Abstract KPNA2 (Importin α1) is a nuclear transport protein that shuttles nuclear proteins into the nucleus. While its role in cancer-associated fibroblasts and the tumor microenvironment is known, its direct function in lung cancer cells remains to be fully elucidated. In this study, we found that high KPNA2 expression is associated with poor prognosis in patients with lung adenocarcinoma. KPNA2 knockdown significantly impaired cell migration and invasion and sensitized cells to anticancer drugs in vitro. In vivo, KPNA2 depletion decreased primary tumor growth and metastasis in an orthotopic model. Mechanistically, RNA sequencing revealed that KPNA2 regulates the epithelial-mesenchymal transition (EMT) pathway. Functional studies demonstrated that KPNA2 specifically increases the responsiveness of lung cancer cells to EMT-inducing factors like TGFβ, evidenced by enhanced plasticity in 3D Matrigel cultures. These findings establish KPNA2 as a critical regulator of lung cancer stemness and chemoresistance, representing a potential therapeutic target to suppress metastasis. Citation Format: Seongran Cho, Inyoung Cheon, Seoree Kim, Yoon Ho Ko, Young-Ho Ahn. KPNA2 drives cancer stemness, which enhances drug resistance and facilitates cancer progression in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4840.

TAM (TYRO3, AXL, MERTK) receptor tyrosine kinases (RTKs) have intrinsic roles in tumor cell proliferation, migration, chemoresistance, and suppression of antitumor immunity. The overexpression of TAM RTKs is associated with poor prognosis in various types of cancer. Single-target agents of TAM RTKs have limited efficacy because of an adaptive feedback mechanism resulting from the cooperation of TAM family members. This suggests that multiple targeting of members has the potential for a more potent anticancer effect. The present study used a deep-learning based drug-target interaction (DTI) prediction model called molecule transformer-DTI (MT-DTI) to identify commercially available drugs that may inhibit the three members of TAM RTKs. The results showed that fostamatinib, a spleen tyrosine kinase (Syk) inhibitor, could inhibit the three receptor kinases of the TAM family with an IC50 <1 µM. Notably, no other Syk inhibitors were predicted by the MT-DTI model. To verify this result, this study performed in vitro studies with various types of cancer cell lines. Consistent with the DTI results, this study observed that fostamatinib suppressed cell proliferation by inhibiting TAM RTKs, while other Syk inhibitors showed no inhibitory activity. These results suggest that fostamatinib could exhibit anticancer activity as a pan-TAM inhibitor. Taken together, these findings demonstrated that this artificial intelligence model could be effectively used for drug repurposing and repositioning. Furthermore, by identifying its novel mechanism of action, this study confirmed the potential for fostamatinib to expand its indications as a TAM inhibitor.

(1) Background: MicroRNAs (miRNAs) are candidate biomarkers of therapeutic re-sponse; this study sequenced tumor miRNAs before and after neoadjuvant chemoradi-ation (CRT) in cohorts with locally advanced rectal cancer undergoing total mesorectal excision. (2) Materials and Methods: A total of 79 tumor samples, with 36 in the pre-operative (pre-OP) and 43 in the post-operative (post-OP) group, underwent miRNA profiling with the NanoString nCounter Human v3 assay and functional tar-get/pathway analysis using miRDB and TargetScanHuman. (3) Results: NanoString nCounter profiling of 798 miRNAs showed an overall higher expression in post-OP versus pre-OP samples, with 93 miRNAs upregulated in the post-OP group. Tar-get/pathway analyses of the top upregulated miRNAs indicated enrichment across 37 KEGG pathways—including MAPK and Ras signaling and proteoglycans in can-cer—and qRT-PCR validated significant post-OP increases in six miRNAs (miR-143-3p, miR-145-5p, miR-99a-5p, miR-125b-5p, miR-100-5p, and let-7c-5p). (4) Conclusion: We found and validated significant differentially expressed (DE) miRNAs in the post-OP group compared to the pre-OP group in patients with rectal cancer undergoing con-current CRT. These DE miRNAs might serve as the key molecules in CRT-induced suppression of tumor progression and immunomodulation. The further role of DE miRNAs as significant biomarkers needs to be explored in future studies.

