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Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however, with no systematical investigation for prognostic genomic features. Here we report a systematic investigation conducted in 1868 Chinese gastric cancer patients indicating that signet-ring cells content was related to multiple clinical characteristics and treatment outcomes. We thus perform whole-genome sequencing on 32 pairs of SRC samples, and identify frequent  CLDN18-ARHGAP26/6  fusion (25%). With 797 additional patients for validation, prevalence of  CLDN18-ARHGAP26/6  fusion is noticed to be associated with signet-ring cell content, age at diagnosis, female/male ratio, and TNM stage. Importantly, patients with  CLDN18-ARHGAP26/6  fusion have worse survival outcomes, and get no benefit from oxaliplatin/fluoropyrimidines-based chemotherapy, which is consistent with the fact of chemo-drug resistance acquired in  CLDN18-ARHGAP26  introduced cell lines. Overall, this study provides insights into the clinical and genomic features of SRCC, and highlights the importance of frequent  CLDN18-ARHGAP26/6  fusions in chemotherapy response for SRCC.

Prognostic significance of frequent CLDN18-ARHGAP26/6 fusion in gastric signet-ring cell cancer