RT Journal Article
SR Electronic
T1 Quantifying Immune-Based Counterselection of Somatic Mutations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 219576
DO 10.1101/219576
A1 Fan Yang
A1 Dae-Kyum Kim
A1 Hidewaki Nakagawa
A1 Shuto Hayashi
A1 Seiya Imoto
A1 Lincoln Stein
A1 Frederick P. Roth
YR 2018
UL http://biorxiv.org/content/early/2018/06/08/219576.abstract
AB It is now well established that somatic mutations in protein-coding regions can generate ‘neoantigens’, and that these can be recognized by the immune system and contribute to clearance of developing cancers. However, there is currently no model that can quantitatively predict the neoantigenic effect of any given somatic mutation. Here, we examined signatures of immune selection pressure on the distribution of somatic mutations. We quantified the extent to which somatic mutations are significantly depleted in peptides that are predicted to be displayed by major histocompatibility complex (MHC) class I proteins. We characterized the dependence of this depletion on expression level. We then examined whether immune selection pressure on somatic mutations changes depending on whether the patient had either one or two MHC-encoding alleles that can display the peptide. Our results indicate that MHC-encoding alleles are, in general, incompletely dominant, i.e., that having two copies of the display-enabling allele is more effective in displaying that peptide than having just one copy. More generally, a quantitative understanding of counter-selection of identifiable subclasses of neoantigenic somatic variation could guide immunotherapy or aid in developing personalized cancer vaccines.