Distinct genomic landscape of colorectal signet ring cell carcinoma reveals frequent KMT2 family alterations and SMAD4 inactivation.

Authors

Krittiya Korphaisarn, Jirapat Aiamsophon, Nuttapong Ngamphaiboon, Napat Angkathunyakul, Ananya Pongpaibul, Ekkapong Roothumnong, Charuwan Akewanlop, Manop Pithukpakorn

Published in

BMC cancer. Jul 13, 2026. Epub Jul 13, 2026.

Abstract

Colorectal signet-ring cell carcinoma (SRCC) is a rare and highly aggressive subtype of colorectal cancer (CRC) associated with poor clinical outcomes. Despite its distinct pathology, colorectal SRCC remains underrepresented in large genomic datasets, and its molecular drivers are incompletely defined. We performed comprehensive genomic profiling to characterize the mutational landscape of colorectal SRCC and explore potential therapeutic implications.
Formalin-fixed, paraffin-embedded tumor specimens from 39 patients with histologically confirmed colorectal SRCC were analyzed using targeted next-generation sequencing with the Oncomine™ Comprehensive Assay Plus, covering 517 cancer-related genes. Somatic alterations were identified, and tumor mutational burden (TMB) was calculated.
High tumor mutational burden (TMB-H; ≥10 mutations/Mb) was observed in 15.4% of cases. The most frequently altered genes were KMT2C and SMAD4 (49% each), followed by TP53 (41%), CIC (31%), and ZFHX3 (28%). Recurrent alterations were also detected in KMT2A, KMT2D, CSMD3, and ZMYM3 (each 26%). In contrast, canonical CRC driver mutations-including APC (23%), KRAS (15%), NRAS (2.5%), BRAF (10%), and PIK3CA (10%)-were less frequent than typically reported in conventional colorectal adenocarcinoma.
Colorectal SRCC exhibits a distinct genomic landscape characterized by frequent alterations in epigenetic regulators, particularly the KMT2 gene family, and recurrent disruption of the TGF-β signaling pathway through SMAD4 inactivation. The relative reduced frequency of canonical CRC driver mutations suggests alternative oncogenic mechanisms underlying SRCC tumorigenesis. These findings provide genomic insights into this aggressive subtype and may inform future subtype-specific therapeutic strategies, including epigenetic-targeted therapies and immunotherapy in selected patients.

PMID:
42443809
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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