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. 2022 Mar 15;16(8):1746–1760. doi: 10.1002/1878-0261.13206

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

Yuan Peng 1, Yonghong Chen 1, Mengmeng Song 2, Xiaoyue Zhang 1, Pansong Li 2, Xian Yu 1, Yusheng Huang 1, Ni Zhang 1, Liyan Ji 2, Lei Xia 1, Xuefeng Xia 2, Xin Yi 2, Benxu Tan 1,✉, Zhenzhou Yang 1,✉
PMCID: PMC9019898  PMID: 35253368

Abstract

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/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/B HD and IFN‐I HD had shorter disease‐free survival and overall survival compared with CDKN2A/B WT patients. CDKN2A/B HD IFN‐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.

Keywords: CDKN2A/B, homozygous deletion, tumor immune microenvironment, type I interferons

CDKN2A/B homozygous deletion (CDKN2A/BHD) was a common event and associated with poor outcomes in lung adenocarcinoma (LUAD). Homozygous deletion of type I interferons (IFN‐IHD) frequently co‐occurred with CDKN2A/BHD. CDKN2A/BHDIFN‐IHD had shorter survival times than CDKN2A/BWT and downregulated immune response pathways, suggesting that poor prognosis in CDKN2A/BHD LUAD could potentially be attributed to an immunosuppressive tumor microenvironment owing to IFN‐I depletion.

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Abbreviations

CNV

copy‐number variation

DFS

disease‐free survival

GSEA

gene set enrichment analysis

HD

homozygous deletion

IFN‐I

type I interferons

LUAD

lung adenocarcinoma

NSCLC

non‐small cell lung carcinoma

OS

overall survival

TCGA

The Cancer Genome Atlas

TMB

tumor mutational burden

TSG

tumor suppressor gene

1. Introduction

As typical tumor suppressor genes (TSGs), the cyclin‐dependent kinase inhibitors CDKN2A and CDKN2B located on chromosome 9, band p21.3, are frequently mutated, deleted, or dysregulated in a variety of cancers [1, 2, 3, 4, 5]. Deficient function of TSGs leads to tumor proliferation and progression. Homozygous deletion (HD) and corresponding loss of function of CDKN2A and CDKN2B is associated with poor prognosis in diffuse malignant IDH‐mutant glioma [6], thymic carcinoma [7], pleural mesothelioma [8], urothelial bladder carcinoma [9], neuroblastoma [10], T cell acute lymphoblastic leukemia [11], and pancreatic cancer [12]. This suggests that CDKN2A and CDKN2B play an important role in certain cancer types.

Knowledge of the roles of CDKN2A and CDKN2B HD in lung adenocarcinoma (LUAD) is scarce. CDKN2A was mutated or homozygously deleted in 20 of 32 (63%) non‐small cell lung carcinoma (NSCLC) cell lines, and CDKN2B HD was also detected in the same lines [13]. Two‐hit inactivation of CDKN2A/2B was frequently found in KRAS‐mutant LUAD in The Cancer Genome Atlas (TCGA) database, and loss of CDKN2A/B fostered cellular proliferation, cancer cell differentiation, and metastatic behavior in genetically engineered mouse models of KRAS‐mutant lung tumorigenesis [14]. Recently, loss of CDKN2A function was found to be related to NSCLC clinical outcomes. CDKN2A HD was detected in 24.4% (31/127) of LUADs in a Chinese cohort, and the occurrence of CDKN2A HD in EGFR‐mutant LUADs was associated with poor response to EGFR tyrosine kinase inhibitors (TKIs) [15]. These findings support the significance of CDKN2A HD in the clinical management of LUAD; however, the mechanisms of CDKN2A/B HD and its effects on the tumor immune microenvironment have not been revealed.

In this study, we aimed to reveal the key genomic and immune‐related mechanisms of the prognostic effects of CDKN2A and CDKN2B HD on LUAD prognosis. We found that HD of type I interferon (IFN‐I) genes was the most frequent type of copy‐number variation (CNV) accompanying CDKN2A and CDKN2B HD in LUAD. A previous report suggested that homozygous co‐deletion of IFN‐I and CDKN2A is a potential biomarker for therapy in thoracic cancers [16]. There are 16 IFN‐I genes located on chromosome 9p21 that share a common receptor, induce immune response, and participate in cell antiviral and anti‐tumor defense. We found that co‐deletion of IFN‐I and CDKN2A or CDKN2B was associated with poor clinical outcomes and downregulated expression of genes related to inflammatory response, adaptive immune response, and JAK‐STAT signaling in the tumor microenvironment. These findings provide fundamental knowledge about LUAD with cyclin‐dependent kinase inhibitor dysfunction and indicate the necessity of tailored treatment for patients with this molecular subtype of lung cancer.

