Discovery and Validation of Tandem Mutations Driving Cancer
Analysis of cancer genomes has traditionally focused on patterns of individual pathogenic mutations in genes, independent of the presence of other potentially critical genetic variants. However, classical work has demonstrated that multiple cooperative mutations to a single gene play a key role in oncogenesis, e.g. in acquired resistance to targeted therapy by second-site mutations and in biallelic inactivation of tumor suppressors. In this project, we propose to computationally analyze and functionally characterize tandem mutations in targeted sequencing data from 20,000 patients with cancer. We will develop statistical models to identify genes with an enrichment of tandem mutations and determine the allelic configuration of recurrent tandem mutations using computational methods. Prioritizing tandem mutations in druggable kinases, we will also functionally validate the consequences of tandem mutations, test their sensitivity to targeted therapies, and determine their correlation to response to therapy and survival.
Final Report (August 2020)
Our grant from the ICI Brown Fund (2018-2020) on “Discovery and Validation of Tandem Mutations Driving Cancer” allowed us the financial freedom and flexibility to pursue this high-risk project that was not funded through traditional sources. We were able to leverage and optimize tumor sequencing data from MSK IMPACT for this work. We have benefited from this collaboration greatly, and this work has culminated in two high-profile primary research articles:
- “Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Ka inhibitors” (Vasan et al, Science 2019)
- “Phase and context shape the function of composite oncogenic mutations” (Gorelick et al, Nature 2020).
Dr. Vasan is first author on the first paper (Dr. Reznik is also a coauthor), and Dr. Reznik is co-corresponding author on the second paper (Dr. Vasan is also a coauthor).
Per the stated aims of our ICI grant, computational data on identified tandem mutations, genes enriched for tandem mutations, and recurrent mutant tandem alleles are fully described in the Nature manuscript. The code to reproduce the analyses producing these results is available here: https://github.com/taylor-lab/composite-mutations
This work has led to an NIH R21 grant (PI: Maurizio Scaltriti) and an NIH K08 award (PI: Neil Vasan).
Additionally, both these papers will provide a preclinical rationale for the design of clinical trials investigating PI3K inhibitors in multiple PIK3CA mutant cancers.