Molecular and Cellular Pathobiology Activationof theNOTCHPathway inHeadandNeckCancer

نویسندگان

Wenyue Sun

Daria A. Gaykalova

Michael F. Ochs

Elizabeth Mambo

Demetri Arnaoutakis

Yan Liu

Myriam Loyo

Nishant Agrawal

Jason Howard

Ryan Li

Sun Ahn

Elana Fertig

David Sidransky

Jeffery Houghton

Kalyan Buddavarapu

Tiffany Sanford

Ashish Choudhary

Will Darden

Alex Adai

Gary Latham

Justin Bishop

Rajni Sharma

William H. Westra

Patrick Hennessey

Christine H. Chung

Joseph A. Califano

چکیده

NOTCH1 mutations have been reported to occur in 10% to 15% of head and neck squamous cell carcinomas (HNSCC). To determine the significance of thesemutations, we embarked upon a comprehensive study ofNOTCH signaling in a cohort of 44 HNSCC tumors and 25 normal mucosal samples through a set of expression, copy number, methylation, and mutation analyses. Copy number increases were identified in NOTCH pathway genes, including the NOTCH ligand JAG1. Gene set analysis defined a differential expression of the NOTCH signaling pathway in HNSCC relative to normal tissues. Analysis of individual pathway-related genes revealed overexpression of ligands JAG1 and JAG2 and receptor NOTCH3. In 32% of the HNSCC examined, activation of the downstream NOTCH effectors HES1/HEY1 was documented. Notably, exomic sequencing identified 5 novel inactivating NOTCH1mutations in 4 of the 37 tumors analyzed, with none of these tumors exhibitingHES1/HEY1 overexpression. Our results revealed a bimodal pattern of NOTCH pathway alterations in HNSCC, with a smaller subset exhibiting inactivating NOTCH1 receptor mutations but a larger subset exhibiting otherNOTCH1 pathway alterations, including increases in expression or gene copy number of the receptor or ligands as well as downstream pathway activation. Our results imply that therapies that target the NOTCH pathway may be more widely suitable for HNSCC treatment than appreciated currently. Cancer Res; 74(4); 1091–104. 2013 AACR.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Pathobiology introduces a new category.

متن کامل

Bispecific antibodies: molecules that enable novel therapeutic strategies.

Bispecific antibodies are unique in the sense that they can bind simultaneously two different antigens. This property enables the development of therapeutic strategies that are not possible with conventional monoclonal antibodies. The large panel of imaginative bispecific antibody formats that has been developed reflects the strong interest for these molecules. Although in many cases the manufa...

متن کامل

Vitamin D suppresses cellular pathways of diabetes complication in liver

Objective(s): The aim of this study was to investigate the effect of vitamin D on glucose metabolism, as well as the expression of five key genes involved in the development of diabetes complications in liver tissue of diabetic rats. Materials and Methods: Twenty-four male Sprague–Dawley rats were randomly divided into three groups (8 ra...

متن کامل

Changing pathology with changing drugs: skin cancer.

Today skin cancer is mainly treated by surgical interventions. New findings concerning molecular biology and the signaling pathways in epithelial skin cancers such as basal cell carcinoma, squamous cell carcinoma or melanoma, and mesenchymal skin cancers such as angiosarcoma and dermatofibrosarcoma protuberans (DFSP) have identified new molecular targets for a systemic or local treatment approa...

متن کامل