Abstract 1515: Tumor molecular profiling and spatial transcriptomics to assess colorectal cancer heterogeneity and microenvironment

Abstract Introduction: CRC is the second leading cause of cancer mortality in the United States. Clinical factors and molecular characteristics may impact therapeutics and prognosis. Scientific studies have uncovered significant aberrations, including critical genes and pathways. Despite these efforts, few studies have utilized similar sample sizes to TCGA, heterogeneous populations and integrative clinical data to compare their reported genomic changes, even though little is known about the tumor microenvironment and its significance for colorectal tumorigenesis. Methods: Clinical and DNA genomic data from 262 colorectal tumor/normal DNA samples were obtained for whole exome sequencing analysis from the Oncology Research Information Exchange Network and two colorectal tissue samples for Spatial Transcriptomics profiling from the USC colorectal cancer Moonshot project. Whole Exome Sequencing data analysis was used for identifying genetic alterations. Samples were stratified based on microsatellite instability, age group, anatomical subsites, and histological subtypes. Emphasis was given to comparing molecular characteristics among Hispanic/Latino patients since their reported higher mortality and cancer disparities. Mutation frequencies from our cohort were compared to those from the TCGA. An ongoing spatial transcriptomics analysis consists in processing two fresh-frozen tissue samples through the visium spatial gene expression library using standard short-read sequencing. Results: Tumor molecular profiling revealed 20 genes significantly mutated. We found differences in gene mutation frequencies among our samples, highlighting APC (60%), TP53 (56%), TTN (49%), and KRAS (44%) gene mutations. In comparison with TCGA data, in addition to the expected APC, TP53, PIK3CA, and KRAS mutations, we found frequent mutations in POLE and TTN. To assess the basis for the considerably different mutation rates, we evaluated MSI. Among the 262 tumors, 41 (16%) had high levels of MSI, 2 (1%) had low levels of MSI (MSI-L), and 215 (82%) were microsatellite stable (MSS). Cancer heterogeneity was reported among tumors with different characteristics such as age group, anatomical subsite, and histological subtypes. The ongoing spatial transcriptomics analysis that will be ready before the annual meeting will identify cellular populations and map immunological and inflammatory signals in the microenvironment. Conclusions: Our study reveals the impact of molecularly profiling tumors using considerable sample sizes and stratified samples in several subgroups. Our study adds important information about tumor heterogeneity and the tumor microenvironment in colorectal cancer by including our spatial transcriptomics data analysis. Citation Format: Enrique Velazquez Villarreal, Seeta Rajpara, Yuxin Jin, Jing Qian, Bohan Zhang, Brigette Waldrup, Donna Loza, Heinz-Josef Lenz, David W. Craig, John D. Carpten. Tumor molecular profiling and spatial transcriptomics to assess colorectal cancer heterogeneity and microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1515.