2. Materials and methods

2.1. Datasets from the TCGA and MSK‐IMPACT Cohorts

We used the TCGAbiolinks R package to download data of 517 TCGA‐LUAD primary tumor samples and matched nontumor samples, including somatic mutation and masked CNV segment data, RNA sequencing data, and clinical data [17]. We downloaded corresponding patient follow‐up data from the cBioportal database (http://www.cbioportal.org/). In addition, we downloaded data of 788 primary LUAD tumor samples and matched control samples from the MSK‐IMPACT clinical sequencing cohort using the cBioportal website.

2.2. Focal‐level and arm‐level identification

There were multiple primary tissue samples for some of the patients; however, to ensure consistency of the CDKN2A/B mutation status, we only used one primary tumor sample from each patient. If more than one sample was available for a given patient, we selected a single sample with HD of CDKN2A or CDKN2B (CDKN2A/BHD ). In cases where a single patient had more than one sample with CDKN2A/BHD , we randomly selected one of these samples to use.

To identify genes with somatic CNV, we used GISTIC2 [18] with the following parameters: ‐ta 0.1, ‐armpeel 1, ‐brlen 0.7, ‐cap 1.5, ‐conf 0.99, ‐td 0.1, ‐genegistic 1, ‐gcm extreme, ‐js 4, ‐maxseg 2000, ‐qvt 0.25, ‐rx 0, ‐savegene 1, ‐broad 1, and all other parameters set to default values. The copy number for each gene was given in an all_thresholded.by_genes.txt file, with values of −2, −1, 0, 1, and 2 representing deep deletion (HD), shallow deletion, diploid, low‐level gain, and high‐level gain, respectively.

2.3. Mutation signature analysis

We extracted mutation signatures from the samples using the Sigminer R package. First, we used the read_maf method to load all the somatic mutations and tallied components in each sample. We then generated a sample‐by‐component matrix using the sig_tally method. Then, we used sig_fit to perform a signature decomposition of the mutation catalog and compute the absolute exposure of all COSMIC mutation signatures from the spectrum of each sample. This resulted in an absolute exposure matrix, in which the rows represented the samples and the columns represented the COSMIC signatures. We then used Fisher’s exact test to determine whether or not each signature was associated with CDKN2A/B CNV status.

2.4. Immunity analysis and gene set enrichment analysis

We performed immunity analysis using the GSVA [19] package and 25 previously reported immune‐related gene sets covering the innate and adaptive immune responses [20]. This produced an enrichment score for each immune‐related gene set in each sample. We used gene set enrichment analysis (GSEA) software to identify biological pathways that were differentially enriched (P‐value > 0.05 and absolute value of enrichment score > 1) between tumor molecular subtypes [21].

2.5. Statistical analysis

We performed Kaplan–Meier survival analyses implemented in the R package survival. We then used log‐rank tests to determine significant differences in survival curves. We reported median overall survival (OS) with 95% confidence intervals in relevant cases. We used Fisher’s exact tests to determine associations between genomic characteristics and clinical characteristics and to determine which mutations/CNV co‐occurred or were mutually exclusive with CDKN2A/B HD. We used Mann–Whitney tests to compare differences between different tumor molecular subtypes. P‐values less than 0.05 were considered statistically significant.

3. Results

3.1. CDKN2A/B HD was highly recurrent and indicated poor prognosis in LUAD

We first investigated the prevalence of CDKN2A and CDKN2B HD in two independent LUAD cohorts. In the TCGA‐LUAD cohort, the frequencies of CDKN2A HD and CDKN2B HD were 19.0% (98/517) and 18.4% (95/517), respectively. Co‐deletion of both genes within the same patient was very common (P < 0.001, OR = 7572.3), so we decided to analyze both genes in combination. The patient characteristics of the TCGA‐LUAD cohort are described in Table S1. HD of CDKN2A or CDKN2B (CDKN2A/B HD) was the most prevalent CNV event in the TCGA‐LUAD cohort, appearing in 19.1% (99/517) of the patients. CDKN2A/B HD was also one of the prevalent CNV events in the MSK‐IMPACT cohort, appearing in 5.7% (45/788) of the patients. These results confirmed that CDKN2A/B HD is a common genetic event in LUAD, which is consistent with previous reports [22].

