Genomic landscape and clinical characteristics of ERBB2/HER2-mutated colorectal cancers

Q: What was the main objective of the study on ERBB2/HER2-mutated colorectal cancers?

To comprehensively characterize the genomic landscape and clinical features of ERBB2/HER2-mutated colorectal cancers and compare them with ERBB2/HER2-amplified colorectal cancers.

Q: Which dataset and patient cohort were analyzed?

The study analyzed cBioPortal data from 4,348 colorectal cancer patients with available ERBB2/HER2 profiling.

Sep 22, 2026

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Molecular underpinnings and clinical characteristics of ERBB2/HER2-mutated colorectal cancers remain incompletely understood. Using cBioPortal data from 4,348 CRC patients with ERBB2/HER2 profiling, the study evaluated clinicodemographic factors, MSI, tumor mutational burden, and alterations in 94 cancer-associated genes. 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.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Abstract

Background

Patients and methods

Results

Conclusion

Introduction

The Oncologist, 2026, 31, oyag302 [https://doi.org/10.1093/oncolo/oyag302](https://doi.org/10.1093/oncolo/oyag302) [Published: July 31](Published: July 31), 2026 Original Article Genomic landscape and clinical characteristics of ERBB2/HER2-mutated colorectal cancers Muhammed Dogukan Aksu1, Paola Zinser Peniche2, Doga Kahramangil Baytar2, Bhaghyasree Jambunathan2, Yu Jen Alexander Jan2, Ronan Hsieh3, Shafia Rahman4, John C. Krauss5, Christine M. Veenstra5, , Ibrahim Halil Sahin*,5, 1 Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN, 55905, United States 2 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 4 Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 432120, United States 5 Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, 48109, United States *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)) . Abstract Background: 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. Patients 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. Results: 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 < .001), alongside MSI enrichment (37.2% vs 1.6%; P < .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. Conclusion: 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. Key words: colorectal neoplasms; colon; rectum; mutation; genomics; ERBB2/HER2 Implications for Practice This 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

FAQs

What was the main objective of the study on ERBB2/HER2-mutated colorectal cancers?

To comprehensively characterize the genomic landscape and clinical features of ERBB2/HER2-mutated colorectal cancers and compare them with ERBB2/HER2-amplified colorectal cancers.

Which dataset and patient cohort were analyzed?

The study analyzed cBioPortal data from 4,348 colorectal cancer patients with available ERBB2/HER2 profiling.

What key genomic and clinical differences were observed between ERBB2/HER2-mutated and ERBB2/HER2-amplified tumors?

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.

Sep 22, 2026

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