Purpose:Interferon-induced transmembrane protein 1 (IFITM1) is associated with a poor prognosis in triple-negative breast cancer (TNBC); however, the mechanisms by which IFITM1 contributes to oncogenesis in TNBC are unclear. Materials and Methods:We established two stable cell lines: IFITM1-overexpressing cell line (MB-231-IFITM1-OE) and IFITM1 knockdown cell line (BT-20-IFITM1-KD). The transcriptional activity of β-catenin and the cytotoxic activity of natural killer (NK) cells were evaluated using the luciferase assay and the lactate dehydrogenase cytotoxicity assay. The expression of IFITM1, β-catenin, and HLA class I was assessed by immunohistochemistry in patients with TNBC. Results:Knockdown of IFITM1 in BT-20 cells reduced cell proliferation and ectopically expressed IFITM1 in MB-231 cells increased cell proliferation. RNA sequencing analysis revealed that IFITM1 expression positively correlated with the Wnt/β-catenin signaling pathway and NK cell-mediated cytotoxicity. MB-231-IFITM1-OE cells showed increased β-catenin transcriptional activity and NK cell cytotoxic activity compared with controls, while transient knockdown of IFITM1 in MB-231-IFITM1-OE cells led to a decrease in β-catenin transcriptional activity and NK cell cytotoxic activity. MB-231-IFITM1-OE cells exhibited decreased HLA class I expression, which may have contributed to their increased susceptibility to NK cell-mediated lysis. β-catenin or JAK inhibitor reduced NK cell-mediated cytotoxicity via upregulation of HLA class I. Patients with IFITM1 overexpression showed a trend toward increased β-catenin positivity and HLA class I negativity. Conclusion:IFITM1 overexpression was associated with Wnt/β-catenin signaling and NK cell-mediated cytotoxicity via downregulation of HLA class I in TNBC cells, suggesting that IFITM1 might have immunoregulatory effects on the tumor microenvironment.

KPNA2 (Importin α1) is a nuclear transporter that mediates the nuclear import of proteins, such as transcription factors and nuclear proteins. Previous studies have highlighted KPNA2 as an important factor influencing CAF activity, prompting us to explore its role and mechanisms in the migration, invasion, and metastasis of lung cancer cells. Immunohistochemistry on tumor samples from lung cancer patients revealed that higher expression of KPNA2 was linked to poorer survival outcomes. To further investigate its function, we used shRNAs to knock down KPNA2 in human and mouse lung cancer cells. This led to a reduction in cancer cell migration, invasion, and metastasis. In contrast, overexpressing KPNA2 enhanced cancer cell migration and invasion. RNA sequencing analysis showed that KPNA2 regulates focal adhesion and NF-κB signaling pathways. Additionally, protein microarray analysis identified Golgi-associated and RNA-associated proteins as potential KPNA2-binding partners, which require further study. These results indicate that KPNA2 plays a crucial role in promoting cancer cell migration, invasion, and metastasis, making it a promising therapeutic target in lung adenocarcinoma. Seongran Cho, Inyoung Cheon, Seoree Kim, Yoon Ho Ko, Young-Ho Ahn. KPNA2 promotes the progression of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 101.

