Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing

Department of Medical Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA.
Cell (Impact Factor: 32.24). 09/2012; 150(6):1107-20. DOI: 10.1016/j.cell.2012.08.029
Source: PubMed


Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.

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Available from: Alice H Berger, Feb 20, 2014
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    • "IPA analysis was also used to determine significant mRNAs and miRNAs in the blood of all exposure groups that were identified in the literature (based upon the IPA Knowledge Base®) to be associated with lung diseases, including the IPA disease and functions idiopathic pulmonary fibrosis, inflammation of respiratory system, fibrosis of lung, lung cancer and non-small cell lung adenocarcinoma (Fig. 3). Five mRNAs and miRNAs, pdgfrb (FDA, 2013), miR- 18b-5p (Pandit et al., 2010), miR-19b-3p (Pandit et al., 2010), miR- 29b-3p (Pandit et al., 2010, 2011) and miR-27a (Oak et al., 2011), were associated with 'idiopathic pulmonary fibrosis'; six mRNAs and miRNAs, smad7 (Hanada and Yoshimura, 2002), pdgrfb (FDA, 2013), miR-18b-5p (Pandit et al., 2010), miR-19b-3p (Pandit et al., 2010), miR-29b-3p (Pandit et al., 2010, 2011) and miR-27a (Oak et al., 2011), were associated with 'inflammation of the respiratory system'; six mRNAs and miRNAs, pdgfrb (FDA, 2013), smad7 (Gressner et al., 2002; Nakao et al., 1999), miR-27a (Oak et al., 2011), miR-29b-3p (Pandit et al., 2010, 2011), miR-18b-5p (Pandit et al., 2010) and miR-19b-3p (Pandit et al., 2010), were associated with 'fibrosis of the lung'; 10 mRNAs and miRNAs, hpgd (NCI, 2007), pdgfrb (FDA, 2008), il7r (COSMIC, 2014a), krt6b (Imielinski et al., 2012; Savci-Heijink et al., 2009), scai (COSMIC, 2014b), miR- 497-5p (Bandi et al., 2009), miR-18b-5p (Hwang and Mendell, 2007), miR-19b-3p (Garofalo and Croce, 2011; Hwang and Mendell, 2007), miR-27b-3p (Wang et al., 2011) and miR-210-3p (Puissegur et al., 2011; Raponi et al., 2009; Redova et al., 2011; Seike et al., 2009), were associated with 'lung cancer'; and three mRNAs and miRNAs, scai (COSMIC, 2014b), krt6b (COSMIC, 2014a) and Figure 2. Regulatory networks between mRNAs and miRNAs. Regulatory networks between significant mRNAs [false discovery rate (FDR) 10%, fold change (FC) > 1.5] and miRNAs (FDR 10%, FC > 1.2) in the (A) methylcholanthrene (MCA) bronchiolo-alveolar adenoma, (B) multi-walled carbon nanotubes (MWCNT) hyperplasia and (C) MCA+MWCNT fibrosis categories were determined by using an Ingenuity Pathway Analysis (IPA) miRNA Target Filter. "
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    ABSTRACT: Inhalation exposure to multi-walled carbon nanotubes (MWCNT) in mice results in inflammation, fibrosis and the promotion of lung adenocarcinoma; however, the molecular basis behind these pathologies is unknown. This study determined global mRNA and miRNA profiles in whole blood from mice exposed by inhalation to MWCNT that correlated with the presence of lung hyperplasia, fibrosis, and bronchiolo-alveolar adenoma and adenocarcinoma. Six-week-old, male, B6C3F1 mice received a single intraperitoneal injection of either the DNA-damaging agent methylcholanthrene (MCA, 10 µg g(-1) body weight) or vehicle (corn oil). One week after injections, mice were exposed by inhalation to MWCNT (5 mg m(-3) , 5 hours per day, 5 days per week) or filtered air (control) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for the development of pathological changes in the lung, and whole blood was collected and analyzed using microarray analysis for global mRNA and miRNA expression. Numerous mRNAs and miRNAs in the blood were significantly up- or down-regulated in animals developing pathological changes in the lung after MCA/corn oil administration followed by MWCNT/air inhalation, including fcrl5 and miR-122-5p in the presence of hyperplasia, mthfd2 and miR-206-3p in the presence of fibrosis, fam178a and miR-130a-3p in the presence of bronchiolo-alveolar adenoma, and il7r and miR-210-3p in the presence of bronchiolo-alveolar adenocarcinoma, among others. The changes in miRNA and mRNA expression, and their respective regulatory networks, identified in this study may potentially serve as blood biomarkers for MWCNT-induced lung pathological changes. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Full-text · Article · Apr 2015 · Journal of Applied Toxicology
