Genetic Variation and Regulation of MICA Alters Natural Killer Cell-Mediated Immunosurveillance in Early-Onset Colorectal Cancer
Authors: McGee Heather M. , Bonner Joseph D. , Egelston Colt , Fu Yubo , Flores Oscar Colunga , Lindsey Sidney , Shaktah Lawrence , Moratalla-Navarro Ferran , Kamal Yasmin , Tsang Kevin , Walker Christopher P. , Idos Gregory , McDonnell Kevin J. , Rennert Hedy , Barry Elizabeth L , Brenner Hermann , Buchanan Daniel D. , Campbell Peter T. , Chan Andrew T. , Chang-Claude Jenny , Figueiredo Jane C. , Gago-Dominguez Manuela , Hoffmeister Michael , Hsu Li , Huyghe Jeroen R. , Jenkins Mark A. , Le Marchand Loic , Lenz Heinz-Josef , Li Li , Lindblom Annika , Liu (Ruby) Yun Ru , Lynch Brigid M. , Newton Christina C. , Offit Kenneth , Ogino Shuji , Pamplona Rebeca Sanz , Pellatt Andrew J. , Pharoah Paul D. P. , Phipps Amanda , Reynaga Lorena , Templeton Allyson , Um Caroline Y. , Wolk Alicja , Woods Michael O. , Wu Anna H. , Yun Yen , Zheng Wei , Williams Terence M. , Conti David V , Peters Ulrike , Lejbkowicz Flavio , Greenson Joel K. , Schmit Stephanie L. , Gauderman William J , Hamilton Stanley R. , Moreno Victor , Rennert Gad , Gruber Stephen B. 
Published: September 2024

The incidence of colorectal cancer (CRC) among individuals under age 50, or early-onset CRC (EOCRC), has been rising over the past few decades for unclear reasons, and the etiology of the disease remains largely unknown. Known genetic risk factors do not explain this increase, pointing to possible environmental and as-yet unidentified genetic contributors and their interactions. Previous research linked genetic variation on chromosome 6 to increased CRC risk. This region harbors multiple immune genes, including the gene encoding Major Histocompatibility Complex (MHC) class I polypeptide-related sequence A (MICA). MICA is a polygenic ligand for the Natural Killer Group 2D receptor (NKG2D), a receptor expressed on Natural Killer (NK) cells and other lymphocytes. Given that intra-tumoral NK cell infiltration correlates with favorable CRC outcomes, we hypothesized that germline genetic variation inMICAcould influence CRC risk. In a discovery set of 40,125 cases and controls, we show that the minor G allele at Chr6:31373718C>G (hg19) is associated with increased risk for CRC (odds ratio (OR) = 1.09, 95% confidence interval (CI) 1.04 - 1.15, p = 0.0009). The effect is stronger in EOCRC (OR = 1.26, 95% CI 1.08 - 1.44, p = 0.0023) than in those 50 and over (OR = 1.07, 95% CI 1.02 - 1.13; p = 0.012) (Ratio of ORs = 1.32, 95% CI 1.14 - 1.52, p = 0.0002). In an independent validation set of 77,983 cases and controls, the adjusted interaction by age-of-onset was significant at OR = 1.15 (95% CI 1.03 - 1.34, p = 0.0150) with a higher risk in EOCRC. Expression quantitative trait locus analysis in normal colonic epithelia showed that MICA RNA expression decreases linearly with each additional copy of the minor G allele (p = 3.345 × 10e-18). Bulk RNA analysis of the tumor immune microenvironment revealed that tumors from patients with CG or GG genotypes have lower resting and activated NK cell infiltration as compared to tumors from patients with CC genotype. Multiplex immunofluorescence analysis demonstrated that patients with a G allele (i.e. CG or GG genotype, but not CC genotype) have a statistically significant decrease in the number of NK cells in tumor compared to adjacent normal colonic mucosa. Taken together, population-based epidemiologic, molecular, genetic, cellular and immunologic evidence demonstrate thatMICAgenotype is associated with increased risk of EOCRC and reduced number of NK cells in colorectal tumors, suggesting that patients with a G allele have altered NK cell-mediated immunosurveillance. These novel findings suggest that EOCRC may have a previously unrecognized innate immune-mediated etiology which merits further investigation.