MHC-I Genotype Restricts the Oncogenic Mutational Landscape

Area of Science:

• Immunology
• Oncology
• Genetics

Background:

• Human leukocyte antigen class I (MHC-I) molecules present intracellular peptides to T cells, crucial for immune surveillance.
• The specific set of MHC-I alleles an individual possesses defines their unique sub-peptidome, influencing immune recognition.
• Cancer development may be influenced by 'gaps' in an individual's MHC-I presentation, allowing specific mutations to evade immune detection.

Purpose of the Study:

• To investigate if human leukocyte antigen class I (MHC-I) presentation gaps influence the emergence of oncogenic mutations in human cancer.
• To develop a predictive model for mutation occurrence based on patient MHC-I genotype and presentation capacity.

Main Methods:

• Developed a residue-centric patient presentation score.
• Applied the score to analyze 9,176 cancer patients and 1,018 recurrent oncogenic mutations.
• Correlated patient MHC-I genotype-based presentation scores with mutation frequency in tumors.

Main Results:

• Patient MHC-I genotype-based scores effectively predicted the likelihood of specific mutations arising in tumors.
• Mutations with poor MHC-I presentation across patient cohorts were found at higher frequencies in tumors.
• Demonstrated a link between MHC-I genotype-restricted presentation and the observed landscape of oncogenic mutations.

Conclusions:

• Human leukocyte antigen class I (MHC-I) genotype-restricted immunoediting significantly shapes the spectrum of oncogenic mutations during tumor formation.
• Understanding individual MHC-I presentation capabilities can aid in predicting personal cancer susceptibilities.
• This research opens avenues for personalized cancer risk assessment based on MHC-I genetics.