Evolutionary dynamics of neoantigens in growing tumors.
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Authors
Lakatos, E
Williams, MJ
Schenck, RO
Cross, WCH
Househam, J
Zapata, L
Werner, B
Gatenbee, C
Robertson-Tessi, M
Barnes, CP
Anderson, ARA
Sottoriva, A
Graham, TA
Williams, MJ
Schenck, RO
Cross, WCH
Househam, J
Zapata, L
Werner, B
Gatenbee, C
Robertson-Tessi, M
Barnes, CP
Anderson, ARA
Sottoriva, A
Graham, TA
Document Type
Journal Article
Date
2020-10-01
Date Accepted
2020-07-06
Abstract
Cancers accumulate mutations that lead to neoantigens, novel peptides that elicit an immune response, and consequently undergo evolutionary selection. Here we establish how negative selection shapes the clonality of neoantigens in a growing cancer by constructing a mathematical model of neoantigen evolution. The model predicts that, without immune escape, tumor neoantigens are either clonal or at low frequency; hypermutated tumors can only establish after the evolution of immune escape. Moreover, the site frequency spectrum of somatic variants under negative selection appears more neutral as the strength of negative selection increases, which is consistent with classical neutral theory. These predictions are corroborated by the analysis of neoantigen frequencies and immune escape in exome and RNA sequencing data from 879 colon, stomach and endometrial cancers.
Citation
Nature genetics, 2020, 52 (10), pp. 1057 - 1066
Source Title
Publisher
NATURE PORTFOLIO
ISSN
1061-4036
eISSN
1546-1718