# Distinct Molecular and Prognostic Profiles of Left‐ and Right‐Sided Colorectal Cancer Revealed by NGS Analysis: The Role of SMAD4 and SETD2 Mutations

## TL;DR

This study finds that left- and right-sided colorectal cancers have distinct genetic and prognostic profiles, with SMAD4 and SETD2 mutations playing key roles in predicting survival.

## Contribution

The study identifies SMAD4 and SETD2 mutations as novel independent prognostic biomarkers for left- and right-sided colorectal cancer.

## Key findings

- Right-sided CRC shows higher BRAF mutations and more frequent alterations in PI3K, HDR, and MMR pathways compared to left-sided CRC.
- SMAD4 mutations are an independent predictor of worse overall survival in CRC, confirmed in an external cohort.
- SETD2 mutations are associated with poor prognosis in left-sided CRC, while ARID1A and PRDM1 mutations correlate with shorter progression-free survival in right-sided CRC.

## Abstract

Colorectal cancer (CRC) isthe third most common cancer and the second leading cause of cancer‐relateddeath worldwide. Its genetic heterogeneity complicates treatment. This studyaimed to compare clinicopathological, molecular, and prognostic factors betweenleft‐sided (LCC) and right‐sided (RCC) CRC.

We retrospectively analyzed 48 CRCpatients who received next‐generation sequencing (NGS) of tumor tissue andmatched leukocytes using a 425‐gene panel. Clinicopathological, molecular, andprognostic factors were compared between LCC and RCC.

RCC exhibited a higher frequencyof BRAF mutations (33.3% vs. 7.1%, p = 0.042) and more frequent alterations in PI3K (p = 0.033), homology‐dependent recombination (HDR, p = 0.018), and mismatch repair (MMR, p = 0.002) pathways than LCC. Multivariate analysis identified SMAD4 mutation as an independentpredictor of worse overall survival (OS) (HR = 3.88, 95% CI 1.05–14.29, p = 0.042), which was confirmed in an external cohort of 1796 CRCpatients. In subgroup analyses, SETD2 mutationswere associated with poor prognosis in LCC (HR = 2.20, 95% CI 0.80–6.06, p = 0.026), while ARID1A (p = 0.040) and PRDM1 (p = 0.021) mutations correlated with shorter progression‐free survival in RCC. Patients harboring both SMAD4 and SETD2 mutationshad the shortest OS (median: 17.7 months, p < 0.0001).

These findings reveal criticalmolecular and prognostic differences between LCC and RCC and highlight SMAD4 and SETD2 asimportant prognostic biomarkers, suggesting the potential value of location‐and mutation‐guided precision therapies in CRC.