We next analyzed the potential influence of CDKN2A/B HD on LUAD outcomes, using disease‐fee survival (DFS) and OS as the primary endpoints. In the TCGA‐LUAD cohort, patients with CDKN2A/B HD tumors had significantly shorter DFS (P = 0.015, HR 0.66, 95% CI 0.45–0.97; Fig. 1A) and OS (P = 0.040, HR 0.70, 95% CI 0.49–1.02; Fig. 1B) than patients with wild‐type CDKN2A/B (CDKN2A/B WT) tumors. CDKN2A/B HD was also associated with shortened OS in the MSK‐IMPACT cohort (P < 0.001, HR 0.45, 95% CI 0.24–0.85; Fig. 1C). The MSK‐IMPACT cohort did not provide DFS data. These results confirmed CDKN2A/B HD poor prognostic factor in LUAD.

Fig. 1.

Fig. 1

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Relationship between CDKN2A/B homozygous deletion and survival in the TCGA‐LUAD cohort and the MSK‐IMPACT cohort. (A) Disease‐free survival in patients with CDKN2A/B homozygous deletion (n = 87) or wild‐type CDKN2A/B (n = 373) in the TCGA‐LUAD cohort. (B) Overall survival in patients with CDKN2A/B homozygous deletion (n = 99) or wild‐type CDKN2A/B (n = 409) in the TCGA‐LUAD cohort. (C) Overall survival in patients with CDKN2A/B homozygous deletion (n = 43) or wild‐type CDKN2A/B (n = 678) in the MSK‐IMPACT cohort. The log‐rank test was used to compare the survival times between two groups. A 95% confidence interval was used to indicate the precision of the estimated hazard ratio.

3.2. CDKN2A/B HD tumors had disparate mutational features compared with CDKN2A/BWT tumors

To explore the prognostic mechanism of CDKN2A/B HD in LUAD, we first analyzed common clinical characteristics including age, gender, smoking history, and tumor stage. The results revealed no significant differences in clinical characteristics between patients with CDKN2A/B HD and patients with CDKN2A/B WT in the TCGA‐LUAD cohort (Figs. 2A‐D). Furthermore, although high tumor mutational burden (TMB) was associated with better prognosis in a previous study of patients with resected LUAD [23], there was no significant difference in TMB between CDKN2A/B HD tumors and CDKN2A/B WT tumors in the TCGA‐LUAD cohort (Fig. 2E).

Fig. 2.

Fig. 2

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Comparison of clinical characteristics and genomic features between patients with CDKN2A/B homozygous deletion and patients with wild‐type CDKN2A/B. The associations between CDKN2A/B CNV status (CDKN2A/B homozygous deletion: n = 99, wild‐type CDKN2A/B: n = 418) and (A) age, (B) smoking history, (C) gender, and (D) tumor stage (CDKN2A/B homozygous deletion: n = 98, wild‐type CDKN2A/B: n = 411). (E) Comparison of mutational burden between tumors with CDKN2A/B homozygous deletion (n = 96) and tumors with wild‐type CDKN2A/B (n = 407). (F) The mutation landscape of tumors with CDKN2A/B homozygous deletion (n = 96). (G) Comparison of the frequencies of recurrently mutated genes between tumors with CDKN2A/B homozygous deletion (n = 96) and tumors with wild‐type CDKN2A/B (n = 407). (H) Mutations that co‐occurred or were mutually exclusive with CDKN2A/B homozygous deletion (n = 96, wild‐type CDKN2A/B: n = 407). (I) The distribution of mutational signatures in tumors with CDKN2A/B homozygous deletion (n = 96) and tumors with wild‐type CDKN2A/B (n = 407). The graph showed the estimates and 95% confidence intervals. (J) The distribution of mutant pathways in tumors with CDKN2A/B homozygous deletion (n = 96) and tumors with wild‐type CDKN2A/B (n = 407). (A, E) P‐values were calculated by Mann–Whitney test. The centerline of the boxplot represents the median, while the lower and upper limits of the box correspond to the 25th and 75th percentiles. Whiskers extend from the box limit to the minimum or maximum, not exceeding the 1.5 * quartile range. (B, C, D, H, I, J) P‐values were calculated by Fisher’s test.

