Oncogenic Signaling Pathways in The Cancer Genome Atlas

Sanchez‐Vega, Francisco; Mina, Marco; Armenia, Joshua; Chatila, Walid K.; Luna, Augustin; La, Konnor; Dimitriadoy, Sofia; Liu, David L.; Kantheti, Havish S.; Saghafinia, Sadegh; Chakravarty, Debyani; Daian, Foysal; Gao, Qingsong; Bailey, Matthew H.; Liang, Wen-Wei; Foltz, Steven M.; Shmulevich, Ilya; Li, Ding; Heins, Zachary J.; Ochoa, Angelica; Groß, Benjamin; Gao, Jianjiong; Zhang, Hongxin; Kundra, Ritika; Kandoth, Cyriac; Bahceci, Istemi; Dervishi, Leonard; Doğrusöz, Uğur; Zhou, Wanding; Shen, Hui; Laird, Peter W.; Way, Gregory P.; Greene, Casey S.; Liang, Han; Xiao, Yonghong; Wang, Linghua; Iavarone, Antonio; Berger, Alice H.; Bivona, Trever G.; Lazar, Alexander J.; Hammer, Gary D.; Giordano, Thomas J.; Kwong, Lawrence N.; McArthur, Grant A.; Huang, Chenfei; Tward, Aaron D.; Frederick, Mitchell J.; McCormick, Frank; Meyerson, Matthew; Allen, Eliezer M. Van; Cherniack, Andrew D.; Ciriello, Giovanni; Sander, Chris; Schultz, Nikolaus

doi:10.1016/j.cell.2018.03.035

Cited by 2,414 publications

(2,136 citation statements)

References 79 publications

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“…TCGA considered different types of genomic alterations (mutations, copy‐number changes, mRNA expression, gene fusions and DNA methylation), whereas in our study we only had mutations, which might cause some bias in frequency estimation. For all cancer types analyzed in TCGA, the RTK–RAS (also called RTK/RAS/MAP‐Kinase) pathway had the highest median frequency of alterations (46% of samples altered) . In our penile cancer sample, the RTK–RAS pathway was ranked in the second highest place, with an alteration rate of 26.7%.…”

Section: Discussionmentioning

confidence: 99%

“…The frequently mutated genes (>10%) in these pathways were proven to be expressed in penile tumors. Targeting these pathways might provide therapeutic opportunities for this malignancy . Many pathway‐targeting efforts have been made, and some attempts have proven to be effective in treating other types of cancers …”

Section: Discussionmentioning

confidence: 99%

“…Somatic alteration characterization for the 10 oncogenic signaling pathways derived from TCGA PanCancer Atlas was accessed through the PathwayMapper tool (http://pathwaymapper.org/). Enrichment analysis was performed through The Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8 .…”

Section: Methodsmentioning

confidence: 99%

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Mutational landscape of penile squamous cell carcinoma in a Chinese population

Wang

Chen

et al. 2019

Intl Journal of Cancer

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Penile squamous cell carcinoma (PSCC) is a malignancy that affects the skin and tissues of the penis, but the knowledge of pathogenesis and carcinogenesis is limited. Here, we characterize the PSCC genomic landscape using whole‐exome sequencing. Of the 30 paired blood and tumor samples, we identified recurrent mutations in 11 genes; confirmed previous findings for FAT1 (4/30), HRAS (4/30), NOTCH1 (4/30), TP53 (3/30) and PIK3CA (3/30); and revealed novel candidate driver genes [CASP8 (4/30), SLITRK2 (3/30), FLG (3/30) and TRRAP (3/30)]. Our in vitro experiments suggested CASP8 was involved in mediating TRAIL‐induced apoptosis of penile cancer cell lines. We also observed the frequently altered pathways for potential therapeutic implications: alterations in the Notch (30% of sample altered), RTK–RAS (26.7% altered) and Hippo (23.3% altered) pathways accounted for over 50% of tumors. The frequently altered genes (>10%) in these pathways were proved to be expressed in penile tumors by immunohistochemistry assay. These findings provide new insight into the mutational and pathway landscapes of PSCC and suggest potential novel therapeutic opportunities for this malignancy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mutational landscape of penile squamous cell carcinoma in a Chinese population

