KMT2A Mutations and High Prevalence of dMMR-associated Mutational Signatures as Prognostic Indicators in Metastatic Colorectal Cancer

TL;DR

This study identifies KMT2A mutations and dMMR-related mutational signatures as indicators of poor prognosis in metastatic colorectal cancer patients.

Contribution

The study introduces KMT2A mutations and dMMR-associated mutational signatures as novel independent prognostic markers in metastatic colorectal cancer.

Findings

Patients with BRCA2 and KMT2A mutations had worse outcomes after chemotherapy.

Altered homologous recombination and KMT2A signaling were linked to shorter progression-free survival.

Higher dMMR-related mutational signatures correlated with worse prognosis in mCRC patients.

Abstract

The conventional treatment strategies for patients with metastatic colorectal cancer (mCRC) are predominantly guided by the status of RAS and BRAF mutations. Although patients may exhibit analogous pathological characteristics and undergo similar treatment regimens, notable disparities in their prognostic outcomes can be observed. Therefore, tissue and plasma samples from 40 mCRC patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Genomic variations and canonical oncogenic pathways were investigated for their prognostic effects in association with progression-free survival (PFS) of these patients. We found that patients with BRCA2 and KMT2A mutations exhibited worse prognostic outcomes after chemotherapy-based treatment (univariate, P < 0.01). Further pathway analysis indicated that alterations in the homologous recombination pathway and in the KMT2A signaling network were also significantly associated with shortened PFS (univariate, P < 0.01). Additionally, mutation signature analysis showed that patients with higher proportions of defective mismatch repair (dMMR)-related mutational signatures. Had a worse prognosis (univariate, P = 0.02). KMT2A mutations (hazard ratio [HR], 4.47; 95% confidence interval [CI], 1-19.93; P =0.050) and dMMR signature proportions (HR, 3.57; 95% CI, 1.42-8.96; P = 0.007) remained independently associated with PFS after multivariate analysis and the results were further externally validated. These findings may enhance our understanding of this disease and may potentially facilitate the optimization of its treatment approaches.

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