Dataset Information

Frequent alterations in cytoskeleton remodeling genes in primary and metastatic Chinese lung adenocarcinomas

ABSTRACT: The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.

PROVIDER: EGAS00001000982 | EGA |

REPOSITORIES: EGA

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Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas.

Wu Kui K Zhang Xin X Li Fuqiang F Xiao Dakai D Hou Yong Y Zhu Shida S Liu Dongbing D Ye Xiaofei X Ye Mingzhi M Yang Jie J Shao Libin L Pan Hui H Lu Na N Yu Yuan Y Liu Liping L Li Jin J Huang Liyan L Tang Hailing H Deng Qiuhua Q Zheng Yue Y Peng Lihua L Liu Geng G Gu Xia X He Ping P Gu Yingying Y Lin Weixuan W He Huiming H Xie Guoyun G Liang Han H An Na N Wang Hui H Teixeira Manuel M Vieira Joana J Liang Wenhua W Zhao Xin X Peng Zhiyu Z Mu Feng F Zhang Xiuqing X Xu Xun X Yang Huanming H Kristiansen Karsten K Wang Jian J Zhong Nanshan N Wang Jun J Pan-Hammarström Qiang Q He Jianxing J

Nature communications 20151209

The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched i ...[more]

PMID: 26647728

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Project description:Despite the high prevalence and poor outcome of patients with metastatic lung cancer, the mechanisms of tumour progression and metastasis remain largely uncharacterized. We modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS1 and inactivation of the p53-pathway2, using conditional alleles in mice3-5. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of KrasLSL-G12D/+;p53flox/flox mice initiates lung adenocarcinoma development4. Although tumours are initiated synchronously by defined genetic alterations, only a subset become malignant, suggesting that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK-2 related homeobox transcription factor Nkx2-1 (Ttf-1/Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1-negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1 regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically-restricted chromatin regulator Hmga2. While focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function6-9, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability, and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor. 23 cell lines derived from primary tumor or metastasis. 6 samples analyzed to determine the effect of Nkx2-1 knockdown on gene expression

Dataset Information

Frequent alterations in cytoskeleton remodeling genes in primary and metastatic Chinese lung adenocarcinomas

Publications

Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas.

Similar Datasets

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