Wang

Chen

et al. 2019

Intl Journal of Cancer

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“…42,43 In mammals, four types of Notch receptors (Notch1-4) have been described. 42,43 In mammals, four types of Notch receptors (Notch1-4) have been described.…”

Section: Discussionmentioning

confidence: 99%

Hypomethylation‐mediated activation of cancer/testis antigen KK‐LC‐1 facilitates hepatocellular carcinoma progression through activating the Notch1/Hes1 signalling

Chen

Zuo

et al. 2019

Cell Proliferation

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Objectives: Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a cancer/testis antigen reactivated in several human malignancies. So far, the major focus of studies on KK-LC-1 has been on its potential as diagnostic biomarker and immunotherapy target.However, its biological functions and molecular mechanisms in cancer progression remain unknown. Materials and Methods: Expression of KK-LC-1 in HCC was analysed using RT-qPCR,Western blot and immunohistochemistry. The roles of KK-LC-1 on HCC progression were examined by loss-of-function and gain-of-function approaches. Pathway inhibitor DAPT was employed to confirm the regulatory effect of KK-LC-1 on the downstream Notch signalling. The interaction of KK-LC-1 with presenilin-1 was determined by co-immunoprecipitation. The association of CpG island methylation status with KK-LC-1 reactivation was evaluated by methylation-specific PCR, bisulphite sequencing PCR and 5-Aza-dC treatment. Results:We identified that HCC tissues exhibited increased levels of KK-LC-1. High KK-LC-1 level independently predicted poor survival outcome. KK-LC-1 promoted cell growth, migration, invasion and epithelial-mesenchymal transition in vitro and in vivo.KK-LC-1 modulated the Notch1/Hes1 pathway to exacerbate HCC progression through physically interacting with presenilin-1. Upregulation of KK-LC-1 in HCC was attributed to hypomethylated CpG islands.

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“…Indeed, activating mutations of components of the ERK1/2 cascade (Raf, MEK, ERK1/2) and their immediate upstream activator Ras are the cause of 35–40% of all cancer types [86], and are responsible for more than 10% of all cancer cases [87]. MEK mutations are found only in a few cancers [88-90] and are responsible for ∼1% of cases, while ERK1/2 mutations are rare [91, 92].…”

Section: Mapk Cascades In Diseasementioning

confidence: 99%

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

et al. 2018

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The mitogen-activated protein kinase (MAPK) cascades are central signaling pathways that play a central role in the regulation of most stimulated cellular processes including proliferation, differentiation, stress response and apoptosis. Currently 4 such cascades are known, each termed by its downstream MAPK components: the extracellular signal-regulated kinase 1/2 (ERK1/2), cJun-N-terminal kinase (JNK), p38 and ERK5. One of the hallmarks of these cascades is the stimulated nuclear translocation of their MAPK components using distinct mechanisms. ERK1/2 are shuttled into the nucleus by importin7, JNK and p38 by a dimer of importin3 with either importin9 or importin7, and ERK5 by importin-α/β. Dysregulation of these cascades often results in diseases, including cancer and inflammation, as well as developmental and neurological disorders. Much effort has been invested over the years in developing inhibitors to the MAPK cascades to combat these diseases. Although some inhibitors are already in clinical use or clinical trials, their effects are hampered by development of resistance or adverse side-effects. Recently, our group developed 2 myristoylated peptides: EPE peptide, which inhibits the interaction of ERK1/2 with importin7, and PERY peptide, which prevents JNK/p38 interaction with either importin7 or importin9. These peptides block the nuclear translocation of their corresponding kinases, resulting in prevention of several cancers, while the PERY peptide also inhibits inflammation-induced diseases. These peptides provide a proof of concept for the use of the nuclear translocation of MAPKs as therapeutic targets for cancer and/or inflammation.

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Oncogenic Signaling Pathways in The Cancer Genome Atlas

Cited by 2,414 publications

References 79 publications

Mutational landscape of penile squamous cell carcinoma in a Chinese population

Mutational landscape of penile squamous cell carcinoma in a Chinese population

Hypomethylation‐mediated activation of cancer/testis antigen KK‐LC‐1 facilitates hepatocellular carcinoma progression through activating the Notch1/Hes1 signalling

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

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