We compared the genomic landscapes between CDKN2A/B HD tumors and CDKN2A/B WT tumors in the TCGA cohort to identify potentially prognostic genetic factors. The most frequently mutated genes, including TP53 (46% vs. 48%), TTN (43% vs. 46%), MUC16 (35% vs. 41%), and CSMD3 (33% vs. 38%), had roughly equivalent mutation frequencies in both molecular subtypes of tumors (Fig. 2F). Also, the mutation frequencies of 11 genes that represented the union of the top 10 recurrently mutated genes in both tumor molecular subtypes were similar (Fig. 2G). We next used Fisher’s exact tests to comprehensively examine co‐occurring and mutually exclusive mutation events. The results showed that mutations in several genes either co‐occurred (e.g., EGFR) or were mutually exclusive (e.g., RB1) with CDKN2A/BHD (Fig. 2H). Further analysis showed that co‐occurring or mutually exclusive mutations were not prognostic in the TCGA cohort (Fig. S1A,B), indicating that the prognostic effect of CDKN2A/B HD was not influenced by these mutations.

To identify the processes driving mutagenesis, we analyzed all the samples in the TCGA‐LUAD cohort to determine the proportion of mutations in each sample that were attributable to COSMIC mutational signatures (v2) on the basis of their flanking trinucleotide context. We then used Fisher’s exact test to test whether each COSMIC signature was associated with CDKN2A/B HD. We found significant associations for three out of 30 COSMIC signatures: signature 4 (associated with tobacco use; OR = 0.53 [0.32–0.89], P = 0.02) and signatures 15 and 26 (associated with defective DNA mismatch repair; OR = 2.26 [1.24–4.05], P = 0.01; Fig. 2I).

We also compared mutations in 10 typical signaling pathways between CDKN2A/B HD tumors and CDKN2A/B WT tumors in the TCGA‐LUAD cohort. If a given pathway contained at least one mutated gene, then we considered the pathway to be mutated. We found that the NOTCH signaling pathway was more likely to mutated in CDKN2A/B WT tumors than in CDKN2A/B HD tumors (P = 0.05; Fig. 2J).

3.3. Variation causing loss of IFN‐I function was the most frequent co‐occurring CNV event with CDKN2A/B HD

Next, we investigated the difference in CNV between CDKN2A/B HD tumors and CDKN2A/B WT tumors to identify potentially prognostic CNV events. The frequencies of copy‐number amplification and deletion in each chromosome region are shown in Fig. 3A. The results showed that the CDKN2A/B HD tumors had a high frequency of deletion in the chromosome 9p region. Differences in copy‐number amplifications between the CDKN2A/B HD tumors and the CDKN2A/B WT tumors mainly appeared on chromosomes 14 and 15 (Fig. 3B), whereas differences in copy‐number deletions appeared on chromosomes 5, 9, 12, 14, 18, 19, and 20. The most significant copy‐number deletions are shown in Fig. 3C. There were no significant differences in genome‐instability index, whole‐genome doubling, or tumor ploidy between the two groups (Fig. 3D,E,F). These results suggested that CDKN2A/B HD LUAD is not associated with broad chromosome‐level instability, which contributes to poor prognosis by accelerating the development of anticancer drug resistance [24].

Fig. 3.

Fig. 3

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Genome‐wide somatic copy‐number variations in patients with wild‐type CDKN2A/B and patients with CDKN2A/B homozygous deletion. (A) The frequencies of genome‐wide somatic copy‐number gain (top) and loss (bottom) in tumors with CDKN2A/B homozygous deletion (n = 99, red line) and wild‐type CDKN2A/B (n = 418, blue line). Significantly different gain (B) or loss (C) frequencies of cytobands in tumors with CDKN2A/B homozygous deletion (n = 99) versus tumors with wild‐type CDKN2A/B (n = 418). Comparison of (D) tumor ploidy, (E) whole‐genome doubling, and (F) genome‐instability index between tumors with CDKN2A/B homozygous deletion (n = 99) and tumors with wild‐type CDKN2A/B (n = 418). (G) Copy‐number variation that was co‐occurring or mutually exclusive with CDKN2A/B homozygous deletion (n = 99). (B, C, E, G) P‐values were calculated by Fisher’s test. (D, F) The centerline of the boxplot represents the median, while the lower and upper limits of the box correspond to the 25th and 75th percentiles. Whiskers extend from the box limit to the minimum or maximum, not exceeding the 1.5 * quartile range. P‐values were calculated by Mann–Whitney test.

