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Comprehensive molecular profiling of lung adenocarcinoma.

- Nature (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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Pathway alterations in lung adenocarcinomaa, 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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Figure 4: Pathway alterations in lung adenocarcinomaa, 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.

Mentions: 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%).


Comprehensive molecular profiling of lung adenocarcinoma.

- Nature (2014)

Pathway alterations in lung adenocarcinomaa, 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231481&req=5

Figure 4: Pathway alterations in lung adenocarcinomaa, 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.
Mentions: 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%).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

Show MeSH
Related in: MedlinePlus