Integrative Genomic Characterization of Oral Squamous Cell Carcinoma Identifies Frequent Somatic Drivers
Curtis R. Pickering,Jiexin Zhang,Suk Young Yoo,Linnea Bengtsson,Shhyam Moorthy,David M. Neskey,Mei Zhao,Marcus V. Ortega Alves,Kyle Chang,Jennifer Drummond,Elsa Cortez,Tong Xin Xie,Di Zhang,Woonbok Chung,Jean Pierre J. Issa,Patrick A. Zweidler-McKay,Xifeng Wu,Adel K. El-Naggar,John N. Weinstein,Jing Wang,Donna M. Muzny,Richard A. Gibbs,Richard A. Gibbs,David A. Wheeler,Jeffrey N. Myers,Mitchell J. Frederick +25 more
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TLDR
Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating subset of head and neck cancers.Abstract:
The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we performed comprehensive genomic analysis of gene expression, copy number, methylation and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of CASP8 defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating disease.read more
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Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974
Jun Liu,Shifeng Pan,Mindy H. Hsieh,Nicholas Ng,Fangxian Sun,Tao Wang,Shailaja Kasibhatla,Alwin Schuller,Allen G. Li,Dai Cheng,Jie Li,Celin Tompkins,Anne Marie Pferdekamper,Auzon Steffy,Jane Cheng,Colleen Kowal,Van Phung,Gui-Rong Guo,Yan Wang,Martin P. Graham,Shannon Flynn,J. Chad Brenner,Chun Li,M. Cristina Villarroel,Peter G. Schultz,Xu Wu,Peter McNamara,William R. Sellers,Lilli Petruzzelli,Anthony Boral,H. Martin Seidel,Margaret E. McLaughlin,Jianwei Che,Thomas E. Carey,Gary J. Vanasse,Jennifer L. Harris +35 more
TL;DR: LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV–Wnt1 and a human head and neck squamous cell carcinoma model (HN30).
Journal ArticleDOI
Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas
Tanguy Y. Seiwert,Zhixiang Zuo,Michaela K. Keck,Arun Khattri,Chandra Sekhar Pedamallu,Thomas Stricker,Christopher D. Brown,Trevor J. Pugh,Trevor J. Pugh,Petar Stojanov,Juok Cho,Michael S. Lawrence,Gad Getz,Johannes Brägelmann,Rebecca DeBoer,Ralph R. Weichselbaum,Alexander Langerman,Louis G. Portugal,Elizabeth A. Blair,Kerstin M. Stenson,Mark W. Lingen,Ezra E.W. Cohen,Everett E. Vokes,Kevin P. White,Peter S. Hammerman,Peter S. Hammerman +25 more
TL;DR: The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes, includingtargetable genomic alterations in FGFR1, DDR2, EGFR, FGFR2/3, EPHA2, and PIK3CA.
Journal ArticleDOI
Mutational Landscape of Aggressive Cutaneous Squamous Cell Carcinoma
Curtis R. Pickering,Jane H. Zhou,J. Jack Lee,Jennifer Drummond,S. Andrew Peng,Rami E. Saade,Kenneth Y. Tsai,Jonathan L. Curry,Michael T. Tetzlaff,Stephen Y. Lai,Jun Yu,Donna M. Muzny,Harshavardhan Doddapaneni,Eve Shinbrot,Kyle R. Covington,Jianhua Zhang,Sahil Seth,Carlos Caulin,Gary L. Clayman,Adel K. El-Naggar,Richard A. Gibbs,Randal S. Weber,Jeffrey N. Myers,David A. Wheeler,Mitchell J. Frederick +24 more
TL;DR: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes, which improve the foundation for understanding this disease and should aid in identifying and treating aggressive cS CC.
Journal ArticleDOI
Therapeutic modulation of Notch signalling — are we there yet?
