Abstract Colorectal cancer (CRC) is the third most commonly diagnosed cancer and has the second-highest mortality rate overall in the United States (US). Appreciable population differences in incidence and mortality rates persist in the US. These differences are particularly pronounced among Alaska Native peoples who, for over 40 years, have experienced the highest incidence and mortality rates, despite dedicated screening efforts. The reasons underlying these high rates are not understood. A key knowledge gap is the lack of studies characterizing the molecular features of colorectal tumors in Alaska Native patients. This study aims to identify tumor and tumor microenvironment (TME) features present at time of diagnosis that are associated with CRC mortality, and that may contribute to the elevated mortality rate.We analyzed treatment-naïve tumor tissue samples from 217 Alaska Native participants with stage I-III CRC diagnosed at the Alaska Native Medical Center from 2000 to 2017. Participants who died from CRC (n=60) were matched 1:2 to participants who did not die from CRC and who lived at least as long after diagnosis as the participant they were matched to (n=157). Matching was based on age at diagnosis, sex, year of diagnosis, and tumor site and stage. The present study included 139 females (64.1%) and 78 males (35.9%). The median age at diagnosis was 68 years (range: 36-85). At diagnosis, 33 participants (15.2%) had stage I, 93 (42.9%) had stage II, and 91 (41.9%) had stage III CRC. We constructed tissue microarrays (TMAs) from formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks (2 tumor center cores and 1 invasive margin core per tissue) and performed spatial transcriptomics profiling using the GeoMx DSP platform and the Whole Transcriptome Atlas panel. We measured gene expression separately in epithelial and stromal tissue compartments. After quality control, adjustment for batch effects, and normalization, we used DESeq2 to find genes associated with CRC mortality. Analysis was stratified by tissue compartment and tumor location. We performed gene set enrichment analyses using the fgsea R package. Differential gene expression results showed significant downregulation of SPINK4 (3.2-fold decrease, false discovery rate FDR-adjusted p=4.72e-3) and MUC2 (2.6-fold decrease, FDR-adjusted p=1.37e-3) genes in the tumor center epithelial compartment in participants who died from CRC. Gene set enrichment analyses showed that upregulation of interferon gamma response hallmark genes was associated with favorable prognosis across tissue compartments and tumor locations, while upregulation of epithelial-mesenchymal transition hallmark genes in the tumor margin was associated with worse prognosis (all FDR-adjusted p0.05). Additional ongoing work includes cell type deconvolution analyses and expansion of the study size to over 400 Alaska Native participants with CRC. Citation Format: Garrick Chang, Diana Redwood, Amanda L. Koehne, Matthew Fitzgibbon, Conghui Qu, Hang Yin, Elizabeth Donato, Mingang Lin, Cecilia Yeung, James J. Tiesinga, Sushma Thomas, Li Hsu, Christopher I. Li, Timothy K. Thomas, Riki (Ulrike) Peters, Jeroen Huyghe. Spatial transcriptomics profiling of colorectal cancer tumors in Alaska Native peoples: Discovery of prognostic biomarkers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6749.
Chang et al. (Fri,) studied this question.