TY - JOUR
T1 - Integrative genomic analyses of APOBEC-mutational signature, expression and germline deletion of APOBEC3 genes, and immunogenicity in multiple cancer types
AU - Chen, Zhishan
AU - Wen, Wanqing
AU - Bao, Jiandong
AU - Kuhs, Krystle L.
AU - Cai, Qiuyin
AU - Long, Jirong
AU - Shu, Xiao Ou
AU - Zheng, Wei
AU - Guo, Xingyi
N1 - Publisher Copyright:
© 2019 The Author(s).
PY - 2019/9/18
Y1 - 2019/9/18
N2 - Background: Although APOBEC-mutational signature is found in tumor tissues of multiple cancers, how a common germline APOBEC3A/B deletion affects the mutational signature remains unclear. Methods: Using data from 10 cancer types generated as part of TCGA, we performed integrative genomic and association analyses to assess inter-relationship of expressions for isoforms APOBEC3A and APOBEC3B, APOBEC-mutational signature, germline APOBEC3A/B deletions, neoantigen loads, and tumor infiltration lymphocytes (TILs). Results: We found that expression level of the isoform uc011aoc transcribed from the APOBEC3A/B chimera was associated with a greater burden of APOBEC-mutational signature only in breast cancer, while germline APOBEC3A/B deletion led to an increased expression level of uc011aoc in multiple cancer types. Furthermore, we found that the deletion was associated with elevated APOBEC-mutational signature, neoantigen loads and relative composition of T cells (CD8+) in TILs only in breast cancer. Additionally, we also found that APOBEC-mutational signature significantly contributed to neoantigen loads and certain immune cell abundances in TILs across cancer types. Conclusions: These findings reveal new insights into understanding the genetic, biological and immunological mechanisms through which APOBEC genes may be involved in carcinogenesis, and provide potential genetic biomarker for the development of disease prevention and cancer immunotherapy.
AB - Background: Although APOBEC-mutational signature is found in tumor tissues of multiple cancers, how a common germline APOBEC3A/B deletion affects the mutational signature remains unclear. Methods: Using data from 10 cancer types generated as part of TCGA, we performed integrative genomic and association analyses to assess inter-relationship of expressions for isoforms APOBEC3A and APOBEC3B, APOBEC-mutational signature, germline APOBEC3A/B deletions, neoantigen loads, and tumor infiltration lymphocytes (TILs). Results: We found that expression level of the isoform uc011aoc transcribed from the APOBEC3A/B chimera was associated with a greater burden of APOBEC-mutational signature only in breast cancer, while germline APOBEC3A/B deletion led to an increased expression level of uc011aoc in multiple cancer types. Furthermore, we found that the deletion was associated with elevated APOBEC-mutational signature, neoantigen loads and relative composition of T cells (CD8+) in TILs only in breast cancer. Additionally, we also found that APOBEC-mutational signature significantly contributed to neoantigen loads and certain immune cell abundances in TILs across cancer types. Conclusions: These findings reveal new insights into understanding the genetic, biological and immunological mechanisms through which APOBEC genes may be involved in carcinogenesis, and provide potential genetic biomarker for the development of disease prevention and cancer immunotherapy.
KW - APOBEC
KW - APOBEC-signature mutations
KW - Gene expression
KW - Germline APOBEC3A/B deletion
KW - Isoforms
KW - Neoantigen
KW - Pan-cancer
KW - TILs
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U2 - 10.1186/s12920-019-0579-3
DO - 10.1186/s12920-019-0579-3
M3 - Article
C2 - 31533728
AN - SCOPUS:85072386126
VL - 12
IS - 1
M1 - 131
ER -