Prevalence and Heterogeneity of KRAS, BRAF, and PIK3CA Mutations in Primary Colorectal Adenocarcinomas and Their Corresponding Metastases
Abstract
Purpose: Epidermal growth factor receptor (EGFR) antibody therapy is established in patients with wild-type KRAS colorectal carcinoma; however, up to 50% of these patients do not respond to this therapy. To identify the possible causes of this therapy failure, we searched for mutations in different EGFR-dependent signaling proteins and analyzed their distribution patterns in primary tumors and corresponding metastases. Experimental Design: Tumor tissues, macrodissected from tumor centers, invasion fronts (n = 100), lymph nodes (n = 55), and distant metastases (n = 20), respectively, were subjected to DNA extraction and mutation analysis of KRAS, BRAF, and PIK3CA. Results: Activating mutations were detected in 41% (KRAS), 7% (BRAF), and 21% (PIK3CA) of the primary tumors. By comparing tumor centers and invasion fronts, the intratumoral heterogeneity of KRAS, BRAF, and PIK3CA mutations was observed in 8%, 1%, and 5% of primary tumors, respectively. Heterogeneity between primary tumors and lymph node metastases was found in 31% (KRAS), 4% (BRAF), and 13% (PIK3CA) of the cases. Heterogeneity between primary tumors and distant metastases was present in two patients (10%) for KRAS and one patient for PIK3CA (5%), but not for BRAF. Discordant results between primary tumors and metastases could markedly be reduced by testing the additional tumor samples. Conclusions: Failure of EGFR antibody therapy in patients with wild-type KRAS colorectal cancer may result from activating BRAF or PIK3CA mutations and false-negative sequencing results caused by intratumoral heterogeneity. Due to the particularly high rates of heterogeneity between primary tumors and lymph node metastases, the latter are least suitable for diagnostic mutation analysis. Clin Cancer Res; 16(3); 790–9
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RAS mutations occur early in colorectal cancer development, so the mutation status of the tumor's mucosal and invasive regions is generally consistent, with a concordance rate of over 97% for KRAS exon 2 mutations between surgical specimens and endoscopic biopsy samples in the same case.
“RAS mutations occur early in colorectal cancer development, so the mutation status of the tumor’s mucosal and invasive regions is generally consistent, with a concordance rate of over 97% for KRAS exon 2 mutations between surgical specimens and endoscopic biopsy samples in the same case [51]”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [51]
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- Authors
- Baldus, S. E., Schaefer, K.-L., Engers, R., Hartleb, D., Stoecklein, N. H., & Gabbert, H. E.
- Affiliations
- Heinrich Heine University Düsseldorf (DE)
- Venue
- Clinical Cancer Research
- Published
- 2010-02-01
- Volume
- 16
- Issue
- 3
- Pages
- 790-799
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2100543432
- Cited by
- 432
- References
- 58
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 10 · 2023: 8 · 2022: 10 · 2021: 9 · 2020: 24 · 2019: 26 · 2018: 27 · 2017: 22 · 2016: 32 · 2015: 46 · 2014: 54 · 2013: 50 · 2012: 53
- FWCI
- 23.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- KRAS mutation, BRAF mutation, PIK3CA mutation, colorectal adenocarcinoma, intratumoral heterogeneity, primary tumor versus metastasis discordance, lymph node metastasis, distant metastasis, EGFR signaling
- MeSH terms
- Adenocarcinoma, Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Lymphatic Metastasis, Male, Middle Aged, Mutation, Neoplasm Metastasis, Genes, ras, Genetic Variation, Colorectal Neoplasms, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins B-raf, Class I Phosphatidylinositol 3-Kinases
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