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    • "From a demographic perspective, data from these large cancer genomic studies are not always representative of the general population and can be skewed if recruitment of patients depends heavily on advanced-stage disease to ensure adequate tissue is available for testing. While some projects embedded in the International Cancer Genome Consortium and the Cancer Genome Atlas (TCGA; Wood et al, 2007; Hudson et al, 2010; Imielinski et al, 2012; Shah et al, 2012; Kandoth et al, 2013) have specifically selected primary, pre-treatment tumours, the individual institutions are usually large tertiary or quaternary centres rather than hospitals with a majority of samples from these studies being fresh-frozen rather than clinical samples. Consequently , it is unknown whether the mutational spectrum seen in these large-scale studies will be mirrored in the general population of cancer patients. "
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    ABSTRACT: Introduction: Recent discoveries in cancer research have revealed a plethora of clinically actionable mutations that provide therapeutic, prognostic and predictive benefit to patients. The feasibility of screening mutations as part of the routine clinical care of patients remains relatively unexplored as the demonstration of massively parallel sequencing (MPS) of tumours in the general population is required to assess its value towards the health-care system. Methods: Cancer 2015 study is a large-scale, prospective, multisite cohort of newly diagnosed cancer patients from Victoria, Australia with 1094 patients recruited. MPS was performed using the Illumina TruSeq Amplicon Cancer Panel. Results: Overall, 854 patients were successfully sequenced for 48 common cancer genes. Accurate determination of clinically relevant mutations was possible including in less characterised cancer types; however, technical limitations including formalin-induced sequencing artefacts were uncovered. Applying strict filtering criteria, clinically relevant mutations were identified in 63% of patients, with 26% of patients displaying a mutation with therapeutic implications. A subset of patients was validated for canonical mutations using the Agena Bioscience MassARRAY system with 100% concordance. Whereas the prevalence of mutations was consistent with other institutionally based series for some tumour streams (breast carcinoma and colorectal adenocarcinoma), others were different (lung adenocarcinoma and head and neck squamous cell carcinoma), which has significant implications for health economic modelling of particular targeted agents. Actionable mutations in tumours not usually thought to harbour such genetic changes were also identified. Conclusions: Reliable delivery of a diagnostic assay able to screen for a range of actionable mutations in this cohort was achieved, opening unexpected avenues for investigation and treatment of cancer patients.
    Full-text · Article · Mar 2015 · British Journal of Cancer
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    • "The eighty six translocations reported so far in adenocarcinomas of the lung greatly differ from that ones found in squamous cell carcinoma, or that ones found in small cell carcinoma. They are the following: t(X;X)(p22;q13) EDA/MID1 (Seo et al., 2012) t(X;1)(q23;q24) ACSL4/DCAF6 (Govindan et al., 2012) t(X;20)(p11;p12) SPTLC3/MAOA (Seo et al., 2012) t(1;1)(p36;p36) UBR4/ATP13A2 (Seo et al., 2012) t(1;1)(p36;p34) ARHGEF16/TCTEX1D4 (Seo et al., 2012) t(1;1)(p35;p35) SRSF4/SNRNP40 (Seo et al., 2012) t(1;1)(p34;p32) FGGY/TESK2 (Majewski et al., 2013) t(1;1)(p13;p12) IGSF3/MAN1A2 (Seo et al., 2012) t(1;1)(p13;p12) VANGL1/HAO2 (Govindan et al., 2012) t(1;1)(q24;q24) CD247/GPR161 (Imielinski et al., 2012) t(1;6)(p32;q14) ZFYVE9/CGA (Seo et al., 2012) t(1;6)(q21;q22) TPM3/ROS1 (Takeuchi et al., 2012) t(1;19)(q23;p13) TCF3/PBX1 (Mo et al., 2013) t(2;2)(p23;p22) STRN/ALK (Majewski et al., 2013) inv(2)(p21p23) del(2)(p21p23) EML4/ALK (Rikova et al., 2007; Choi et al., 2008; Koivunen et al., 2008; Majewski et al., 2013) t(2;2)(p22;p21) MAP4K3/PRKCE (Seo et al., 2012) t(2;2)(q21;q22) MGAT5/HNMT (Seo et al., 2012) "

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