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

Q: How did the study compare left-sided and right-sided colorectal cancer?

It retrospectively analyzed 48 CRC patients who received next-generation sequencing on tumor tissue and matched leukocytes using a 425-gene panel, then compared clinicopathological, molecular, and prognostic factors between LCC and RCC.

Q: Which mutations and pathways were more frequent in right-sided colorectal cancer?

Right-sided colorectal cancer showed a higher frequency of BRAF mutations and more frequent alterations in PI3K, homology-dependent recombination (HDR), and mismatch repair (MMR) pathways compared with left-sided disease.

Q: What roles do SMAD4 and SETD2 mutations play in prognosis?

SMAD4 mutation was identified as an independent predictor of worse overall survival and confirmed in an external cohort. SETD2 mutations were associated with poor prognosis in left-sided colorectal cancer, while ARID1A and PRDM1 correlated with shorter progression-free survival in right-sided colorectal cancer.

Sep 22, 2026

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This open-access research article compares clinicopathological, molecular, and prognostic factors between left-sided and right-sided colorectal cancer using next-generation sequencing. Forty-eight CRC patients underwent NGS with a 425-gene panel for tumor tissue and matched leukocytes. Right-sided tumors showed higher BRAF mutation frequency and greater pathway alterations across PI3K, HDR, and MMR. Multivariate and external-cohort analyses identify SMAD4 mutation as an independent predictor of worse overall survival.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

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Abstract

Background

Methods

Results

Conclusions

Introduction

Cancer Medicine RESEARCH ARTICLE OPEN ACCESS Distinct Molecular and Prognostic Profiles of Left-and Right-Sided Colorectal Cancer Revealed by NGS Analysis: The Role ofSMAD4 and SETD2 Mutations Wenlei Zhao1 | Yuxuan Qiu1 | Na Bai2 | Chunhong He2 | Jiani C. Yin2 | Qianru Xu1 | Kaiyu Jian1 | Baolei Jia1 | Lin Jiang1 | Feng Liang1 1Department of General Surgery, First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China | 2Geneseeq Research Institute, Nanjing Geneseeq Technology Inc. , Nanjing, China Correspondence: Feng Liang ([lfpeakcool@126.com](lfpeakcool@126.com)) Received: 25 August 2025 | Revised: 15 December 2025 | Accepted: 5 January 2026 Keywords: colorectal neoplasms | genetic variation | next-generation sequencing | prognosis | tumor location ABSTRACT Background: 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. Methods: 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. Results: 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) . Conclusions: 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. | Abbreviations: 5-FU, 5-fluorouracil; BER, base excision repair; BWA, Burrows-Wheeler Aligner; CAP, College of American Pathologists; CI, confidence interval; CIMP-H, high CpG island methylator phenotype; CIN, chromosomal instability; CLIA, Clinical Laboratory Improvement Amendments; CMS-1, consensus molecular subtype-1; CNV, copy number variation; CRC, colorectal cancer; DDR, DNA damage response; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; FA, Fanconi anemia; FFPE, formalin-fixed paraffin-embedded; GATK, Genome Analysis Toolkit; HDR, homology-dependent recombination; hg19, Human genome version 19; HR, hazard ratio; IGV, Integrative Genomics Viewer; indel, insertion/deletion; ISO, International Organization for Standardization; LCC, left-sided colorectal cancer; Mb, megabase; MMR, mismatch repair; mOS, median OS; MS, microsatellite; MSI-H, high microsatellite instability; MSS, microsatellite stability; NGS, next-generation sequencing; OS, overall survival; PFS, progression-free survival; RCC, right-sided colorectal cancer; SNV, single nucleotide variant; TMB, tumor mutation burden; TMB-H, high TMB; TMB-L, low TMB; VAF, variant allele frequency.
Wenlei Zhao and Yuxuan Qiu contributed equally to this work. | | --- | | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
© 2026 The Author(s). Cancer Medicine published by John Wiley

FAQs

How did the study compare left-sided and right-sided colorectal cancer?

It retrospectively analyzed 48 CRC patients who received next-generation sequencing on tumor tissue and matched leukocytes using a 425-gene panel, then compared clinicopathological, molecular, and prognostic factors between LCC and RCC.

Which mutations and pathways were more frequent in right-sided colorectal cancer?

Right-sided colorectal cancer showed a higher frequency of BRAF mutations and more frequent alterations in PI3K, homology-dependent recombination (HDR), and mismatch repair (MMR) pathways compared with left-sided disease.

What roles do SMAD4 and SETD2 mutations play in prognosis?

SMAD4 mutation was identified as an independent predictor of worse overall survival and confirmed in an external cohort. SETD2 mutations were associated with poor prognosis in left-sided colorectal cancer, while ARID1A and PRDM1 correlated with shorter progression-free survival in right-sided colorectal cancer.

Sep 22, 2026

Upload by Finn