Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer
The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1. Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.
Authors
- Debyani Chakravarty (ORCID: https://orcid.org/0000-0001-8629-5732)
- Samuel I. Gould (ORCID: https://orcid.org/0000-0003-2617-5215)
- Adam J. Schoenfeld (ORCID: https://orcid.org/0000-0002-2644-1416)
- Rohit Thummalapalli (ORCID: https://orcid.org/0000-0002-8865-0299)
- Mark Zucker (ORCID: https://orcid.org/0000-0002-2999-0146)
- Jason S. Chang (ORCID: https://orcid.org/0000-0002-8227-7382)
- Charles Swanton (ORCID: https://orcid.org/0000-0002-4299-3018)
- Francisco J. Sánchez‐Rivera (ORCID: https://orcid.org/0000-0002-8466-8563)
- Pedram Razavi (ORCID: https://orcid.org/0000-0003-4236-0576)
- Anton Safonov (ORCID: https://orcid.org/0000-0002-4100-8071)
- Nikolaus Schultz (ORCID: https://orcid.org/0000-0002-0131-4904)
- Yonina R. Murciano‐Goroff (ORCID: https://orcid.org/0000-0001-9027-2891)
- Mark T.A. Donoghue (ORCID: https://orcid.org/0000-0003-4538-6069)
- Miika M. Mehine (ORCID: https://orcid.org/0000-0003-0443-0625)
- Sarat Chandarlapaty (ORCID: https://orcid.org/0000-0003-4532-8053)
- Arielle Elkrief (ORCID: https://orcid.org/0000-0003-1981-1535)
- Marc Ladanyi (ORCID: https://orcid.org/0000-0001-9055-7213)
- Mariam Jamal‐Hanjani (ORCID: https://orcid.org/0000-0003-1212-1259)
- Nicholas McGranahan (ORCID: https://orcid.org/0000-0001-9537-4045)
- Kristiana Grigoriadis (ORCID: https://orcid.org/0000-0002-8435-0176)
- Maria Perry (ORCID: https://orcid.org/0000-0002-8789-251X)
- Ed Reznik (ORCID: https://orcid.org/0000-0002-6511-5947)
- Chaitanya Bandlamudi (ORCID: https://orcid.org/0000-0003-1108-4919)
- A. Rose Brannon (ORCID: https://orcid.org/0000-0003-4610-0149)
- Yuan Chen
- David B. Solit (ORCID: https://orcid.org/0000-0002-6614-802X)
- Ronglai Shen (ORCID: https://orcid.org/0000-0002-8192-7531)
- Michael F. Berger
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- London Cancer (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
- Molecular Oncology (United States) (US)
- University College London (GB)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Cell
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1016/j.cell.2024.11.010
- Citations
- 17
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 3.97
Funders
- U.S. Department of Defense
- Howard Hughes Medical Institute
- American Society of Clinical Oncology
- Cancer Research Society
- Andrew Sabin Family Foundation
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- National Institutes of Health
- Ludwig Center at Harvard
- Canadian Institutes of Health Research
- National Cancer Institute