PUBLICATION: https://stke.sciencemag.org/content/11/526/eaan6776.long

Truncation and motif based Pan-cancer analysis highlights novel tumor suppressing kinases.

SUMMARY: A unique computational pan-cancer analysis pinpoints novel tumor suppressing kinases, and highlights the power of functional genomics by defining the JNK pathway as tumor suppressive in gastric cancer.

Andrew M. Hudson, Natalie L. Stephenson, Cynthia Li, Eleanor Trotter, Adam J. Fletcher, Gitta Katona, Patrycja Bieniasz-Krzywiec, Matthew Howell, Chris Wirth, Simon Furney, Crispin J. Miller, John Brognard

ABSTRACT: A major challenge in cancer genomics is identifying driver mutations from the large numbers of neutral "passenger" mutations within a given tumor. Here, we utilize kinase sequence information to functionally filter genomic data to identify driver mutations that would otherwise be lost within mutational noise. Firstly, we identify a putative tumor suppressing kinome by identifying kinases with truncation mutations occurring within or before the kinase domain. We aligned these kinase sequences and, utilizing data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas databases, identified amino acids that represent hotspots for loss-of-function mutations. The functional consequences of new hotspot residues were functionally validated and the top 15 hotspot residues were used in a pan-cancer analysis to define the tumor-suppressing kinome. A ranked list revealed MAP2K7 as a candidate tumor suppressor in gastric cancer, despite the mutational frequency of MAP2K7 falling within the mutational noise for this cancer type.The majority of mutations in MAP2K7 abolished catalytic activity compared to the wild type kinase, consistent with a tumor suppressive role for MAP2K7 in gastric cancer. Furthermore, reactivation of the JNK pathway in gastric cancer cells harboring LOF mutations in MAP2K7 or JNK1 suppresses clonogenicity and growth in soft agar, demonstrating the functional importance of inactivating the JNK pathway in gastric cancer. In summary, our data highlights a broadly applicable strategy to identify functional cancer driver mutations leading us to define the JNK pathway as tumor suppressive in gastric cancer.