Abstract 2167: Unbiased genomic approaches identify 2 major subclasses of Gastric Cancer with prognostic and predictive value superior to Lauren's and also reveals subtype-specific treatment opportunities

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: The Lauren's classification of gastric cancer (GC) is widely used with 2 subtypes, intestinal and diffuses having distinct histo-pathological and epidemiological characteristics. Beyond diagnosis, Lauren's classes have limited prognostic and no predictive value. Methods: We performed gene expression profiling on 37 GC cell lines (GCCL) and 2 independent cohorts of 200 (SG) and 68 (AU) primary GC tumors. We used integrative molecular profiling to discover and characterise molecular subtypes of GC. Results: Unsupervised hierarchal clustering in GCCLs identified 2 distinct major molecular subtypes termed “G1”and “G2”. Linear models for microarray data (LIMMA) identified 171 distinguishing genes. These were mapped into 2 independent datasets of primary tumors where G1 and G2 subclasses were again identified. G1/G2 subtypes, discovered by unbiased techniques, were found to be related to intestinal and diffuse histology respectively (p < 0.001, chi square test) with 69% concordance. We found G1/G2 but not Lauren's classes to be prognostic (G1 vs G2: median survival: 41 vs 25 mths, HR 1.5, 95% CI: 1.1-2.0 p=0.02; Laurens: p=0.6). Among discordant cases, survival approximated G1/G2 classes rather than Laurens. Survival was superior in “G1 but diffuse” compared to “G2 but intestinal” (median 36 vs 17 months, p=0.08). We next examined the interaction of the subclasses with 5-fluorouracil (5-FU), the only chemotherapy approved for adjuvant treatment of GC. 5 -FU sensitivity as measured by GI-50 in a previous publication was greater in G1 lines (p=0.04). In primary tumours, G1 patients had improved progression free survival with 5FU/RT of borderline significance (test for interaction, p=0.09). We next applied genomic pathway analysis using an approach we previously published (Ooi et al. Plos Genetics 2009). Her2/Ras/ER/PR/BRCA pathways and VEGF/p53/EGFR pathways were deregulated in G1 and G2 subtype respectively suggesting possible subtype specific treatment opportunities. Conclusion: We describe an unbiased genomic approach that improves upon Lauren's to identify the two major subclasses of gastric cancer. G1/G2 classes have superior prognostic and predictive value and subclass specific therapeutic opportunities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2167.