We further analyzed the focal and arm‐level copy‐number profiles of the CDKN2A/B HD and CDKN2A/B WT tumors using GISTIC2.0. The CDKN2A/B HD tumors showed a higher degree of arm‐level CNV than the CDKN2A/B WT tumors, and the difference was most pronounced in deletions including 9p, 9q, 18q, and Xp (Fig. 4A). We also identified 41 regions of significant focal‐level CNV in the CDKN2A/B HD tumors (FDR < 0.25; Fig. 4C), including 19 regions of recurrent amplification covering common drivers such as EGFR, MET, FGFR1, MYC, and KRAS, and 22 regions of recurrent deletion, which contained NOTCH2, ATM, and CDKN2A. The frequently mutated 9p21.3 region, where CDKN2A and CDKN2B are located, contains numerous IFN‐I genes, which were the sites of the most common homozygous deletions that co‐occurred with CDKN2A/B HD (Fig. 3G).

Fig. 4.

Fig. 4

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Significant arm‐level and focal somatic copy‐number variations in patients with wild‐type CDKN2A/B and patients with CDKN2A/B homozygous deletion. (A) Somatic CNV of arm‐level amplifications and deletions in CDKN2A/B wild‐type (n = 99) and CDKN2A/B homozygous deletion (n = 418). P‐values were calculated by Fisher’s test. (B) Somatic CNV of focal amplifications and deletions in CDKN2A/B wild‐type (n = 418) and (C) CDKN2A/B homozygous deletion (n = 99).

3.4. Poor outcomes in CDKN2A/B HD LUAD were associated with IFN‐I HD genetic events

IFN‐I is a proinflammatory cytokine induced by viruses and other environmental stressors. It is also an important driver of anti‐tumor immunity, potentially enhancing the ability of immune cells to clear tumor cells [25]. Therefore, we asked whether IFN‐I variation was associated with outcomes in CDKN2A/B HD LUAD. We compared survival among patients with CDKN2A/B WT tumors and patients with CDKN2A/B HD tumors with or without accompanying homozygous deletion in all IFN‐I genes (CDKN2A/B HD IFN‐I HD and CDKN2A/B HD IFN‐I WT, respectively). We found that the patients with CDKN2A/B HD IFN‐I HD tumors had shorter DFS (P < 0.001, HR 0.42, 95% CI 0.22–0.81) and OS (P = 0.02, HR 0.56, 95% CI 0.31–1.03) than the patients with CDKN2A/B WT tumors (Fig. 5A), whereas there was no difference between the patients with CDKN2A/B HD IFN‐I WT tumors and the patients with CDKN2A/B WT tumors in DFS (P = 0.58, HR 0.88, 95% CI 0.55–1.41; Fig. 5C) or OS (P = 0.32, HR 0.81, 95% CI 0.52–1.27; Fig. 5D). These results indicated that concomitant functional deletions of IFN‐I genes contribute to the prognosis of CDKN2A/B HD LUAD.

Fig. 5.

Fig. 5

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Kaplan–Meier curves comparison of disease‐free survival and overall survival between tumors with wild‐type CDKN2A/B and tumors with CDKN2A/B homozygous deletion and wild‐type IFN‐I/IFN‐I homozygous deletion. Differences in (A) disease‐free survival and (B) overall survival between patients with homozygous deletion of both CDKN2A/B and IFN‐I (A: n = 30, B: n = 34) and patients with wild‐type CDKN2A/B (A: n = 373, B: n = 409). Differences in (C) disease‐free survival and (D) overall survival between patients with CDKN2A/B homozygous deletion and wild‐type IFN‐I (C: n = 57, D: n = 65) and patients with wild‐type CDKN2A/B (C: n = 373, D: n = 409). (A, B, C, D) The log‐rank test was used to compare the survival times between two groups. A 95% confidence interval was used to indicate the precision of the estimated hazard ratio.

