Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway

Li, Maolan; Zhang, Zhou; Li, Xiaoguang; Ye, Junyi; Wu, Xiangsong; Tan, Zhen; Liu, Chang; Shen, Baiyong; Wang, Xuan; Wu, Wenzhi; Zhou, Daizhan; Zhang, Di; Wang, Ting; Liu, Bingya; Qu, Kai; Ding, Qichen; Weng, Hao; Ding, Qi; Mu, Jian; Shu, Yijun; Bao, Runfa; Yang, Cao; Chen, Peizhan; Li, Tianyu; Jiang, Lin; Hu, Yunping; Dong, Ping; Gu, Jun; Lü, Wei; Shi, Wei; Lu, Jianhua; Gong, Weiwei; Tang, Zhaohui; Zhang, Yong; Wang, Xuefeng; Chin, Y. Eugene; Weng, Xiaoling; Zhang, Hong; Tang, Wei; Zheng, Yonglan; He, Lin; Wang, Hui; Liu, Yun; Liu, Yingbin

doi:10.1038/ng.3030

Cited by 346 publications

(384 citation statements)

References 32 publications

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“…Notably, the present study revealed relatively high frequency (22.2%) of PIK3CA mutations in Japanese BTCs, compared with previous reports (15,16,18,23,36,37,(39)(40)(41). In Caucasian BTC, the frequencies of PIK3CA mutation are limited (16,23,36,37).…”

Section: Discussioncontrasting

confidence: 76%

Genetic alterations in Japanese extrahepatic biliary tract cancer

et al. 2017

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Section: Discussioncontrasting

confidence: 76%

Genetic alterations in Japanese extrahepatic biliary tract cancer

et al. 2017

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“…To further understand the somatic mutation spectrum in GBC, Li et al performed a combined WES and ultra-deep sequencing of 57 tumornormal pairs of pathologically confirmed cases of GBC (31). Their sequencing efforts revealed TP53 and KRAS as being recurrently mutated, with mutation rates of 47.1% and 7.8% respectively.…”

Section: Gbcmentioning

confidence: 99%

Molecular landscape and sub-classification of gastrointestinal cancers: a review of literature

Fakhri¹,

Lim²

2017

J. Gastrointest. Oncol.

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Abstract:The historical approach of diagnosing cancer types based entirely on anatomic origin and histologic features, and the "one-size-fit-all" therapeutic approach, are inadequate in modern cancer treatment. From decades of research we now know that cancer is a highly heterogeneous disease driven by complex genetic or epigenetic alterations. The advent of various high throughput molecular tools has now enabled us to view and sub-classify each cancer type based on their distinct molecular features, in addition to histologic classification, with the promise of individualized treatment strategies tailored towards each specific subtype to improve patient outcomes. In this review, we have made an effort to systematically review the most up-to-date, leading literature in molecular analysis and/or subtyping of major gastrointestinal cancers. These include esophageal squamous cell carcinoma (ESCC), gastric cancer (GC) adenocarcinoma, pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), gallbladder cancer (GBC), and colorectal cancer (CRC). For each cancer type we summarized the global mutational landscape, subgroup classification based on genomics, epigenetics, gene expression and/or proteomic analysis, and their salient clinicopathological features. We have highlighted the actionable mutations or mutational pathways that could help guide targeted therapies in the future.

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“…These include activating mutations in PIK3CA (4–7%) (Nakamura et al ., 2015; Riener et al ., 2008), inactivating mutations in PIK3R1 (4%), TSC1 (3%), TSC2 (1%) and amplifications in AKT3 (3%) (Nakamura et al ., 2015). Finally, 5–30% of BTCs harbour mutations, amplifications and fusions in receptor tyrosine kinases of the Erb and FGFR families, and c‐MET (Hezel et al ., 2010; Li et al ., 2014; Nakamura et al ., 2015; Voss et al ., 2013), which can all activate signalling through the PI3K/AKT/mTOR pathway.…”

Section: Introductionmentioning

confidence: 99%

K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

et al. 2017

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Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signalling pathway is hyperactivated in a subset of BTCs, and clinical activity of the mTOR inhibitor everolimus has been observed in some patients with BTC. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways. K‐Ras mutations and/or amplifications were identified in 45% of cell lines and were associated with resistance to everolimus. Activating mutations in PIK3CA or loss of PTEN was not predictive of everolimus response; however, high basal levels of pAKT were associated with sensitivity, independent of Ras/MAPK pathway activation status. Notably, everolimus inhibited mTOR signalling to a similar extent in sensitive and resistant cell lines, suggesting that relative dependence on the mTOR pathway rather than the magnitude of pathway inhibition determines everolimus response. Consistent with the known limitations of rapalogs, everolimus induced feedback‐mediated activation of AKT in BTC cell lines, which could be overcome by cotreatment with an AKT inhibitor or ATP‐competitive mTORC1/mTORC2 inhibitors. However, both approaches failed to induce greater apoptosis compared to everolimus, and mTORC1/mTORC2 kinase inhibitors induced compensatory activation of pERK, identifying an inherent limitation of these agents in BTC cell lines. These findings suggest that future trials of everolimus in BTC would benefit from preselecting patients based on their K‐Ras and PI3K/mTOR pathway activation status. The study also identifies strategies for enhancing inhibition of the PI3K/mTOR pathway in BTC cell lines.

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Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway

Cited by 346 publications

References 32 publications

Genetic alterations in Japanese extrahepatic biliary tract cancer

Genetic alterations in Japanese extrahepatic biliary tract cancer

Molecular landscape and sub-classification of gastrointestinal cancers: a review of literature

K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

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