PIK3CA Mutated Colorectal Cancers Without KRAS, NRAS and BRAF Mutations Possess Common and Potentially Targetable Mutations in Epigenetic Modifiers and DNA Damage Response Genes

Sep 21, 2026

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Metastatic colorectal cancer often remains fatal despite advances, highlighting the need for new strategies grounded in molecular pathogenesis. This study interrogates publicly available colorectal cancer genomic series using cBioportal, focusing on cohorts lacking extended RAS panel mutations (KRAS/NRAS/BRAF) to assess PIK3CA alterations. PIK3CA mutations occur in about 3.7%–7.6% of cases, while quadruple wild type accounts for 32.2%–39.9%. Triple wild type/PIK3CA-mutated tumors show higher high-TMB prevalence and frequent epigenetic modifier and DNA damage response mutations, with comparable prognosis to quadruple wild type.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Abstract

Background/Aim

Materials and Methods

Results

Conclusion

Introduction

Targeted therapy landscape in colorectal cancer

PI3K signaling and relevance to PIK3CA

CANCER GENOMICS & PROTEOMICS 21: 533-548 (2024) doi:10.21873/cgp.20470 PIK3CA Mutated Colorectal Cancers Without KRAS, NRAS and BRAF Mutations Possess Common and Potentially Targetable Mutations in Epigenetic Modifiers and DNA Damage Response Genes IOANNIS A. VOUTSADAKIS 1,2 1Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, ON, Canada; 2Division of Clinical Sciences, Section of Internal Medicine, Northern Ontario School of Medicine, Sudbury, ON, Canada Abstract. Background/Aim: Despite therapeutic advancements, metastatic colorectal cancer is usually fatal, necessitating novel approaches based on the molecular pathogenesis to improve outcomes. Some colorectal cancers have no mutations in the extended RAS panel (KRAS, NRAS, BRAF) genes and represent a special subset, which deserves particular therapeutic considerations. Materials and Methods: The genomic landscape of colorectal cancers from publicly available genomic series was interrogated, using the cBioportal platform. Colorectal cancer cohorts with cancers devoid of KRAS/NRAS or BRAF mutations were evaluated for the presence of mutations in the catalytic sub-unit alpha of kinase PI3K, encoded by the gene PIK3CA. Results: PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations were observed in 3. 7% to 7.6% of colorectal cancers in the different series examined. Patients with all four genes in wildtype configuration (quadruple wild type) represented 32.2% to 39.9% of cases in the different series examined. Compared with quadruple wild type cancers, triple (KRAS/NRAS/BRAF) wild type/PIK3CA mutated cancers had a higher prevalence of high TMB cases and additional mutations in colorectal cancer associated genes except for mutations in TP53. Mutations in genes encoding for epigenetic modifiers and the DNA damage response (DDR) were also more frequent in Correspondence to: Ioannis A. Voutsadakis, Division of Medical Oncology, Sault Area Hospital, 750 Great Northern Road, Sault Ste Marie, ON P6B 0A8, Canada. Tel: +1 7057593434, e-mail: [ivoutsadakis@nosm.ca](ivoutsadakis@nosm.ca) Key Words: PI3K, genomic studies, targeted therapy, quadruple wild type, extended RAS panel. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license ([https://creativecommons.org/licenses/by-nc-nd/4.0](https://creativecommons.org/licenses/by-nc-nd/4.0)). triple wild type/PIK3CA mutated cancers. The prognosis of the two groups was comparable. Conclusion: Colorectal cancers with PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations have frequently mutations in epigenetic modifiers and DDR response genes, which may provide opportunities for targeting. These mutations are present in a smaller subset of quadruple wild type cancers. Progress in the elucidation of the molecular pathogenesis of colorectal cancer has had a positive impact on therapeutics for the disease (1) . Several targeted therapies are currently available for the treatment of molecularly defined groups of colorectal cancers, which have improved the outcomes of metastatic disease. Targetable alterations are observed only in a minority of colon cancers and therefore the treatment of most patients relies on cytotoxic chemotherapy. Colorectal cancer patients with targeted treatment options include those with microsatellite unstable tumors (Microsatellite Instability high, MSI-high) who are candidates for checkpoint inhibitor immunotherapy (2) . In addition, patients with BRAF mutations are candidates for BRAF kinase inhibitors in combination with anti-EGFR monoclonal antibodies, patients with KRAS G12C mutations are candidates for KRAS inhibitors in combination with anti-EGFR monoclonal antibodies, and those with HER2 amplifications are candidates for HER2 targeted therapies (3-5) . Additional cancers with mutations of the KRAS/BRAF cascade, including those with mutations in KRAS other than G12C, m

FAQs

What was the study trying to determine about PIK3CA in colorectal cancer?

The study evaluated whether colorectal cancers without KRAS/NRAS/BRAF mutations (extended RAS panel) show mutations in PIK3CA and what other potentially targetable alterations co-occur.

How often were PIK3CA mutations found in KRAS/NRAS/BRAF mutation–negative colorectal cancers?

PIK3CA mutations were observed in about 3.7% to 7.6% of colorectal cancers across the examined genomic series.

What genetic patterns characterized triple wild type/PIK3CA-mutated cancers compared with quadruple wild type?

Compared with quadruple wild type, triple wild type/PIK3CA-mutated cancers had a higher prevalence of high TMB and additional mutations in colorectal cancer–associated genes, with more frequent epigenetic modifier and DNA damage response gene mutations.

Sep 21, 2026

Uploaded by Theodore