Survival In Adrenocortical Carcinoma Research Articles

Comprehensive Analysis of the Role of Forkhead Box J3 (FOXJ3) in Human Cancers

Forkhead box J3 (FOXJ3) is a member of the forkhead box (Fox) family. Recently, increasing evidence has revealed the relationship between Fox family members and cancer. FOXJ3 is involved in various types of cancer, including lung cancer, tongue squamous carcinoma, and prostate cancer; however, a comprehensive pan-cancer analysis of FOXJ3 remains lacking. Here, we explored the function of FOXJ3 across cancers using online websites and databases including TIMER2.0, SangerBox, UALCAN, GEPIA2.0, cBioPortal, CancerSEA,STRING, BioGRID and Metascape to analyze the role of FOXJ3 in cancers. Abnormal expression of FOXJ3 was found in various tumors. The genetic alteration percentage in tumors was determined, and elevated FOXJ3 expression was found to be associated with worse overall survival in brain lower grade glioma(LGG), liver hepatocellular carcinoma (LIHC), sarcoma (SARC) and thyroid carcinoma. Elevated FOXJ3 expression was related to worse prognosis with disease-free survival in adrenocortical carcinoma, LGG and LIHC. FOXJ3 expression was related to immune infiltration in several cancers. Enrichment analysis showed that histone modification, the TGF-β signaling pathway, and chromatin organization were the top three enriched ontology clusters of the top 100 similar genes of FOXJ3. Our pan-cancer analysis provides comprehensive insights into FOXJ3 from the perspective of bioinformatics in different cancers, where it serves as a potential biomarker for prognosis, especially in LGG and LIHC. FOXJ3 is also correlated with immune infiltrates in certain human tumors.

The effect of hormonal secretion on survival in adrenocortical carcinoma: A multi-center study

BackgroundCurrent evidence suggests that cortisol secreting adrenocortical carcinoma has worse prognosis compared to non-secreting adrenocortical carcinoma. However, the effect of other secretory subtypes is unknown. MethodsThis multicenter study within the American-Australian-Asian Adrenal Alliance included adults with adrenocortical carcinoma (1997–2020). We compared overall survival and disease-free survival among cortisol secreting, mixed cortisol/androgen secreting, androgen secreting, and non-secreting adrenocortical carcinoma. ResultsOf the 807 patients (mean age 50), 719 included in the secretory subtype analysis: 24.5% were cortisol secreting, 13% androgen secreting, 28% mixed cortisol/androgen, 32.5% non-secreting, and 2% were mineralocorticoid secreting.Median overall survival and disease-free survival for the entire cohort were 60 and 9 months, respectively. Median overall survival was 36 months for cortisol, 30 for mixed, 60 for androgen secreting, and 115 for non-secreting adrenocortical carcinoma, P < .01. Median disease-free survival was 7 months for cortisol, 8 for mixed, 10 for androgen, and 12 for non-secreting adrenocortical carcinoma, P = .06.On multivariable analysis of age, sex, Ki67%, secretory subtype, stage, resection, and adjuvant therapy, predictors of worse overall survival were older age, higher Ki67%, stage IV, mixed secreting, R1, and no adjuvant therapy, P < .05. On subgroup analysis of R0 resection, predictors of worse overall survival included older age and higher Ki67%. Ki67% ≥40, stage III and cortisol secretion were associated with worse disease-free survival. ConclusionMixed cortisol/androgen secreting adrenocortical carcinoma was associated with worse overall survival, while cortisol or androgen secreting alone were not. Notably, among patients after R0 resection, secretory subtype did not affect overall survival. Cortisol secreting adrenocortical carcinoma demonstrated worse disease-free survival. Ki67% remained a strong predictor of worse overall survival and disease-free survival independent of stage.

Non-SMC condensin I complex subunit D2 (NCAPD2) reveals its prognostic and immunologic features in human cancers.