3.5. Suppression of the tumor immune microenvironment contributed to poor prognosis in CDKN2A/B HD IFN‐I HD LUAD

It was reported that IFN‐I HD in human cancer was associated with immunotherapy resistance [26]. To further explore how the co‐deletion of IFN‐I influences outcomes in CDKN2A/B HD LUAD, we examined the tumor immune microenvironment by performing an immunity estimation of 25 gene sets associated with innate and adaptive immunity. A detailed gene list of the 25 gene sets is shown in Table S2. Comparison of the enrichment scores for the 25 gene sets between CDKN2A/B HD IFN‐I HD tumors and CDKN2A/B HD IFN‐I WT tumors showed that six immune‐related gene sets were relatively downregulated in the CDKN2A/B HD IFN‐I HD tumors, including signatures related to inflammatory response, acute inflammatory response, JAK‐STAT signaling, adaptive immune response, macrophage activation, and myeloid cell activation (Fig. 6A‐F). The results for the other 19 gene sets are shown in Fig. S2.

Fig. 6.

Fig. 6

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Comparison of immune‐related gene sets and pathway enrichment analysis between two different IFN‐I CNV statuses in patients with CDKN2A/B homozygous deletion. (A–F) Comparison of immune‐related gene sets between tumors with homozygous deletion of both CDKN2A/B and IFN‐I (n = 34) and tumors with CDKN2A/B homozygous deletion and wild‐type IFN‐I (n = 65). The centerline of the boxplot represents the median, while the lower and upper limits of the box correspond to the 25th and 75th percentiles. Whiskers extend from the box limit to the minimum or maximum, not exceeding the 1.5 * quartile range. P‐values were calculated by Mann–Whitney test. (G–L) Pathways with significant enrichment in tumors with homozygous deletion of both CDKN2A/B and IFN‐I. (M‐O) Pathways with significant enrichment in tumors with CDKN2A/B homozygous deletion and wild‐type IFN‐I.

A pathway enrichment analysis based on the GSEA results showed that negative regulation of the canonical WNT signaling pathway, negative regulation of DNA binding, and negative regulation of double‐strand break repair via homologous recombination were enriched in the CDKN2A/B HD IFN‐I HD tumors compared with the CDKN2A/B HD IFN‐I WT tumors. In the CDKN2A/B HD IFN‐I WT tumors, IFN‐I receptor binding, T helper cell differentiation, Tαβ cell differentiation, CD4αβ T cell differentiation, and myeloid cell development were upregulated (Fig. 6G,O). IFN‐I can activate the STAT3/4‐granzyme B pathway in tumor‐infiltrating CD8+ T cells, inhibit tumor growth [27, 28], and directly maintain the clonal expansion of CD4 T cells to fight virus infection [29]. We compared several key marker genes in activated CD4+ T cells, activated CD8+ T cells, and granzymes between CDKN2A/B HD IFN‐I WT tumors and CDKN2A/B HD IFN‐I HD tumors. KNTC1 (marker for activated CD4+ T cell) and AHSA1 (marker for activated CD8+ T cell) had significantly higher expression levels in CDKN2A/BHDIFN‐IHD tumors, whereas there were no significant differences in granzymes genes (Fig. 7A,B,C). KNTC1 knockdown was previously shown to suppress cell proliferation and viability in various cancers [30, 31, 32]. AHSA1 is a therapeutic target for the treatment of multiple myeloma [33]. IFN‐I signaling pathways in tumor cells are associated with the efficacy of immune checkpoint (such as PD1 and PD‐L1) inhibitor immunotherapy [34, 35]. However, our results showed that PD1/PD‐L1 expression was not significantly different between CDKN2A/B HD IFN‐I WT tumors and CDKN2A/B HD IFN‐I HD tumors (Fig. 7D,E). Innate immune cells respond to type I IFNs by enhancing antigen presentation and production of immune response mediators such as cytokines and chemokines [25, 36]. Expression of the chemokine receptor CX3CR1, which has a major role in proinflammatory and anti‐inflammatory responses [37], was lower in CDKN2A/B HD IFN‐I HD tumors than in CDKN2A/B HD IFN‐I WT tumors (Fig. 7F). We observed similar results for IFNA1. Conversely, expression of XCL1, which when produced by tumor cells may induce PD1/PD‐L1 interaction and dysfunction of CD8+ T cells in the tumor microenvironment [38], was higher in CDKN2A/B HD IFN‐I HD tumors than in CDKN2A/B HD IFN‐I WT tumors (Fig. 7G).

