Somatic mutations affect key pathways in lung adenocarcinoma

Li, Ding; Getz, Gad; Wheeler, David A.; Mardis, Elaine R.; McLellan, Michael D.; Cibulskis, Kristian; Sougnez, Carrie; Greulich, Heidi; Muzny, Donna M.; Morgan, Margaret; Fulton, Lucinda L.; Fulton, Robert S.; Zhang, Qunyuan; Wendl, Michael C.; Lawrence, Michael S.; Larson, David E.; Chen, Ken; Dooling, David J.; Sabo, Aniko; Hawes, Alicia; Shen, Hua; Jhangiani, Shalini N.; Lewis, Lora; Hall, Otis; Zhu, Yiping; Mathew, Tittu; Ren, Yanru; Yao, Jiqiang; Scherer, Steven E.; Clerc, Kerstin; Metcalf, Ginger; ng, B. D. J.; Milosavljevic, Aleksandar; Gonzalez-Garay, Manuel L.; Osborne, John R.; Meyer, Rick; Shi, Xiaoqi; Tang, Yuzhu; Koboldt, Daniel C.; Li, Gang; Abbott, Rachel M.; Miner, Tracie L.; Pohl, Craig; Fewell, Ginger A.; Haipek, Carrie A.; Schmidt, Heather; Dunford-Shore, Brian H.; Kraja, Aldi T.; Crosby, Seth D.; Sawyer, Christopher S.; Vickery, Tammi L.; Sander, Sacha N.; Robinson, Jody S.; Winckler, Wendy; Baldwin, Jennifer; Chirieac, Lucian R.; Dutt, Amit; Fennell, Tim; Hanna, Megan; Johnson, Bruce E.; Onofrio, Robert C.; Thomas, Roman K.; Tonon, Giovanni; Weir, Barbara A.; Zhao, Xiaojun; Ziaugra, Liuda; Zody, Michael C.; Giordano, Thomas J.; Orringer, Mark B.; Roth, Jack A.; Spitz, Margaret R.; Wistuba, Ignacio I.; Ozenberger, Bradley A.; Good, Peter J.; Chang, Andrew C.; Beer, David G.; Watson, Mark A.; Ladanyi, Marc; Broderick, Stephen; Yoshizawa, Akihiko; Travis, William D.; Pao, William; Province, Michael A.; Weinstock, George M.; Varmus, Harold; Gabriel, Stacey; Lander, Eric S.; Gibbs, Richard A.; Meyerson, Matthew; Wilson, Richard K.

doi:10.1038/nature07423

Cited by 2,421 publications

(2,182 citation statements)

References 48 publications

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“…Taken together, our data suggest that selective targeting of ErbB4 JM-a isoforms by mAb 1479 may suppress growth of other tumor types with demonstrated ErbB4 JM-a overexpression (Paatero and Elenius, 2008), or tumors with somatic ErbB4 mutations, such as lung cancer (Ding et al, 2008). The mechanism by which this antibody regulates cell behavior is dependent of ErbB4 JM-a expression by the target cell, and probably involves inhibition of ErbB4 phosphorylation and cleavage, as well as downregulation of the levels of functional cell-surface protein.…”

Section: Discussionmentioning

confidence: 62%

Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms

Hollmén

Määttä

Bald³

et al. 2009

Oncogene

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Section: Discussionmentioning

confidence: 62%

Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms

Hollmén

Määttä

Bald³

et al. 2009

Oncogene

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“…63 EGFR and KRAS mutations are rarely detected in the same tumor, suggesting that they may perform functionally equivalent roles in lung tumorigenesis. 205,206 KRAS mutation is a negative predictor of response to anti-EGFR monoclonal antibodies and is also an important mechanism of resistance to TKIs in lung adenocarcinomas. 55 A meta-analysis by Linardou et al 207 provided empirical evidence that somatic mutations of the KRAS oncogene are highly specific negative predictors of response to single-agent EGFR TKIs in advanced lung cancers, mostly adenocarcinomas.…”

Section: Kras Mutationsmentioning

confidence: 99%

“…215 BRAF mutations are found in 1-3% of lung cancers, most of which are adenocarcinomas. 206,212 BRAF mutations are found in a mutually exclusive pattern with KRAS mutations, suggesting that these genetic events activate a set of common downstream effectors of transformation. However, BRAF exon 15 mutations were tested on 96 paired samples of primary lung adenocarcinomas and corresponding locoregional lymph node metastases.…”

Section: Braf Mutationmentioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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“…According to the existing data, the probability of HER‐2 mutations is 1.67% in breast cancer, 1–4% in lung cancer and 2.9% in colorectal 6, 7, 8, 9, 10, 11, 12. Other human tumour types have also been reported to harbour HER‐2 mutations, including head and neck cancers, bladder cancers, gastric cancers, ovarian cancers, hepatic cancers 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21. Mutational activation of HER‐2 can result from three types of somatic molecular alterations: small insertions and missense mutations in the kinase domain, missense mutations in the extracellular domain, or large deletions of the extracellular domain which yield a truncated form of HER‐2 22, 23.…”

Section: Introductionmentioning

confidence: 99%

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Sun

Shi

Shen

et al. 2015

J Cellular Molecular Medi

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Studies over the last two decades have identified that amplified human epidermal growth factor receptor (HER‐2; c‐erbB‐2, neu) and its overexpression have been frequently implicated in the carcinogenesis and prognosis in a variety of solid tumours, especially breast cancer. Lots of painstaking efforts were invested on the HER‐2 targeted agents, and significantly improved outcome and prolonged the survival of patients. However, some patients classified as ‘HER‐2‐positive’ would be still resistant to the anti‐HER‐2 therapy. Various mechanisms of drug resistance have been illustrated and the alteration of HER‐2 was considered as a crucial mechanism. However, systematic researches in regard to the HER‐2 mutations and variants are still inadequate. Notably, the alterations of HER‐2 play an important role in drug resistance, but also have a potential association with the cancer risk. In this review, we summarize the possible mutations and focus on HER‐2 variants’ role in breast cancer tumourigenesis. Additionally, the alteration of HER‐2, as a potential mechanism of resistance to trastuzumab, is discussed here. We hope that HER‐2 related activating mutations could potentially offer more therapeutic opportunities to a broader range of patients than previously classified as HER‐2 overexpressed.

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Somatic mutations affect key pathways in lung adenocarcinoma

Cited by 2,421 publications

References 48 publications

Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms

Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms

Molecular pathology of lung cancer: key to personalized medicine

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

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