Comprehensive clinicogenomic profiling of signet ring cell carcinoma across multiple organ sites.

Abstract

3138 Background: Signet ring cell carcinoma (SRCC) is a rare, aggressive histological subtype of adenocarcinoma that is associated with earlier age of onset and poor prognosis. It most commonly arises from the stomach but can originate elsewhere. Few studies have compared molecular alterations in SRCC across various primary sites. Utilizing the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) v17.0, we performed a comprehensive analysis of clinicogenomic variables in SRCC across different primary sites. Methods: The AACR GENIE v17.0 database was used to select tumor samples classified as SRCC by the Oncotree Code. We excluded primary SRCC sites with < 10 tumor samples. Samples were analyzed for clinicogenomic characteristics including gender, race, ethnicity, age at sequencing, and oncogenic molecular alterations by OncoKB classification (somatic mutations, structural variants, copy number alterations). We classified “early onset” SRCC as age of sequencing < 50. Chi-square testing was used to compare categorical variables, and Benjamini-Hochberg procedure was used to control the false discovery rate (statistical significance for q < 0.05). Results: From 355 patients with SRCC, 358 tumor samples were analyzed, with the following distribution among primary sites: stomach (n = 168), colon/rectum (n = 125), appendix (n = 38), and bladder (n = 27). There were high rates of early onset SRCC in the stomach (29.2%), colon/rectum (47.2%), and appendix (36.8%). Female gender was numerically higher in stomach (56.9%) and appendix (55.3%) SRCC cases compared to colon/rectum (47.2%) and bladder (33.3%) SRCC cases. The most prevalent altered genes included TP53 (45.0%), CDH1 (19.4%), ARID1A (14.8%), KRAS (12.9%), and SMAD4 (12.3%). There was differential enrichment of molecular alterations across various sites in TP53 , CDH1 , KRAS , SMAD4 , TERT , APC , and BRAF (q < 0.05). Conclusions: To our knowledge, this study represents the largest molecular analysis of SRCC across multiple organ sites, revealing high rates of early onset SRCC and distinctive molecular alteration patterns. These findings underscore the further need to investigate functional implications and potential therapeutic targets for site-specific molecular alterations in SRCC. Highlighted clinicogenomic features. Clinical Variable/ Alteration Total Stomach Colon/Rectum Appendix Bladder q-value Age of Sequencing <50 (%) 34.4% 29.2% 47.2% 36.8% 3.7% <0.001 Female Gender (%) 51.5% 56.9% 47.2% 55.3% 33.3% 0.24 TP53 45.0% 40.5% 48% 31.6% 77.8% 0.011 CDH1 * 19.4% 26.2% 3.4% 7.9% 63% <0.001 KRAS 12.9% 8.3% 17.6% 26.3% 0% 0.0055 SMAD4 * 12.3% 3.6% 20.3% 21.0% 11.1% <0.001 TERT * 8.7% 1.5% 7.1% 0% 66.7% <0.001 APC 5.7% 1.2% 15.3% 0% 0% <0.001 BRAF 3.9% 1.2% 8.8% 2.6% 0% 0.017 *Not all samples profiled for specific alteration; % reflects percentage of samples with alterations of those profiled.