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ERBB2/HER2-mutated tumors showed KRAS enrichment, MSI enrichment, elevated mutational burden, and broad co-alterations, while amplified tumors displayed left-sided predominance with selective KRAS mutual exclusivity and TP53 co-occurrence.",{"@graph":14,"@context":71},[15,34,54],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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\n[https://doi.org/10.1093/oncolo/oyag302](https://doi.org/10.1093/oncolo/oyag302)  \n[Published: July 31](Published: July 31), 2026  \nOriginal Article  \nGenomic landscape and clinical characteristics of ERBB2/HER2-mutated colorectal cancers  \nMuhammed Dogukan Aksu1, Paola Zinser Peniche2, Doga Kahramangil Baytar2,  \nBhaghyasree Jambunathan2, Yu Jen Alexander Jan2, Ronan Hsieh3, Shafia Rahman4, John C. Krauss5, Christine M. Veenstra5, , Ibrahim Halil Sahin*,5,   \n1 Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN, 55905, United States  \n2 Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, United States 3 Division of Hematology and Oncology, Swedish Cancer Institute, Seattle, WA, 98104, United States  \n4 Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 432120, United States  \n5 Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, 48109, United States  \n*Corresponding author: Ibrahim Halil Sahin, MD, Department of Medicine, University of Michigan Medical School, Rogel Comprehensive Cancer Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109, USA ([sahinih@med.umich.edu](sahinih@med.umich.edu)) .  \nAbstract  \nBackground: Molecular underpinnings and clinical characteristics of ERBB2/HER2-mutated colorectal cancers (CRCs) remain poorly understood. We aimed to comprehensively characterize the genomic landscape and clinical features of ERBB2/HER2-mutated CRC and to compare them with those of ERBB2/HER2-amplified CRC.  \nPatients and methods: We analyzed cBioPortal data from 4348 CRC patients with available ERBB2/HER2 profiling. Clinicodemographic features, microsatellite instability (MSI), tumor mutational burden, and alterations in 94 cancerassociated genes were evaluated using chi-square/Fisher’s exact test, Kruskal–Wallis test, and hierarchical clustering.  \nResults: ERBB2/HER2 putative driver mutations were identified in 95 patients (2.2%), amplifications in 87 (2.0%), and wildtype status in 4166 (95.8%). In the overall cohort, ERBB2/HER2-mutated tumors demonstrated significant KRAS enrichment (50.5%) compared to wild-type (37.7%; P = .014) and amplified tumors (18.4%; P \u003C .001), alongside MSI enrichment (37.2% vs 1.6%; P \u003C .001), elevated tumor mutational burden, and right-sided predominance. ERBB2/HER2-mutated tumors also showed broad driver co-alterations largely reflecting their MSI background. In contrast, ERBB2/HER2-amplified tumors exhibited left-sided predominance, with microsatellite stable (MSS)-restricted analyses revealing selective mutual exclusivity with KRAS (Log2 OR = −1.58; q = 0.019) and TP53 co-occurrence (Log2 OR = 2.04; q = 0.019). Hierarchical clustering confirmed that mutated and amplified tumors consistently occupy separate clusters across anatomical sites.  \nConclusion: ERBB2/HER2 mutations and amplifications represent molecularly and clinically distinct subgroups. ERBB2/ HER2-mutated tumors are characterized by an MSI-enriched, hypermutated background with frequent concurrent KRAS alterations, whereas amplified tumors exhibit selective KRAS mutual exclusivity and TP53 co-occurrence. These exploratory findings support alteration-specific therapeutic strategies in CRC.  \nKey words: colorectal neoplasms; colon; rectum; mutation; genomics; ERBB2/HER2  \nImplications for Practice  \nThis large-scale genomic analysis reveals that ERBB2/HER2-mutated and ERBB2/HER2-amplified colorectal cancers represent distinct molecular and clinical entities that might require different therapeutic approaches. ERBB2/HER2-mutated tumors frequently arise on an MSI-enriched, hypermutated background with concurrent KRAS alterations, suggesting a need for combination therapies and heightened resistance potential. Conversely, ERBB2/HER2-amplified tumors show KRAS mutual exclu","cbCaibyZpjPl3tLo","https://ap.wps.com/l/cbCaibyZpjPl3tLo","pdf",1694190,12,"English","# Abstract\n## Background\n## Patients and methods\n## Results\n## Conclusion\n# Introduction","[{\"question\":\"What was the main objective of the study on ERBB2/HER2-mutated colorectal cancers?\",\"answer\":\"To comprehensively characterize the genomic landscape and clinical features of ERBB2/HER2-mutated colorectal cancers and compare them with ERBB2/HER2-amplified colorectal cancers.\"},{\"question\":\"Which dataset and patient cohort were analyzed?\",\"answer\":\"The study analyzed cBioPortal data from 4,348 colorectal cancer patients with available ERBB2/HER2 profiling.\"},{\"question\":\"What key genomic and clinical differences were observed between ERBB2/HER2-mutated and ERBB2/HER2-amplified tumors?\",\"answer\":\"ERBB2/HER2-mutated tumors showed KRAS enrichment, MSI enrichment, and elevated tumor mutational burden with broad co-alterations, whereas ERBB2/HER2-amplified tumors showed left-sided predominance and selective KRAS mutual exclusivity with TP53 co-occurrence.\"}]","Genomic landscape and clinical characteristics of ERBB2/HER2-mutated colorectal cancers | PDF",1790059580]