Abstract Introduction: Karyopherin α-2 (KPNA2), a nucleocytoplasmic transport protein, regulates the nuclear import of macromolecules and contributes to carcinogenesis. Actually, KPNA2 is upregulated in various types of cancer tissues and serum from cancer patients. In particular, it is associated with cancer invasiveness and poor prognosis in patient. Here, we tried to present the molecular mechanism and clinical significance of KPNA2 in lung cancer progression and metastasis. Method: First, we retrospectively analyzed the data extracted from EMR for patients with non-small cell lung cancer receiving curative surgical resection in Uijeongbu and Bucheon St. Mary’s Hospitals (n=165). Immunohistochemistry staining was performed on the tumor microarray samples using antibodies against KPNA2. The functional assay and gene silencing was conducted. Result: The clinical and pathological information of the experimental group is as follows. Based on the TMA staining, mean KPNA2 score was 36.5 [0-240] and median value was 10. Based on the TMA staining, patients with high KPNA2 expression were related to lymphatic invasion (p = 0.00782), advanced stage (p = 0.0202), and current smoker (p = 0.0074). KPNA2 expression was higher in squamous cell carcinoma than in adenocarcinoma histotype. Patients with high KPNA2 expression showed shorter survival than those with low KPNA2 (median OS (months), 72.8 vs 42.2, P < 0.0001; median RFS (months), 72.8 vs 32.1, P < 0.0011) and relevant to high recurrence (recurrence rate (%), 24.7 vs 44.7, p = 0.007). Further, high KPNA2 expression was associated with poor survival outcomes. Knockdown of KPNA2 in lung cancer cells suppressed the invasion and migration of lung cancer cells and inhibited metastasis in a mouse model of lung cancer. Inversely, KPNA2 overexpression promoted cancer cell growth, invasion, and migration. Moreover, ectopic expression of KPNA2 made lung cancer cells less sensitive to anticancer drugs, Talazoparib and Olaparib, indicating that KPNA2 enhances drug resistance in lung cancer cells. Conclusion: Collectively, this study suggest that KPNA2 promotes invasiveness and metastasis and is associated with poor patient outcomes; therefore, KPNA2 will be a good therapeutic target or a biomarker in lung adenocarcinoma. Citation Format: Inyoung Cheon, Seoree Kim, Sengran Cho, Heejin Lee, Jung-Sook Yoon, Ji Hyun Lee, Sang Hoon Chun, Hye Sung Won, Soon Auck Hong, Yoon Ho Ko, Young-Ho Ahn. Karyopherin α-2, a nuclear export protein, promotes cancer progression in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7269.

Purpose This subgroup analysis of the Korean subset of patients in the phase 3 LASER301 trial evaluated the efficacy and safety of lazertinib versus gefitinib as first-line therapy for epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC). Materials and Methods Patients with locally advanced or metastatic EGFRm NSCLC were randomized 1:1 to lazertinib (240 mg/day) or gefitinib (250 mg/day). The primary endpoint was investigator-assessed progression-free survival (PFS). Results In total, 172 Korean patients were enrolled (lazertinib, n=87; gefitinib, n=85). Baseline characteristics were balanced between the treatment groups. One-third of patients had brain metastases (BM) at baseline. Median PFS was 20.8 months (95% confidence interval [CI], 16.7 to 26.1) for lazertinib and 9.6 months (95% CI, 8.2 to 12.3) for gefitinib (hazard ratio [HR], 0.41; 95% CI, 0.28 to 0.60). This was supported by PFS analysis based on blinded independent central review. Significant PFS benefit with lazertinib was consistently observed across predefined subgroups, including patients with BM (HR, 0.28; 95% CI, 0.15 to 0.53) and those with L858R mutations (HR, 0.36; 95% CI, 0.20 to 0.63). Lazertinib safety data were consistent with its previously reported safety profile. Common adverse events (AEs) in both groups included rash, pruritus, and diarrhoea. Numerically fewer severe AEs and severe treatment-related AEs occurred with lazertinib than gefitinib. Conclusion Consistent with results for the overall LASER301 population, this analysis showed significant PFS benefit with lazertinib versus gefitinib with comparable safety in Korean patients with untreated EGFRm NSCLC, supporting lazertinib as a new potential treatment option for this patient population.

S3. Correlation between gene expression and tumor purity estimated across 21 tumor types.

