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Co-mutation plot from whole exome sequencing of 230 lung adenocarcinomas.
TGCA, Nature, 2014. Comprehensive molecular profiling of lung adenocarcinoma. |
Genomics of Lung and Other Cancers
Altering the kinome.
Despite improvements in prevention, early detection, and therapy in the last two decades, lung cancer remains the leading cause of human cancer death. In our endeavor to unravel the mysteries of the lung cancer genome, we are working to develop a complete map of lung cancer genome alterations, with special focus on those affecting key pathways. The early recognition that kinase inhibitors will be critical for treating human cancer focused our initial lung cancer research efforts on identifying mutations in protein kinase genes, beginning with the discovery of somatic BRAF mutations in lung adenocarcinoma (Naoki, et al., 2002). Working with colleagues at DFCI, we were the first to identify activating mutations in EGFR (Paez, et al., 2004) in lung cancer and to correlate these alterations with patient response to the kinase targeting drug, gefitinib. In the years since, we have discovered numerous such recurrent alterations in kinase genes in lung cancer, e.g. FGFR2 and FGFR3 (Liao, et al., 2013) and DDR2 in squamous cell lung carcinoma (Hammerman, et al, 2011), and RAF1 (Imielinski, et al., 2014) in lung adenocarcinoma.
Beyond the kinome.
We have identified multiple genes subject to recurrent driver mutations in lung adenocarcinoma, including the U2AF1 splicing factor gene and the putative splicing factor, BRM10 in lung adenocarcinoma (Imielinski, et al., 2012). Through our studies of lung cancer genomes as part of The Cancer Genome Atlas, we discovered loss of function mutations in the HLA-A gene in squamous cell lung carcinoma (TCGA, 2012) and in the MGA tumor suppressor gene in the MYC pathway in lung adenocarcinoma (TCGA, 2014), among others.
To identify additional mutations that play a key role in NSCLC, we conducted the most comprehensive genomic analysis to date of non-small cell lung cancer exomes, studying mutations in over 1000 cases mostly from TCGA. These analyses revealed new mutated driver genes, including mutations in PPP3CA, DOT1L, and FTSJD1/CMTR2 in lung adenocarcinomas, RASA1 in squamous cell carcinomas, and KLF5, EP300, and CREBBP in both lung cancer subtypes (Campbell, et al., 2016).
Recently, we have reported super-enhancer amplifications targeting MYC in lung adenocarcinoma and other cancer types (Zhang, et al., 2016) as well as KLF5 in lung squamous cancer and other cancer types (Zhang, et al., 2018). We have also discovered somatic hotspot indels in non-coding regions of lineage-defining genes in cancer, such as surfactant protein genes in lung cancers (Imielinski, et al., 2017).
Finally, our report on MET exon 14 splice mutations in lung adenocarcinoma (TCGA, 2014) and follow-up collaborative studies (Lu, et al., 2017) have helped stimulate multiple studies showing responses to small molecular Met inhibitors (Frampton, et al., 2015).
Despite improvements in prevention, early detection, and therapy in the last two decades, lung cancer remains the leading cause of human cancer death. In our endeavor to unravel the mysteries of the lung cancer genome, we are working to develop a complete map of lung cancer genome alterations, with special focus on those affecting key pathways. The early recognition that kinase inhibitors will be critical for treating human cancer focused our initial lung cancer research efforts on identifying mutations in protein kinase genes, beginning with the discovery of somatic BRAF mutations in lung adenocarcinoma (Naoki, et al., 2002). Working with colleagues at DFCI, we were the first to identify activating mutations in EGFR (Paez, et al., 2004) in lung cancer and to correlate these alterations with patient response to the kinase targeting drug, gefitinib. In the years since, we have discovered numerous such recurrent alterations in kinase genes in lung cancer, e.g. FGFR2 and FGFR3 (Liao, et al., 2013) and DDR2 in squamous cell lung carcinoma (Hammerman, et al, 2011), and RAF1 (Imielinski, et al., 2014) in lung adenocarcinoma.
Beyond the kinome.
We have identified multiple genes subject to recurrent driver mutations in lung adenocarcinoma, including the U2AF1 splicing factor gene and the putative splicing factor, BRM10 in lung adenocarcinoma (Imielinski, et al., 2012). Through our studies of lung cancer genomes as part of The Cancer Genome Atlas, we discovered loss of function mutations in the HLA-A gene in squamous cell lung carcinoma (TCGA, 2012) and in the MGA tumor suppressor gene in the MYC pathway in lung adenocarcinoma (TCGA, 2014), among others.
To identify additional mutations that play a key role in NSCLC, we conducted the most comprehensive genomic analysis to date of non-small cell lung cancer exomes, studying mutations in over 1000 cases mostly from TCGA. These analyses revealed new mutated driver genes, including mutations in PPP3CA, DOT1L, and FTSJD1/CMTR2 in lung adenocarcinomas, RASA1 in squamous cell carcinomas, and KLF5, EP300, and CREBBP in both lung cancer subtypes (Campbell, et al., 2016).
Recently, we have reported super-enhancer amplifications targeting MYC in lung adenocarcinoma and other cancer types (Zhang, et al., 2016) as well as KLF5 in lung squamous cancer and other cancer types (Zhang, et al., 2018). We have also discovered somatic hotspot indels in non-coding regions of lineage-defining genes in cancer, such as surfactant protein genes in lung cancers (Imielinski, et al., 2017).
Finally, our report on MET exon 14 splice mutations in lung adenocarcinoma (TCGA, 2014) and follow-up collaborative studies (Lu, et al., 2017) have helped stimulate multiple studies showing responses to small molecular Met inhibitors (Frampton, et al., 2015).