Co-occurrence of CDKN2A/B and IFN-I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma

作者全名："Peng, Yuan; Chen, Yonghong; Song, Mengmeng; Zhang, Xiaoyue; Li, Pansong; Yu, Xian; Huang, Yusheng; Zhang, Ni; Ji, Liyan; Xia, Lei; Xia, Xuefeng; Yi, Xin; Tan, Benxu; Yang, Zhenzhou"

作者地址："[Peng, Yuan; Chen, Yonghong; Zhang, Xiaoyue; Yu, Xian; Huang, Yusheng; Zhang, Ni; Xia, Lei; Tan, Benxu; Yang, Zhenzhou] Chongqing Med Univ, Affiliated Hosp 2, Dept Canc Ctr, Chongqing 400010, Peoples R China; [Song, Mengmeng; Li, Pansong; Ji, Liyan; Xia, Xuefeng; Yi, Xin] Geneplus Beijing Inst, Beijing, Peoples R China"

通信作者："Tan, BX; Yang, ZZ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Canc Ctr, Chongqing 400010, Peoples R China."

来源：MOLECULAR ONCOLOGY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000769059700001

JCR分区：Q1

影响因子：6.6

年份：2022

卷号：16

期号：8

开始页：1746

结束页：1760

文献类型：Article

关键词：CDKN2A; B; homozygous deletion; tumor immune microenvironment; type I interferons

摘要："Homozygous deletion (HD) of CDKN2A and CDKN2B (CDKN2A/B-HD) is the most frequent copy-number variation (CNV) in lung adenocarcinoma (LUAD). CDKN2A/B-HD has been associated with poor outcomes in LUAD; however, the mechanisms of its prognostic effect remain unknown. We analyzed genome, transcriptome, and clinical data from 517 patients with LUAD from the Cancer Genome Atlas (TCGA) and from 788 primary LUAD tumor and matched control samples from the MSK-IMPACT clinical cohort. CDKN2A/B-HD was present in 19.1% of the TCGA-LUAD cohort and in 5.7% of the MSK-IMPACT cohort. CDKN2A/B-HD patients had shorter disease-free survival and overall survival compared with CDKN2A/B-WT individuals in both cohorts. Differences in clinical features did not influence the outcomes in the CDKN2A/B-HD population. Mutation analyses showed that overall tumor mutational burden and mutations in classical drivers such as EGFR and RB1 were not associated with CDKN2A/B-HD. In contrast, homozygous deletion of type I interferons (IFN-I-HD) frequently co-occurred with CDKN2A/B-HD. CDKN2A/B and IFN-I are co-located in the same p21.3 region of chromosome 9. The co-occurrence of CDKN2A/B-HD and IFN-I-HD was not related to whole-genome doubling, chromosome instability, or aneuploidy. Patients with co-occurring CDKN2A/B-HD and IFN-I-HD had shorter disease-free survival and overall survival compared with CDKN2A/B-WT patients. CDKN2A/(BIFN)-I-HD-I-HD had downregulated several key immune response pathways, suggesting that poor prognosis in CDKN2A/B-HD LUAD could potentially be attributed to an immunosuppressive tumor microenvironment as a result of IFN-I depletion."

基金机构："National Natural Science Foundation of China [81802984, 81972851, 82002448]; Chongqing Talents Program [CQYC20200303151]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (Grant No. 81802984, No. 81972851, and No. 82002448) and the Chongqing Talents Program (Grant CQYC20200303151)."