Purpose: Oxaliplatin, a component of the capecitabine plus oxaliplatin (XELOX) regimen, has a more favorable toxicity profile than cisplatin in patients with advanced gastric cancer (GC). However, oxaliplatin can induce sensory neuropathy and cumulative, dose-related toxicities. Thus, the capecitabine maintenance regimen may achieve the maximum treatment effect while reducing the cumulative neurotoxicity of oxaliplatin. This study aimed to compare the survival of patients with advanced GC between capecitabine maintenance and observation after 1st line XELOX chemotherapy. Materials and Methods: Sixty-three patients treated with six cycles of XELOX for advanced GC in six hospitals of the Catholic University of Korea were randomized 1:1 to receive capecitabine maintenance or observation. The primary endpoint was progression-free survival (PFS), analyzed using a two-sided log-rank test stratified at a 5% significance level. Results: Between 2015 and 2020, 32 and 31 patients were randomized into the maintenance and observation groups, respectively. After randomization, the median number of capecitabine maintenance cycles was 6. The PFS was significantly higher in the maintenance group than the observation group (6.3 vs. 4.1 months, P=0.010). Overall survival was not significantly different between the 2 groups (18.2 vs. 16.5 months, P=0.624). Toxicities, such as hand-foot syndrome, were reported in some maintenance group patients. Maintenance treatment was a significant factor associated with PFS in multivariate analysis (hazard ratio, 0.472; 95% confidence interval, 0.250-0.890; P=0.020). Conclusions: After 6 cycles of XELOX chemotherapy, capecitabine maintenance significantly prolonged PFS compared with observation, and toxicity was manageable. Maintenance treatment was a significant prognostic factor associated with PFS.

MicroRNA transcriptomes from fresh tumors and the adjacent normal tissues were profiled in 10 Korean patients diagnosed with lung adenocarcinoma using a next-generation sequencing (NGS) technique called miRNA-seq. The sequencing quality was assessed using FastQC, and low-quality or adapter-contaminated portions of the reads were removed using Trim Galore. Quality-assured reads were analyzed using miRDeep2 and Bowtie. The abundance of known miRNAs was estimated using the reads per million (RPM) normalization method. Subsequently, using DESeq2 and Wx, we identified differentially expressed miRNAs and potential miRNA biomarkers for lung adenocarcinoma tissues compared to adjacent normal tissues, respectively. We defined reliable miRNA biomarkers for lung adenocarcinoma as those detected by both methods. The miRNA-seq data are available in the Gene Expression Omnibus (GEO) database under accession number GSE196633, and all processed data can be accessed via the Mendeley data website.

e21025 Background: It is emerging that the Karyopherin a-2 (KPNA2), a nucleocytoplasmic transport protein, regulates the nuclear import of macromolecules and contributes to carcinogenesis and changes in cellular phenotype. In particular, it can be a poor prognostic marker by causing aberrant subcellular localization of DNA damage response proteins or OCT4-c MYC pathway molecules depending on the type of carcinoma and inducing anticancer resistance. In some carcinomas, an association with the p53 oncogenic pathway has been reported, showing good prognostic values. We aimed to investigate the clinical significance and metabolic pathway of stable cancer associated fibroblast (CAF) and cancer cells for KPNA2. Methods: We retrospectively analyzed the data extracted from EMR for NSCLC patients receiving curative surgical resection in Uijeongbu and Bucheon St. Mary’s Hospitals (n = 165). Immunohistochemistry staining was performed on the tumor microarray samples using antibodies against KPNA2. The functional assay and gene silencing was conducted. Results: Based on the TMA staining, mean KPNA2 score was 36.5 [0-240] and median value was 10. The clinical and pathological information of the experimental group is as follows. Table 1. Scatter plots and correlation between KPNA2 expression levels and tumor invasiveness markers reveals that high KPNA2 expressor was related to lymphatic invasion (p = 0.00782), advanced stage (p = 0.0202) and current smoker (p = 0.0074). KPNA2 expression was higher in squamous cell carcinoma(SqCC) histotype than in adenocarcinoma (SqCC ratio (%), 13.5 vs 43.4 in Low exp vs High exp; p = 0.007). Patients with high expression of KPNA2 showed shorter survival than other patients (median OS (months), 72.8 vs 42.2, P < 0.0001; median RFS (months), 72.8 vs 32.1, P < 0.0011) and relevant to high recurrence (recurrence rate (%), 24.7 vs 44.7, p = 0.007). Further, high KPNA2 expression was associated with poor survival outcomes. To test the effect of KPNA2 on cancer cell invasion, we knocked down Kpna2 via shRNA. Spheroids composed of H1299, Calu-6, A549, HCC827 lung cancer cells with either Kpna2-overexpression or Kpna2-knockdown, and spheroid invasion was then monitored for two days. Eminently, the 3-D invasion of spheroids was suppressed via Kpna2 knockdown. In addition, Kpna2-overexpressing cells promoted cancer invasion to a greater extent than control. Conclusions: In conclusion, our results suggest that KPNA2 protein expression has a poor prognostic association, revealed by its association with survival outcome or invasiveness markers. Its clinical significance as an oncogenic target molecule is emerging, and further evaluation using an organoid model is in progress.

