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

Abstract

Homozygous deletion (HD) of CDKN2A and CDKN2B (CDKN2A/BHD) is the most frequent copy‐number variation (CNV) in lung adenocarcinoma (LUAD). CDKN2A/BHD 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/BHD was present in 19.1% of the TCGA‐LUAD cohort and in 5.7% of the MSK‐IMPACT cohort. CDKN2A/BHD patients had shorter disease‐free survival and overall survival compared with CDKN2A/BWT individuals in both cohorts. Differences in clinical features did not influence the outcomes in the CDKN2A/BHD population. Mutation analyses showed that overall tumor mutational burden and mutations in classical drivers such as EGFR and RB1 were not associated with CDKN2A/BHD. In contrast, homozygous deletion of type I interferons (IFN‐IHD) frequently co‐occurred with CDKN2A/BHD. CDKN2A/B and IFN‐I are co‐located in the same p21.3 region of chromosome 9. The co‐occurrence of CDKN2A/BHD and IFN‐IHD was not related to whole‐genome doubling, chromosome instability, or aneuploidy. Patients with co‐occurring CDKN2A/BHD and IFN‐IHD had shorter disease‐free survival and overall survival compared with CDKN2A/BWT patients. CDKN2A/BHDIFN‐IHD had downregulated several key immune response pathways, suggesting that poor prognosis in CDKN2A/BHD LUAD could potentially be attributed to an immunosuppressive tumor microenvironment as a result of IFN‐I depletion.

Common and distinct patterns of acquired uniparental disomy and homozygous deletions between lung squamous cell carcinomas and lung adenocarcinoma

“…Interestingly, consistent with previous reports HMD at CDKN2A/B were associated with shorter OS and RFS in LUAD [ 33 , 34 ]. In this study, association between aUPD at CDKN2A/B region worsened survival was also observed.…”

Development of a cuproptosis-related signature for prognosis prediction in lung adenocarcinoma based on WGCNA

“…Notably, the prevalence of CNV loss in CDKN2A exceeded 20%. CDKN2A was a cuproptosis suppressor gene, and homozygous deletion of CDKN2A was associated with shorter disease-free survival and OS ( 25 ).…”

Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

“…However, what is less known is the usual loss of type I interferon genes together with CDKN2A losses (37). Interestingly, those CDKN2A associated type I interferon losses have been shown to present altered immune gene signatures in tumors (38). In myeloma cancer cell lines, which are also frequently depending on IL-6 autocrine signaling, it has been shown that the addition of IFNα in the culture media can downregulate the gene and protein expression of IL-6 receptor subunits and therefore directly hamper the positive feedback loops of the pathway (39).…”