Non-SMC condensin I complex subunit D2 (NCAPD2) is overexpressed in some malignant tumors. However, there are few studies on the function of NCAPD2 in pan-cancer. We used the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), and UALCAN to analyze NCAPD2 expression and promoter methylation levels in 33 tumors and normal samples. We performed immunohistochemistry (IHC) on liver cancer and corresponding normal tissues to examine NCAPD2 protein expression in LIHC. Kaplan-Meier survival and univariate regression analyses were performed to explore the pan-cancer clinical significance of NCAPD2. Moreover, correlative analysis between NCAPD2 expression and clinical characteristics, immune cell infiltration, immune checkpoints, immune regulators, tumor mutation burden (TMB), microsatellite instability (MSI), ribonucleic acid (RNA) methylation regulators, and drug sensitivity was conducted using data from TCGA. We also investigated the effects of NCAPD2 expression on immunotherapy efficacy and prognosis. Gene set enrichment analysis (GSEA) was conducted using NCAPD2. Bioinformatic analysis showed that NCAPD2 was overexpressed in most tumors and correlated with the clinical characteristics of some cancers. IHC results demonstrated that NCAPD2 protein expression was higher in LIHC than in normal liver. NCAPD2 expression was linked with T stage, clinical stage, and histologic grade in LIHC. Overexpression of NCAPD2 resulted in poor overall survival, and disease-specific survival in adrenocortical carcinoma, kidney renal papillary cell carcinoma, brain lower grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, mesothelioma, pancreatic adenocarcinoma, sarcoma, skin cutaneous melanoma, and uterine corpus endometrial carcinoma. NCAPD2 was considered an independent biomarker by Cox regression in LIHC. The time ROC curve demonstrated that the survival rate of 1-, 3-, and 5-year OS and DSS in LIHC was above 0.6. The expression of NCAPD2 was significantly correlated with immune cell infiltration, immune checkpoints, TMB, MSI, and RNA methylation regulators in several tumors. NCAPD2 had a high predictive value for immunotherapy efficiency in certain tumors. In our study, drugs sensitive to NCAPD2 protein were screened by sensitivity analysis. GSEA analysis showed that NCAPD2 mainly participated in the G2M checkpoint, mitotic spindle, and KRAS-signaling. NCAPD2 may act as a prognostic molecular marker in most cancers.

LncRNA WAC-AS1 expression in human tumors correlates with immune infiltration and affects prognosis

BackgroundWAC-antisense RNA1 (WAC-AS1) is a newly identified long non-coding RNA (lncRNA) implicated in the prognosis and development of a few types of tumors. However, the correlations of WAC-AS1 with immune infiltration and patient prognosis in pan-cancer remain unclear. In the present study, we aimed to investigate the prognostic value and immunological functions of WAC-AS1 across 33 different types of cancers.MethodsTo investigate the potential oncogenic roles of WAC-AS1, bioinformatics analyses were performed using the Cancer Genome Atlas (TCGA) and Genotype Tissue-Expression (GTEx) datasets. The correlations of WAC-AS1 with prognosis, clinical phenotype, tumor mutational burden (TMB), microsatellite instability (MSI), tumor regulation-related genes, tumor microenvironment, immune cell infiltration, and drug resistance to commonly used chemotherapy drugs in different types of tumors were explored. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed to explore the biological functions of WAC-AS1 in tumors. In situ hybridization (ISH) was performed in tissue microarray (TMA) to confirm the expression of WAC-AS1 in multiple tumor tissues.ResultsWAC-AS1 showed aberrant expression in most cancers when compared to the normal tissues. It also has prognostic value in multiple types of cancers. Elevated WAC-AS1 expression was associated with poor prognosis and overall survival in adrenocortical carcinoma (ACC), breast invasive carcinoma (BRCA), and liver hepatocellular carcinoma (LIHC). A significant negative correlation between WAC-AS1 expression and overall survival was observed in brain lower-grade glioma (LGG), pancreatic adenocarcinoma (PAAD), and skin cutaneous melanoma (SKCM). The expression of WAC-AS1 also showed a correlation with clinical stage in six types of tumors, and with tumor mutational burden and microsatellite instability in several different types of cancers. The immune scores of those cancers were found to be significant. Additionally, the effectiveness of fluorouracil and four other anticancer drugs was significantly different based on the expression of WAC-AS1 in these cancers. Moreover, the ISH results showed in six types of tumors, the expression of WAC-AS1 was consistent with the Pan-cancer analysis using TCGA and GTEx database.ConclusionsThese results indicate an intensive involvement of WAC-AS1 in the regulation of immune responses, immune cell infiltration, and malignant properties in various types of cancers, suggesting that WAC-AS1 may serve as a prognostic marker across diverse types of cancers.