There is no pathological difference between early and advanced diffuse gastric cancer (DGC), particularly in the gastric mucosa. In this study, we tried to identify microRNAs (miRNAs) as diagnostic biomarkers that can differentiate between early and advanced DGC. miRNA expression profiling was performed by NanoString nCounter method in human DGC tumors. miR-199a and miR-199b (miR-199a/b) were particularly up-regulated in advanced DGC compared with early DGC. Ectopic expression of miR-199a/b accelerated growth, viability, and motility of SNU601, human GC cells, and expedited tumor development in a mouse xenograft model. miR-199a/b also inhibited cell adhesion. Through 3’-UTR luciferase assay, Frizzled-6 (FZD6) was confirmed as a direct target of miR-199a/b. siRNA-mediated depletion of FZD6 increased cell growth and motility and addback of FZD6 restored cell growth, motility, and adhesion. To explore their clinicopathological roles in patients, miR-199a/b levels were measured by in situ hybridization in human DGC tumor sections. High miR-199a/b was correlated with advanced lymphovascular invasion, advanced T stages, and lymph node metastasis. Collectively, miR-199a/b promote the progression of DGC via targeting FZD6. These results imply that miR-199a/b can be used as diagnostic and prognostic biomarkers of DGC. Citation Format: Jihye Park, Sieun Lee, Soon Auck Hong, Yoon Ho Ko, Young-Ho Ahn. miR-199a and miR-199b stimulate the progression of diffuse gastric cancer through direct targeting of Frizzled-6. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3802.

S1. The tumor purity of immune-related genes. S2.

Introduction: Many oncologists began to make sense, that the Karyopherin a-2 (KPNA2), a nucleocytoplasmic transport protein, regulates the nuclear import of macromolecules and changes in cellular phenotype. In particular, it can be a poor prognostic marker by causing aberrant subcellular localization of DNA damage response proteins or OCT4-c MYC pathway molecules depending on the type of carcinoma. An association with the p53 oncogenic pathway has been reported, showing good prognostic values in other types. We aimed to investigate the clinical significance and metabolic pathway of stable CAF and cancer cells for KPNA2 Method: We retrospectively analyzed the data from NSCLC patients receiving curative resection in Uijeongbu and Bucheon St. Mary’s Hospitals (n=165). IHC staining was performed on the tumor microarray samples using antibodies against KPNA2. The positivity was defined as median value of H-score. Result: Based on the TMA staining, mean KPNA2 score was 36.5 [0-240] and median value was 10. Table 1. Scatter plots and correlation between KPNA2 expression levels and tumor invasiveness markers reveals that high KPNA2 expressor was related to lymphatic invasion (p = 0.00782), advanced stage (p = 0.0202) and current smoker (p = 0.0074). KPNA2 expression was higher in squamous cell carcinoma(SqCC) histotype than in adenocarcinoma (SqCC ratio (%), 13.5 vs 43.4 in Low exp vs High exp; p = 0.007). Patients with high expression of KPNA2 showed shorter survival than other patients (median OS (mo), 72.8 vs 42.2, P < 0.0001; median RFS (mo), 72.8 vs 32.1, P < 0.0011) and relevant to high recurrence (recurrence rate (%), 24.7 vs 44.7, p = 0.007). Conclusion: Taken together, our results suggest that KPNA2 protein expression has a poor prognostic association, revealed by its association with survival outcome or invasiveness markers. Its clinical significance as an oncogenic target molecule is emerging, and further evaluation using an organoid model is in progress. Baseline clinical and pathological characteristics Citation Format: Seoree Kim, Heejin Lee, Jung-Sook Yoon, Hyun Woo Lee, Seok Yun Kang, Ji Hyun Lee, Sang Hoon Chun, Hye Sung Won, Soon Auck Hong, Keunsoo Kang, Young-Ho Ahn, Yoon Ho Ko. Identification and characterization of Karyopherin α2 (KPNA2), a member of the nucleocytoplasmic transporter family, in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2165.

