Abstract Background: Mutant allele copy number dosage gains are widely observed in oncogene-driven cancers. Nearly 1 in 5 KRAS-mutated (KRAS MUT) pancreatic cancers harbor KRAS MUT dosage gains that are associated with worse outcomes and aggressive disease. It is unclear if this dosage-dependent prognostic effect, likely mediated by oncogene addiction, extends to other KRAS MUT cancers or to other oncogenes. Herein, we characterize the clinicogenomic effects of mutant dosage gains in KRAS and 10 other oncogenes across cancer types and evaluate the role of KRAS mutant dosage gains in mediating response to RAS-directed therapies. Methods: Our initial study cohort comprised 33, 473 patients across 12 common cancer types with tumors profiled by MSK-IMPACT. Analysis was restricted to 10, 129 patients with diploid tumors harboring an OncoKB-annotated oncogenic mutation in one of the 11 oncogenes. Allele-specific copy number was inferred using FACETS. Normalized data from The Cancer Genome Atlas was used for gene expression analysis. Cell line drug screening data for sotorasib was obtained from the PRISM DepMap study. Results: Among tumors with allelic imbalances, selection for gain or retention of the mutant allele versus wild-type was ubiquitous. Mutant dosage gains were observed in 18% (1, 819 of 10, 129) of all oncogene-mutated tumors. Notably, a majority (87%) of these were 1- or 2-copy gains, whereas only 9% were focal amplifications (ranging from 0% in KRAS MUT endometrial cancer (UEC) to 30% in EGFR MUT LUAD). The prevalence of KRAS MUT gains in LUAD (18%) was comparable to that of colon (23%), rectal (18%), and pancreatic (14%) cancers (PAAD), despite varying distributions of specific KRAS variants. Mutant dosage gains were more common in metastatic tumors (27%) compared to primary tumors (13%, p=1. 3×10-50) pan-cancer. TP53 mutations co-occurred with mutant dosage gains in KRAS MUT and EGFR MUT lung cancers and PIK3CA MUT breast cancers. Interestingly, dosage gains were depleted in microsatellite instability (MSI) -high tumors pan-cancer (8%, vs. 18% in tumors without MSI, p=0. 002) and mutually exclusive with MSI-associated mutations in KRAS MUT UEC. Gene expression analysis revealed that KRAS MUT dosage gains were associated with higher KRAS expression in a dose-dependent manner (p=4. 4×10-13 in LUAD, p=5. 6×10-4 in PAAD). KRAS G12C mutant cell lines with gene-level copy number gains exhibited markedly enhanced sensitivity to sotorasib compared to those without these gains. Additionally, among patients with KRAS G12C lung cancer treated with sotorasib, the rate of partial response (PR) was significantly higher in those with tumors with KRAS MUT gains (57%, 8/14) compared to those without dosage gains (17%, 6/36, p=0. 011). Conclusions: We establish that mutant dosage gains are widespread in oncogenes and represent important on-target biomarkers that may predict sensitivity to targeted therapies. Our findings underscore the need to standardize clinical reporting of mutant dosage gains and elucidate their functional role in therapeutic sensitivity. Citation Format: Maria A. Perry, Allison L. Richards, Adam Price, Sam E. Tischfield, Henry Walch, Helen Xie, Ariaki Dandawate, Karl Pichotta, Christopher Fong, Justin Jee, Nikolaus Schultz, Rohit Thummalapalli, Helena A. Yu, Ping Chi, Anupriya Singhal, Wungki Park, Eileen M. O'Reilly, Yonina Murciano-Goroff, Mark Awad, Rona Yaeger, Kathryn C. Arbour, Mark T. A. Donoghue, Michael F. Berger, Chaitanya Bandlamudi. Mutant allele copy number gains define distinct molecular subtypes of oncogene-driven cancers and are associated with response to allele-specific KRASG12C inhibitor sotorasib in NSCLC abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr A050.
Perry et al. (Thu,) studied this question.