Emma R. Andersson,Urban Lendahl +1 more
TL;DR: This Review focuses on aspects of the Notch signalling pathway that are amenable to therapeutic intervention, diseases that could be targeted and the various Notch pathway modulation strategies that are currently being explored.
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From Fly Wings to Targeted Cancer Therapies: A Centennial for Notch Signaling
TL;DR: The protumorigenic and tumor-suppressive functions of Notch signaling are discussed, and the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors are dissected.
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TL;DR: Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
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Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the Head and Neck
James A. Bonner,Paul M. Harari,Jordi Giralt,Nozar Azarnia,Dong M. Shin,Roger B. Cohen,Christopher U. Jones,Ranjan Sur,David Raben,Jacek Jassem,Roger Ove,Merrill S. Kies,José Baselga,Hagop Youssoufian,Nadia Amellal,Eric K. Rowinsky,Eric K. Rowinsky,K. Kian Ang +17 more
TL;DR: Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoreGional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head andneck.
Journal ArticleDOI
Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia
Andrew P. Weng,Andrew P. Weng,Adolfo A. Ferrando,Adolfo A. Ferrando,Woojoong Lee,Woojoong Lee,John P. Morris,John P. Morris,Lewis B. Silverman,Lewis B. Silverman,Cheryll Sanchez-Irizarry,Cheryll Sanchez-Irizarry,Stephen C. Blacklow,Stephen C. Blacklow,A. Thomas Look,A. Thomas Look,Jon C. Aster,Jon C. Aster +17 more
TL;DR: These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.
Journal ArticleDOI
Somatic mutations affect key pathways in lung adenocarcinoma
Li Ding,Gad Getz,David A. Wheeler,Elaine R. Mardis,Michael D. McLellan,Kristian Cibulskis,Carrie Sougnez,Heidi Greulich,Heidi Greulich,Donna M. Muzny,Margaret Morgan,Lucinda Fulton,Robert S. Fulton,Qunyuan Zhang,Michael C. Wendl,Michael S. Lawrence,David E. Larson,Ken Chen,David J. Dooling,Aniko Sabo,Alicia Hawes,Hua Shen,Shalini N. Jhangiani,Lora Lewis,Otis Hall,Yiming Zhu,Tittu Mathew,Yanru Ren,Jiqiang Yao,Steven E. Scherer,Kerstin Clerc,Ginger A. Metcalf,Brian Ng,Aleksandar Milosavljevic,Manuel L. Gonzalez-Garay,John R. Osborne,Rick Meyer,Xiaoqi Shi,Yuzhu Tang,Daniel C. Koboldt,Ling Lin,Rachel Abbott,Tracie L. Miner,Craig Pohl,Ginger A. Fewell,Carrie A. Haipek,Heather Schmidt,Brian H. Dunford-Shore,Aldi T. Kraja,Seth D. Crosby,Christopher S. Sawyer,Tammi L. Vickery,Sacha N. Sander,Jody S. Robinson,Wendy Winckler,Wendy Winckler,Jennifer Baldwin,Lucian R. Chirieac,Amit Dutt,Amit Dutt,Timothy Fennell,Megan Hanna,Megan Hanna,Bruce E. Johnson,Robert C. Onofrio,Roman K. Thomas,Giovanni Tonon,Barbara A. Weir,Barbara A. Weir,Xiaojun Zhao,Xiaojun Zhao,Liuda Ziaugra,Michael C. Zody,Thomas J. Giordano,Mark B. Orringer,Jack A. Roth,Margaret R. Spitz,Ignacio I. Wistuba,Bradley A. Ozenberger,Peter J. Good,Andrew C. Chang,David G. Beer,Mark A. Watson,Marc Ladanyi,Stephen R. Broderick,Akihiko Yoshizawa,William D. Travis,William Pao,Michael A. Province,George M. Weinstock,Harold E. Varmus,Stacey Gabriel,Eric S. Lander,Richard A. Gibbs,Matthew Meyerson,Matthew Meyerson,Richard K. Wilson +96 more
TL;DR: Somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B are found.
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