Journal of Genetics and Genomics

Pathways towards Precision Medicine in Cancer Management Using Genomic Information

Jingwu Xie

2015, 42(10): 515-516. doi: 10.1016/j.jgg.2015.10.003

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Clonality: A New Marker for Gastric Cancer Survival

Fengju Song, Kexin Chen, Wei Zhang

2015, 42(10): 517-519. doi: 10.1016/j.jgg.2015.08.002

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Oncogenic Signaling Adaptor Proteins

Leo Y. Luo, William C. Hahn

2015, 42(10): 521-529. doi: 10.1016/j.jgg.2015.09.001

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Abstract:
Signal transduction pathways activated by receptor tyrosine kinases (RTK) play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we focus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes, CRKL, GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.

Integrate Omics Data and Molecular Dynamics Simulations toward Better Understanding of Human 14-3-3 Interactomes and Better Drugs for Cancer Therapy

JoAnne J. Babula, Jing-Yuan Liu

2015, 42(10): 531-547. doi: 10.1016/j.jgg.2015.09.002

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The 14-3-3 protein family is among the most extensively studied, yet still largely mysterious protein families in mammals to date. As they are well recognized for their roles in apoptosis, cell cycle regulation, and proliferation in healthy cells, aberrant 14-3-3 expression has unsurprisingly emerged as instrumental in the development of many cancers and in prognosis. Interestingly, while the seven known 14-3-3 isoforms in humans have many similar functions across cell types, evidence of isoform-specific functions and localization has been observed in both healthy and diseased cells. The strikingly high similarity among 14-3-3 isoforms has made it difficult to delineate isoform-specific functions and for isoform-specific targeting. Here, we review our knowledge of 14-3-3 interactome(s) generated by high-throughput techniques, bioinformatics, structural genomics and chemical genomics and point out that integrating the information with molecular dynamics (MD) simulations may bring us new opportunity to the design of isoform-specific inhibitors, which can not only be used as powerful research tools for delineating distinct interactomes of individual 14-3-3 isoforms, but also can serve as potential new anti-cancer drugs that selectively target aberrant 14-3-3 isoform.

Genetic Polymorphism, Telomere Biology and Non-Small Lung Cancer Risk

Rongrong Wei, Frank T. DeVilbiss, Wanqing Liu

2015, 42(10): 549-561. doi: 10.1016/j.jgg.2015.08.005

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Recent genome-wide association studies (GWAS) have identified a number of chromosomal regions associated with the risk of lung cancer. Of these regions, single-nucleotide polymorphisms (SNPs), especially rs2736100 located in the telomerase reverse transcriptase (TERT) gene show unique and significant association with non-small cell lung cancer (NSCLC) in a few subpopulations including women, nonsmokers, East Asians and those with adenocarcinoma. Recent studies have also linked rs2736100 with a longer telomere length and lung cancer risk. In this review, we seek to summarize the relationship between these factors and to further link the underlying telomere biology to lung cancer etiology. We conclude that genetic alleles combined with environmental (e.g., less-smoking) and physiological factors (gender and age) that confer longer telomere length are strong risk factors for NSCLC. This linkage may be particularly relevant in lung adenocarcinoma driven by epidermal growth factor receptor (EGFR) mutations, as these mutations have also been strongly linked to female gender, less-smoking history, adenocarcinoma histology and East Asian ethnicity. By establishing this connection, a strong argument is made for further investigating of the involvement of these entities during the tumorigenesis of NSCLC.

MicroRNA Signaling Pathway Network in Pancreatic Ductal Adenocarcinoma

Longhao Sun, Corrine Ying Xuan Chua, Weijun Tian, Zhixiang Zhang, Paul J. Chiao, Wei Zhang

2015, 42(10): 563-577. doi: 10.1016/j.jgg.2015.07.003

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Pancreatic ductal adenocarcinoma (PDAC) is considered to be the most lethal and aggressive malignancy with high mortality and poor prognosis. Their responses to current multimodal therapeutic regimens are limited. It is urgently needed to identify the molecular mechanism underlying pancreatic oncogenesis. Twelve core signaling cascades have been established critical in PDAC tumorigenesis by governing a wide variety of cellular processes. MicroRNAs (miRNAs) are aberrantly expressed in different types of tumors and play pivotal roles as post-transcriptional regulators of gene expression. Here, we will describe how miRNAs regulate different signaling pathways that contribute to pancreatic oncogenesis and progression.

Integrative Analyses of Lung Squamous Cell Carcinoma in Ten Chinese Patients with Transcriptome Sequencing

Lu-Lu Yang, Xu-Chao Zhang, Shao-Kun Chuai, Zhi-Hong Chen, Zhi Xie, Wei-Bang Guo, Shi-Liang Chen, Yuan-Yuan Lei, Long-Hua Guo, LanYing Gou, Hui-Wen Sun, Qi Zhang, Jin-Ji Yang, Hai-Yan Tu, Jian Su, Yi-Long Wu

2015, 42(10): 579-587. doi: 10.1016/j.jgg.2015.09.007

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Few effective therapies have been developed for the treatment of lung squamous cell carcinoma (SQCC), in part due to a lack of understanding regarding the mechanisms underlying the initiation and development of this disease. Whole transcriptome sequencing not only provides insight into the expression of all transcribed genes, but offers an efficient approach for identifying genetic variations, including gene fusions, mutations and alternative splicing. In this study, we performed whole transcriptome sequencing of 10 patients with stage IIIA lung SQCC, and discovered a large number of single nucleotide variants (SNVs; mean of 12.2 SNVs/Mb), with C>T/G>A and A>G/T>C transitions being the most frequently observed. Additionally, a total of 132 gene fusions were identified based upon TopHat alignments, 70.5% (93/132) of which occurred as a result of intra-chromosomal rearrangements. Based on the number of supporting reads for each fusion, we further validated 20 of the 26 top gene fusions by RT-PCR and Sanger sequencing. Taken together, these data provide an in-depth view of transcriptional alterations in lung SQCC patients, and may be useful for identification of new therapeutic targets.

Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development

Xiaoli Zhang, Nonggao He, Dongsheng Gu, Jeff Wickliffe, James Salazar, Istavan Boldogh, Jingwu Xie

2015, 42(10): 589-596. doi: 10.1016/j.jgg.2015.09.006

Abstract (79) HTML PDF (1)

Abstract:
Lung cancer causes more deaths than breast, colorectal and prostate cancers combined. Despite major advances in targeted therapy in a subset of lung adenocarcinomas, the overall 5-year survival rate for lung cancer worldwide has not significantly changed for the last few decades. DNA repair deficiency is known to contribute to lung cancer development. In fact, human polymorphisms in DNA repair genes such as xeroderma pigmentosum group C (XPC) are highly associated with lung cancer incidence. However, the direct genetic evidence for the role of XPC for lung cancer development is still lacking. Mutations of the Kirsten rat sarcoma viral oncogene homolog (Kras) or its downstream effector genes occur in almost all lung cancer cells, and there are a number of mouse models for lung cancer with these mutations. Using activated Kras, Kras, as a driver for lung cancer development in mice, we showed for the first time that mice with Kras and Xpc knockout had worst outcomes in lung cancer development, and this phenotype was associated with accumulated DNA damage. Using cultured cells, we demonstrated that induced expression of oncogenic KRAS^G12V led to increased levels of reactive oxygen species (ROS) as well as DNA damage, and both can be suppressed by anti-oxidants. Our results suggest that XPC may help repair DNA damage caused by KRAS-mediated production of ROS.

2015 Vol. 42, No. 10