Characterization of LAT1-related gene expression and its impact on prognostic tumor mutations and gastrointestinal (GI) cancer clinical outcomes.

Abstract

849 Background: Expression of the L-type amino acid transporter 1 (LAT1; gene symbol: SLC7A5 ) is significantly enriched across a wide variety of cancers, and has been associated with cancer progression and poor prognosis. Yet the relationship between LAT1 and known prognostic genomic alterations in genes such as TP53 , KRAS , and BRAF remains understudied. We evaluated SLC7A5 expression within gastrointestinal (GI) tumors in the cBioPortal database and characterized its correlation to known genomic/transcriptomic markers of cancer prognosis. Methods: We used 30,993 samples to analyze expression of SLC7A5 expression z-scores relative to diploid samples (RNA Seq V2 RSEM) across malignancies, excluding overlapping samples, from 88 cancer studies within cBioPortal. Sub-analysis were performed in hepatobiliary (HPB), colorectal (CRC), esophagogastric (EGC), and pancreatic cancers (PDAC), along with a combination of these cancer types (pan-GI-cancer). mRNA expression z-scores relative to diploid samples were stratified by SLC7A5 expression quartiles for each sub-analysis. The log2 ratio (L2R) alteration frequency of genomic/transcriptomic markers between quartiles was evaluated within the pan-GI-cancer cohort and each subgroup using a one-way ANOVA test with FDR correction. Results: SLC7A5 enrichment was significantly associated with worsened overall survival across all cancers (Hazard Ratio (HR) 1.361 95% Confidence Interval (CI) 1.282 - 1.445; p < 0.001). In the pan-GI-cancer cohort, tumors with high SLC7A5 expression were enriched for genomic alterations in TP53 (L2R 0.38), APC (L2R 0.98) and KRAS (L2R 0.61; q < 0.001 for all). In particular, KRAS alterations were enriched in CRCs and HPBs with high SLC7A5 (L2R 0.38 and 3.05; q < 0.001), while TP53 alterations were enriched in EGCs and HPBs (L2R 0.33 and 0.81; q < 0.001). Within KRAS mutant GI tumors, SLC7A5 -high expression status trended towards worsened disease free survival (HR 1.143 95% CI 0.745 - 1.753; p = 0.527). Conversely, alterations in CDH1 and SMAD4 were significantly depleted in SLC7A5 -high EGCs (L2R -2.69; q < 0.001) and PDACs (L2R -0.96, q < 0.001), respectively. Neither ERBB2 (HER2) nor CD274 (PD-L1) expression was correlated with SLC7A5 expression status in any GI cancer. Conclusions: SLC7A5 expression levels are correlated with mutations in poor prognostic genomic markers, such as TP53 , KRAS , and APC , in GI malignancies. For KRAS , SLC7A5 -high status appears to be an independent poor prognostic indicator, though larger data sets are necessary to confirm these findings. Future prospective analyses may provide further insight into the mechanisms by which LAT1 expression impacts GI cancer outcomes.