, Angela Hadjipanayis, Semin Lee, Angeliki Pantazi, Xiaojia Ren, Lixing Yang, Peng-Chieh Chen, Michael Parfenov, Andrew Wei Xu, Netty Santoso, Peter J. Park, Raju Kucherlapati & Gad Getz
  10. Massachusetts General Hospital, Boston, 02114, Massachusetts, USA
    Gad Getz, Gad Getz, Marcin Imielinski, Gad Getz & Gad Getz
  11. University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA
    D. Neil Hayes, Matthew D. Wilkerson, Katherine A. Hoadley, J. Todd Auman, Shaowu Meng, Yan Shi, Elizabeth Buda, Scot Waring, Umadevi Veluvolu, Donghui Tan, Piotr A. Mieczkowski, Corbin D. Jones, Janae V. Simons, Matthew G. Soloway, Tom Bodenheimer, Stuart R. Jefferys, Jeffrey Roach, Alan P. Hoyle, Junyuan Wu, Saianand Balu, Darshan Singh, Jan F. Prins, J.S. Marron, Joel S. Parker, D. Neil Hayes, Charles M. Perou, Matthew D. Wilkerson, Joel S. Parker, Katherine A. Hoadley, Patrick K. Kimes, D. Neil Hayes, Charles M. Perou, Mei Huang, Leigh B. Thorne, Lori Boice, Ashley Hill Salazar, William K. Funkhouser, W. Kimryn Rathmell & William K. Funkhouser
  12. University of Texas MD Anderson Cancer Center, Houston, 77054, Texas, USA
    John V. Heymach, Rileen Sinha, John N. Weinstein, Lauren Averett Byers, Robert A. Holt, Harshad S. Mahadeshwar, Alexei Protopopov, Sahil Seth, Xingzhi Song, Jiabin Tang, Jianhua Zhang, Lynda Chin, Lynda Chin, Jianhua Zhang, Bradley M. Broom, Jing Wang, Yiling Lu, Patrick Kwok Shing Ng, Lixia Diao, Lauren Averett Byers, Wenbin Liu, John V. Heymach, Christopher I. Amos, John N. Weinstein, Rehan Akbani, Gordon B. Mills & Richard Hajek
  13. Princess Margaret Cancer Centre, Toronto, Ontario M5G 2M9, Canada.,
    Igor Jurisica, Ming-Sound Tsao & Ming-Sound Tsao
  14. Brigham and Women’s Hospital Boston, 02115, Massachusetts, USA
    David Kwiatkowski, Angela Hadjipanayis, Semin Lee, Angeliki Pantazi, Michael Parfenov, Andrew Wei Xu, Netty Santoso, Peter J. Park, Raju Kucherlapati & William G. Richards
  15. BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.,
    Gordon Robertson, Andy Chu, Miruna Balasundaram, Yaron S. N. Butterfield, Rebecca Carlsen, Andy Chu, Eric Chuah, Noreen Dhalla, Ranabir Guin, Carrie Hirst, Darlene Lee, Haiyan I. Li, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Richard Varhol, A. Gordon Robertson, Natasja Wye, Nina Thiessen, Steven J. M. Jones & Marco A. Marra
  16. Mayo Clinic, Rochester, 55905, Minnesota, USA
    Dennis A. Wigle, Dennis A. Wigle, Michael K. Asiedu & Farhad Kosari
  17. University of Southern California, Los Angeles, 90033, California, USA
    Daniel J. Weisenberger, Peter W. Laird, Daniel J. Weisenberger, Dennis T. Maglinte, Philip H. Lai, Moiz S. Bootwalla, David J. Van Den Berg, Timothy Triche Jr & Peter W. Laird
  18. University of California Santa Cruz, Santa Cruz, 95064, California, USA
    Amie Radenbaugh, Singer Ma, Joshua M. Stuart, Sam Ng, Singer Ma, Jingchun Zhu, Amie Radenbaugh, Joshua M. Stuart & David Haussler
  19. Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA
    Eric S. Lander
  20. University of Kentucky, Lexington, 40515, Kentucky, USA
    Jinze Liu
  21. Buck Institute for Age Research, Novato, 94945, California, USA
    Christopher C. Benz & Christina Yau
  22. Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, 95064, California, USA
    David Haussler
  23. Oregon Health and Science University, Portland, 97239, Oregon, USA
    Paul T. Spellman
  24. International Genomics Consortium, Phoenix, 85004, Arizona, USA
    Erin Curley, Joseph Paulauskis, Kevin Lau, Scott Morris, Troy Shelton, David Mallery, Johanna Gardner & Robert Penny
  25. Analytical Biological Services, Inc., Wilmington, 19801, Delaware, USA
    Charles Saller & Katherine Tarvin
  26. University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA
    Robert Cerfolio & Ayesha Bryant
  27. Cleveland Clinic, Cleveland, 44195, Ohio, USA
    Daniel P. Raymond, Nathan A. Pennell, Carol Farver & Carol Farver
  28. Christiana Care, Newark, 19713, Delaware, USA
    Christine Czerwinski, Lori Huelsenbeck-Dill, Mary Iacocca, Nicholas Petrelli, Brenda Rabeno, Jennifer Brown & Thomas Bauer
  29. Cureline, Inc., South San Francisco, 94080, California, USA
    Oleg Dolzhanskiy, Olga Potapova, Daniil Rotin, Olga Voronina, Elena Nemirovich-Danchenko & Konstantin V. Fedosenko
  30. Emory University, Atlanta, 30322, Georgia, USA
    Anthony Gal, Madhusmita Behera, Suresh S. Ramalingam, Gabriel Sica & Gabriel Sica
  31. Fox Chase Cancer Center, Philadelphia, 19111, Philadelphia, USA
    Douglas Flieder, Jeff Boyd & JoEllen Weaver
  32. ILSbio, Chestertown, 21620, Maryland, USA
    Bernard Kohl & Dang Huy Quoc Thinh
  33. Indiana University School of Medicine, Indianapolis, 46202, Indiana, USA
    George Sandusky
  34. Individumed, Silver Spring, 20910, Maryland, USA
    Hartmut Juhl
  35. The Prince Charles Hospital and the University of Queensland Thoracic Research Center, Brisbane, 4032, Australia.,
    Edwina Duhig, Belinda Clarke, Ian A. Yang, Kwun M. Fong, Lindy Hunter, Morgan Windsor, Rayleen V. Bowman, Belinda Clarke & Edwina Duhig
  36. Sullivan Nicolaides Pathology & John Flynn Hospital, Tugun 4680, Australia.,
    Edwina Duhig & Edwina Duhig
  37. Lahey Hospital and Medical Center, Burlington, 01805, Massachusetts, USA
    Christina Williamson, Eric Burks, Kimberly Rieger-Christ, Antonia Holway & Travis Sullivan
  38. NYU Langone Medical Center, New York, 10016, New York, USA
    Paul Zippile, James Suh, Harvey Pass, Chandra Goparaju, Yvonne Owusu-Sarpong & James Suh
  39. Ontario Tumour Bank, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.,
    John M. S. Bartlett, Sugy Kodeeswaran, Jeremy Parfitt, Harmanjatinder Sekhon & Monique Albert
  40. Penrose St. Francis Health Services, Colorado Springs, 80907, Colorado, USA
    John Eckman & Jerome B. Myers
  41. Roswell Park Cancer Center, Buffalo, 14263, New York, USA
    Richard Cheney, Carl Morrison, Carmelo Gaudioso & Richard Cheney
  42. Rush University Medical Center, Chicago, 60612, Illinois, USA
    Jeffrey A. Borgia, Philip Bonomi, Mark Pool & Michael J. Liptay
  43. St. Petersburg Academic University, St Petersburg 199034, Russia.,
    Fedor Moiseenko & Irina Zaytseva
  44. Thoraxklinik am Universitätsklinikum Heidelberg, 69126 Heidelberg, Germany.,
    Hendrik Dienemann, Michael Meister & Thomas R. Muley
  45. University Heidelberg, 69120 Heidelberg, Germany.,
    Philipp A. Schnabel
  46. University of Cologne, 50931 Cologne, Germany.,
    Martin Peifer
  47. University of Miami, Sylvester Comprehensive Cancer Center, Miami, 33136, Florida, USA
    Carmen Gomez-Fernandez, Lynn Herbert & Sophie Egea
  48. University of Pittsburgh, Pittsburgh, 15213, Pennsylvania, USA
    Rajiv Dhir, Samuel A. Yousem, Sanja Dacic, Frank Schneider, Jill M. Siegfried & Sanja Dacic
  49. Center Hospitalier Universitaire Vaudois, Lausanne and European Thoracic Oncology Platform, CH-1011 Lausanne, Switzerland.,
    Solange Peters & Igor Letovanec
  50. Ziauddin University Hospital, Karachi, 75300, Pakistan.,
    Khurram Z. Khan
  51. SRA International, Inc., Fairfax, 22033, Virginia, USA
    Mark A. Jensen, Eric E. Snyder, Deepak Srinivasan, Ari B. Kahn, Julien Baboud & David A. Pot
  52. National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Kenna R. Mills Shaw, Margi Sheth, Tanja Davidsen, John A. Demchok, Liming Yang, Zhining Wang, Roy Tarnuzzer & Jean Claude Zenklusen
  53. National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Bradley A. Ozenberger & Heidi J. Sofia