S2. Correlation of gene expression and tumor purity estimated from various resources.

Background Brain metastasis is a common complication among patients with lung cancer, yet the underlying mechanisms remain unclear. In this study, we aimed to investigate the pathogenesis of brain metastasis in lung cancer. Methods We established highly colonizing metastatic lung cancer cells, A549-M2, through multiple implantations of A549 human lung cancer cells in the carotid artery of athymic nude mice. Results Compared to parental cells (M0), M2 cells demonstrated slower growth in culture plates and soft agar, as well as lower motility and higher adhesion, key characteristics of mesenchymal–epithelial transition (MET). Further analysis revealed that M2 cells exhibited decreased expression of epithelial–mesenchymal transition markers, including ZEB1 and Vimentin. M2 cells also demonstrated reduced invasiveness in co-culture systems. RNA sequencing and gene set enrichment analysis confirmed that M2 cells underwent MET. Intriguingly, depletion of Noggin, a BMP antagonist, was observed in M2 cells, and replenishment of Noggin restored suppressed migration and invasion of M2 cells. In addition, Noggin knockdown in control M0 cells promoted cell attachment and suppressed cell migration, suggesting that Noggin reduction during brain colonization causes inhibition of migration and invasion of metastatic lung cancer cells. Conclusions Our results suggest that lung cancer cells undergo MET and lose their motility and invasiveness during brain metastatic colonization, which is dependent on Noggin.

S6. Relative abundance of CM and CMM gene pairs across tumor types.

PURPOSE:This study evaluated whether combination therapy is more effective than monotherapy in elderly patients with metastatic or recurrent gastric cancer (MRGC) as first-line chemotherapy.MATERIALS AND METHODS:Elderly (≥ 70 years) chemo-naïve patients with MRGC were allocated to receive either combination therapy (group A: 5-fluorouracil [5-FU]/oxaliplatin, capecitabine/oxaliplatin, capecitabine/cisplatin, or S-1/cisplatin) or monotherapy (group B: 5-FU, capecitabine, or S-1). In group A, starting doses were 80% of standard doses, and they could be escalated to 100% at the discretion of the investigator. Primary endpoint was to confirm superior overall survival (OS) of combination therapy vs. monotherapy.RESULTS:After 111 of the planned 238 patients were randomized, enrollment was terminated due to poor accrual. In the full-analysis population (group A [n=53] and group B [n=51]), median OS of combination therapy vs. monotherapy was 11.5 vs. 7.5 months (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.56 to 1.30; p=0.231). Median progression-free survival (PFS) was 5.6 vs. 3.7 months (HR, 0.53; 95% CI, 0.34 to 0.83; p=0.005). In subgroup analyses, patients aged 70-74 years tended to have superior OS with combination therapy (15.9 vs. 7.2 months, p=0.056). Treatment-related adverse events (TRAEs) occurred more frequently in group A vs. group B. However, among severe TRAEs (≥ grade 3), there were no TRAEs with a frequency difference of > 5%.CONCLUSION:Combination therapy was associated with numerically improved OS, although statistically insignificant, and a significant PFS benefit compared with monotherapy. Although combination therapy showed more frequent TRAEs, there was no difference in the frequency of severe TRAEs.

S7. The frequency of PPI gene pairs across tumor types.