Fig. 7.

Fig. 7

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Boxplots for gene expression of immune‐related biomarkers. (A) activated CD4+ T cell, (B) activated CD8+ T cell, (C) granzymes, (D) PD1, (E) PD‐L1, (F) chemokines, and (G) cytokines between tumors with homozygous deletion of both CDKN2A/B and IFN‐I (n = 34) and tumors with CDKN2A/B homozygous deletion and wild‐type IFN‐I (n = 65). The centerline of the boxplot represents the median, while the lower and upper limits of the box correspond to the 25th and 75th percentiles. Whiskers extend from the box limit to the minimum or maximum, not exceeding the 1.5 * quartile range. P‐values were calculated by Mann–Whitney test.

These results indicated that IFN‐I co‐deletion contributed to poor outcomes in CDKN2A/B HD LUAD by altering the tumor immune microenvironment.

4. Discussion

Recent studies suggested that CDKN2A HD is one of the most frequent genetic alterations in many human cancers, including LUAD [39]. Loss of CDKN2A has been associated with poor clinical prognosis and tumor progression in lung cancer [40]. However, the mechanism by which CDKN2A/B HD leads to poor prognosis has not yet been revealed. We analyzed the genomic events, tumor microenvironment characteristics, and clinical outcomes associated with CDKN2A/B HD LUAD and identified a mechanism involving IFN‐I that leads to poor prognosis.

We confirmed that CDKN2A/B HD LUAD was associated with worse outcomes than CDKN2A/B WT LUAD. Patients in the TCGA and MSK‐IMPACT cohorts with CDKN2A/B HD LUAD had shorter OS than with patients with CDKN2A/B WT LUAD. These results were consistent with those of previous lung cancer studies [15, 40]. Indeed, prognostic effects of CDKN2A/B HD have been observed in a series of cancers [6, 7, 8, 9, 10, 11, 12]. A pan‐cancer study of chromosome arm‐level CNV found that deletions on the 9p arm, which contains the CDKN2A/B genes, were among the most substantial arm‐level events in 33 cancer types [41]. Further survival analysis based on a Cox proportional hazard model revealed that CDKN2A/B copy‐number loss was one of the most significant prognosis‐related factors in low‐grade glioma. Therefore, we hypothesized that CDKN2A/B should be considered in the management of clinical lung cancer.

A previous study indicated that CDKN2A/B HD influenced the EGFR‐TKI response [15]. Although our comprehensive screening of the genomic landscape identified mutation events that either co‐occurred or were mutually exclusive with CDKN2A/B HD in LUAD, none of these events had any prognostic value in the TCGA cohort. Therefore, additional cohort data are needed to study the interaction between CDKN2A/B HD and EGFR in different treatment backgrounds.

Analysis of gene copy numbers revealed a potential prognostic mechanism for CDKN2A/B HD in LUAD. We found no prognostic influence of chromosome instability, whole‐genome doubling, or tumor ploidy, all of which were previously associated with accelerating resistance to anticancer chemotherapy, targeted therapy, and immunotherapy [24, 42, 43]. However, functional deletions of segmentally adjacent IFN‐I genes frequently co‐occurred with CDKN2A/B HD, affecting 34.3% of the CDKN2A/B HD LUADs in TCGA cohort. Patients with CDKN2A/B HD IFN‐I HD tumors, but not those with CDKN2A/B HD IFN‐I WT tumors, had worse outcomes than patients with CDKN2A/B WT tumors, indicating a key role of IFN‐I dysfunction in determining the prognosis of CDKN2A/B HD LUAD.