Consortia

The Cancer Genome Atlas Research Network

Contributions

The Cancer Genome Atlas Research Network contributed collectively to this study. Biospecimens were provided by the tissue source sites and processed by the biospecimen core resource. Data generation and analyses were performed by the genome sequencing centres, cancer genome characterization centres and genome data analysis centres. All data were released through the data coordinating centre. The National Cancer Institute and National Human Genome Research Institute project teams coordinated project activities. We also acknowledge the following TCGA investigators who made substantial contributions to the project: E. A. Collisson (manuscript coordinator); J. D. Campbell, J. Chmielecki, (analysis coordinators); C. Sougnez (data coordinator); J. D. Campbell, M. Rosenberg, W. Lee, J. Chmielecki, M. Ladanyi, and G. Getz (DNA sequence analysis); M. D. Wilkerson, A. N. Brooks, and D. N. Hayes (mRNA sequence analysis); L. Danilova and L. Cope (DNA methylation analysis); A. D. Cherniack (copy number analysis); M. D. Wilkerson and A. Hadjipanayis (translocations); N. Schultz, W. Lee, E. A. Collisson, A. H. Berger, J. Chmielecki, C. J. Creighton, L. A. Byers and M. Ladanyi (pathway analysis); A. Chu and A. G. Robertson (miRNA sequence analysis); W. Travis and D. A. Wigle (pathology and clinical expertise); L. A. Byers and G. B. Mills (reverse phase protein arrays); S. B. Baylin, R. Govindan and M. Meyerson (project chairs).

Corresponding authors

Correspondence toMatthew Meyerson or Matthew Meyerson.

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Competing interests

The author declare no competing financial interests.

Additional information

The primary and processed data used to generate the analyses presented here can be downloaded by registered users from The Cancer Genome Atlas at (https://tcga-data.nci.nih.gov/tcga/tcgaDownload.jsp). All of the primary sequence files are deposited in cgHub and all other data are deposited at the Data Coordinating Center (DCC) for public access (http://cancergenome.nih.gov/), (https://cghub.ucsc.edu/) and (https://tcga-data.nci.nih.gov/docs/publications/luad_2014/).

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Supplementary Information

This file contains Supplementary Methods and Results, Supplementary Figures 1-15 and additional references – see separate excel for Supplementary Tables 1-14). (PDF 12490 kb)

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This file contains Supplementary Tables 1-14 (XLSX 3072 kb)

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The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma.Nature 511, 543–550 (2014). https://doi.org/10.1038/nature13385

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