Abstract 824: Germline genetic regulation of the adaptive immune response in colorectal cancer
Authors: Schmit Stephanie L. , Tsai Ya-Yu , Bonner Joseph , Sanz-Pamplona Rebeca , Joshi Amit D. , Lindsey Sidney S. , Melas Marilena , McDonnell Kevin J. , Idos Gregory E. , Walker Christopher P. , Kast W. Martin , Da Silva Diane , Ugai Tomotaka , Rennert Hedy S. , Robins Harlan S. , Greenson Joel K. , Ogino Shuji , Moreno Victor , Rennert Gad , Gruber Stephen B. 
Published: July 2021

Adaptive immune responses in the tumor microenvironment of colorectal cancer (CRC) play an important role in prognosis. However, the contributions of germline genetic variations to the strength and diversity of T cell responses in CRC are unclear. We conducted a genome-wide association study to examine the relationships between germline genetic variants and measures of the T cell repertoire in colorectal tumors. Germline DNA samples from 5,581 CRC cases recruited into the Molecular Epidemiology of Colorectal Cancer Study (MECC) were genotyped in batches using four different platforms. Genotype data were imputed to the Haplotype Reference Consortium panel separately by genotyping platform. Tumor DNA samples were extracted from paraffin blocks, and tumor infiltrating lymphocytes per high powered field (TILs/hpf) were quantified by a single gastrointestinal pathologist. TCR abundance and clonality within individual CRCs were measured using the immunoSEQ assay (Adaptive Biotechnologies). Appropriate quality control steps and data transformations were applied to fit downstream statistical modeling assumptions. After standard quality control on both imputed genotypes and transformed immune metrics, 2,876 (TILs/hpf) and 2,395 (TCR abundance and clonality) cases with approximately 9 million imputed genetic variants were included in the discovery phase. Logistic or linear regression models were used to evaluate the associations between allelic dosage of each variant and each immune-related outcome, adjusting for sex, age at diagnosis, genotyping platform, and principal components for global ancestry. Three independent datasets were available to replicate our findings using similar quality control measures and regression models: Colonomics (N=96; TILs/hpf, TCR abundance, clonality), the CRC Genetics Study (N=162; TCR abundance, clonality), and the Harvard Cohorts (N=505; TILs/hpf; in progress). The discovery phase identified 5 independent genetic variants associated with TILs/hpf, 15 associated with TCR abundance, and 19 associated with clonality at p&lt;5X10E-06. Replication analyses as well as expression quantitative trait analyses and in silico functional annotation are underway for the loci of interest. Our study suggests that germline genetic variation is associated with the quantity and quality of adaptive immune responses in CRC.

Citation Format: Stephanie L. Schmit, Ya-Yu Tsai, Joseph Bonner, Rebeca Sanz-Pamplona, Amit D. Joshi, Sidney S. Lindsey, Marilena Melas, Kevin J. McDonnell, Gregory E. Idos, Christopher P. Walker, W. Martin Kast, Diane Da Silva, Tomotaka Ugai, Hedy S. Rennert, Harlan S. Robins, Joel K. Greenson, Shuji Ogino, Victor Moreno, Gad Rennert, Stephen B. Gruber. Germline genetic regulation of the adaptive immune response in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 824.