Comprehensive molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon.

Abstract

63 Background: Signet ring cell carcinoma (SRCC) is a rare variant of adenocarcinoma, accounting for about 10% of gastric cancer (GC) and 1% of colorectal cancer (CRC). SRCC is associated with poor prognosis, however little is known about the underlying molecular characteristics. Herein, we aimed to characterize the molecular features of SRCCs, and to compare the molecular profile of SRCC to adenocarcinoma; further, we assessed the impact of tumor location on the molecular profile of SRCC. Methods: SRCCs were analyzed using NGS (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry, and in-situ hybridization. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Chi-square and t-tests were used for comparative analyses. Results: A total of 8,500 CRC and 1,100 GC were screened for SRCC histology. Seventy-six SRCC were identified from the CRC cohort (<1%) and 98 from the GC cohort (9%). The most frequently mutated genes in CRC-SRCC were TP53 (47%), ARID1A (26%), APC (25%), KRAS (22%), RFN43 (16%), KMT2D (12%), KMT2C (11%), SMAD4 (10%) and BRAF (10%), while in GC-SRCC were TP53 (42%), ARID1A (27%), CDH1 (11%), BAP1 (7%), PIK3CA (7%), ERBB2 (5%). When compared to non-SRCC histology (N=3522), CRC-SRCC (N=37) showed more frequently mutation in BRCA1 (11% vs 1%, P < .001) and less mutation in APC (19% vs 78%, P < .001), KRAS (22% vs 51%, P = .001) and TP53 (47% vs 73%, P = .001). Among GC cohort, SRCC (N=54) had a higher frequency of mutations in CDH1, BAP1, and ERBB2, and higher rate of amplification MYB compared to non-SRCC (N=540), although none of these differences were statistically significance. When we compared GC-SRCC vs. CRC-SRCC, only the mutation rate in APC (0% vs 25%) and KRAS (2% vs 22%) genes were significantly different (P < .001). Conclusions: Our research is the first to comprehensively characterize the molecular features of SRCC. Our data suggest that SRCCs harbor similar molecular profile, regardless the tumor location. On the other hand, significant differences were observed between SRCCs and non-SRCC tumors, therefore tailored therapy should be provided to these patients.