Recent studies showed that IFN‐I is a crucial effector cytokine involved in antiviral immunity and mediates antineoplastic effects against several malignancies, which were attributed to its immunostimulatory functions [25]. Our analysis showed that functional damage to IFN‐I negatively regulated several immune responses, including T lymphocyte differentiation, IFN‐I receptor binding, inflammatory response, adaptive immune response, and JAK‐STAT signaling. IFN‐I and IFN‐I receptor heterodimer function as activators of JAK‐STAT signaling, which results in the recruitment of immune‐related signal transducers [44]. These results indicated that loss of IFN‐I function leads to a series of immune response signaling disorders. Furthermore, the clinical activity of a wide range of chemotherapeutic, radiotherapeutic, and immunotherapeutic interventions relies on the induction of IFN‐I signaling in malignant cells, tumor‐infiltrating myeloid cells, or lymphoid organs [25]. Accordingly, our results suggest that reduced myeloid cell activation might be related to IFN‐I deletion. In addition, CDKN2A/B HD IFN HD tumors were associated with canonical WNT signaling pathway negative regulation. Disorganization of canonical WNT signaling should be considered as a prognostic mechanism in cancer, as persistent WNT pathway activation was found to endow cancer cells with self‐renewing properties and was linked to therapy resistance [45].

We found that the negative prognostic effect of CDKN2A/BHD in LUAD was dependent on loss of IFN‐I function. It has been reported that oncogenes such as MYC and KRAS can regulate immune response by suppressing IFN‐I pathways in various cancers. For example, the combined actions of endogenously expressed mutant KRAS and modestly deregulated MYC expression led to NK cell‐mediated immune escape through inhibition of IFN‐I pathways in pancreatic ductal adenocarcinoma and lung cancer [46, 47]. Overexpression of MYC suppresses the recruitment and activation of immune cells by inhibiting the induction of interferon signaling in triple‐negative breast cancer [48]. These studies further confirmed that repression of the type I Interferon pathways underlies oncogenes or tumor suppressor genes‐dependent evasion of immune cells in lung cancer.

5. Conclusions

We showed that CDKN2A/B HD is associated with poor prognosis in LUAD because of frequent co‐occurrence of IFN‐I functional loss, which leads to a suppressed tumor immune microenvironment.

Conflict of interest

The authors declare no conflict of interest.

Peer review

The peer review history for this article is available at https://publons.com/publon/10.1002/1878‐0261.13206.

Author contributions

The conception and design of the study were undertaken by ZZY, BXT, XFX, and XY. Data were downloaded and processed by XYZ, XY, YSH, NZ, and LX. Data analysis and interpretation were performed by MMS and LYJ. Figures were prepared by YP and YHC. MMS, PSL, and YP wrote the manuscript. All authors approved the manuscript.

Supporting information

Fig S1. Survival of patients with CDKN2A/B homozygous deletion and co‐occurring mutation in other genes. The log‐rank test was used to compare the survival times between two groups.

Click here for additional data file. (391.3KB, pdf)

Fig S2. Comparison of immune‐related gene sets with no significant difference in enrichment score between two different IFN‐I CNV statuses in patients with CDKN2A/B homozygous deletion.

Click here for additional data file. (3MB, pdf)

Table S1. Patient characteristics of the TCGA‐LUAD cohort.

Click here for additional data file. (9.5KB, xlsx)

Table S2. Detailed gene list of the 25 immune‐related gene sets.

Click here for additional data file. (19.5KB, xlsx)

Acknowledgments

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).

Yuan Peng, Yonghong Chen, and Mengmeng Song contributed equally to this article.

Contributor Information

Benxu Tan, Email: yangzz@cqmu.edu.cn, Email: hbtbx@126.com.

Zhenzhou Yang, Email: yangzz@cqmu.edu.cn.

Data accessibility

The data that support the findings of this study are available in TCGA at https://www.cancer.gov/about‐nci/organization/ccg/research/structural‐genomics/tcga.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Fig S1. Survival of patients with CDKN2A/B homozygous deletion and co‐occurring mutation in other genes. The log‐rank test was used to compare the survival times between two groups.

Click here for additional data file. (391.3KB, pdf)

Fig S2. Comparison of immune‐related gene sets with no significant difference in enrichment score between two different IFN‐I CNV statuses in patients with CDKN2A/B homozygous deletion.

Click here for additional data file. (3MB, pdf)

Table S1. Patient characteristics of the TCGA‐LUAD cohort.

Click here for additional data file. (9.5KB, xlsx)

Table S2. Detailed gene list of the 25 immune‐related gene sets.

Click here for additional data file. (19.5KB, xlsx)

Data Availability Statement

The data that support the findings of this study are available in TCGA at https://www.cancer.gov/about‐nci/organization/ccg/research/structural‐genomics/tcga.

Articles from Molecular Oncology are provided here courtesy of Wiley

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