Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer.

Autor:	Tsai YY; Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, United States., Qu C; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States., Bonner JD; Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States., Sanz-Pamplona R; Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain.; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.; Hospital Universitario Lozano Blesa, Aragon Health Research Institute (IISA), ARAID Foundation, Aragon Government, Zaragoza, Spain., Lindsey SS; Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States., Melas M; Molecular Diagnostics, New York Genome Center, New York, NY, United States., McDonnell KJ; Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States., Idos GE; Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States., Walker CP; Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States., Tsang KK; Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States., Da Silva DM; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States., Moratalla-Navarro F; Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain.; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.; Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona, Barcelona, Spain., Maoz A; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States., Rennert HS; B. Rappaport Faculty of Medicine, Technion and the Association for Promotion of Research in Precision Medicine (APRPM), Haifa, Israel., Kast WM; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States., Greenson JK; Department of Pathology, University of Michigan, Ann Arbor, MI, United States., Moreno V; Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain.; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.; Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona, Barcelona, Spain., Rennert G; B. Rappaport Faculty of Medicine, Technion and the Association for Promotion of Research in Precision Medicine (APRPM), Haifa, Israel., Gruber SB; Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States., Schmit SL; Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, United States.; Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Oct 24; Vol. 14, pp. 1268117. Date of Electronic Publication: 2023 Oct 24 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1268117
Abstrakt:	Objective: Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC). Methods: We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I ( A , B , and C ) and HLA class -II loci ( DQB1 , DRB1 , and DPB1 ) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357). Results: Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97, p = 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95, p = 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87, p = 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant. Conclusion: Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC. Competing Interests: GI: receives/received research funding from Myriad Genetics and Laboratories. JG: consultant for Guardant Health. VM: owns stock in Aniling. SG: Co-founder of Brogent International LLC with equity. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Tsai, Qu, Bonner, Sanz-Pamplona, Lindsey, Melas, McDonnell, Idos, Walker, Tsang, Da Silva, Moratalla-Navarro, Maoz, Rennert, Kast, Greenson, Moreno, Rennert, Gruber and Schmit.)
Databáze:	MEDLINE
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