Abstract 5286: Matrix metalloproteinase 14 in associated with poor survival in adrenocortical carcinoma

Abstract Adrenocortical carcinoma (ACC) is an aggressive malignancy of the adrenal cortex. Five-year survival in Stage IV disease is 6%. Surgical resection is the mainstay of treatment; however, most patients present with unresectable disease or experience tumor recurrence after surgery. No targeted therapies are available for treatment of ACC. Thus, there is a critical need to understand molecular mechanisms driving advanced ACC. Matrix metalloproteinases (MMPs) have been associated with worse prognosis in other human cancers. Although pan-inhibition had limited clinical success, recent studies suggest select inhibition may improve patient outcomes. Here, we use The Cancer Genome Atlas (TCGA) and single nuclei RNA sequencing data (snRNAseq) to evaluate the expression of MMPs in ACC. RNA sequencing data from 77 ACC patients in TCGA was downloaded from UCSC Treehouse Public Data Tumor Compendium v11. Using the Kaplan-Meier estimator, survival was compared between the highest and lowest quartile of RNA expression for each MMP in R v.4.1. For snRNAseq, normal adrenal and adrenal adenoma samples were collected from a patient diagnosed with adrenal hypercortisolism. Seven primary and metastatic ACC samples were collected from patients diagnosed with ACC at time of surgical resection and included one primary tumor-metastasis pair. Single nuclei were isolated from frozen samples. Sequencing libraries were generated and sequenced on the Illumina NovaSeq 6000. Data were preprocessed using the 10x Genomics CellRanger software suite. Downstream analysis was performed using Seurat v.4 for R. ACC specimens in TCGA expressed all 24 MMPs with MMP14 demonstrating the highest expression. MMP14 expression was associated with significantly worse survival with a hazard ratio of 3.6 (95% CI 1.2 - 11.1). In addition, increased MMP14 expression was associated with higher AJCC tumor stage (p &amp;lt; 0.05). snRNAseq analysis of our ACC primary and metastatic samples identified 7 adrenal cortex clusters and one cluster each - fibroblasts, macrophages, infiltrating lymphocytes, endothelial, and adrenal medulla cells. Two cell clusters were present in primary and metastatic samples but not benign adrenal samples and were characterized by high KI67 expression or high ribosomal content. MMP14 expression was significantly higher in metastatic versus primary tumors in 2 adrenal cortex clusters with 3.6 and 2 fold increased expression, respectively (p &amp;lt; 0.05); and one of these clusters was defined by a 15-fold increase in expression of ZNRF3, which is involved in activation of the Wnt pathway. These data suggest that MMP14 expression is associated with worse survival and may be associated with metastatic progression. Further studies are needed to confirm whether simultaneous targeting of Wnt pathway and MMP14 may result in decreased metastatic progression. Citation Format: Liudmila V. Popova, Elaine Mardis, Katherine Miller, Priya H. Dedhia. Matrix metalloproteinase 14 in associated with poor survival in adrenocortical carcinoma. [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 5286.

Elevated sphingosine-1-phosphate lyase leads to increased metabolism and reduced survival in adrenocortical carcinoma.

Adrenocortical carcinomas (ACCs) are invasive tumours arising in the adrenal cortex, and steroidogenic tumours are associated with worse prognostic outcomes. Loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1) cause primary adrenal insufficiency and as a key degradative enzyme in the sphingolipid pathway, SGPL1 also influences the balance of pro-proliferative and pro-apoptotic sphingolipids. We, therefore, hypothesized increased SGPL1 may be linked to increased disease severity in ACC. Analyse SGPL1 expression impact on patient survival and adrenal cancer cell phenotype. We analysed two ACC cohorts with survival and corresponding transcriptomic data, focusing on SGPL1 and sphingolipid pathway genes. In vitro, we generated SGPL1-knockout and overexpressing H295R adrenocortical cells to investigate the role of SGPL1 in cell signalling in ACCs. We found increased expression of several sphingolipid pathway receptors and enzymes, most notably SGPL1 correlated with reduced patient survival in both cohorts. Overexpression of SGPL1 in the H295R cell line increased proliferation and migration while reducing apoptosis, while SGPL1 knockout had the opposite effect. RNA-seq revealed a global increase in the expression of genes in the electron transport chain in overexpressing cells, correlating with increased aerobic respiration and glycolysis. Furthermore, the opposite phenotype was seen in cells lacking SGPL1. We subsequently found the increased proliferation is linked to metabolic substrate availability and increased capacity to use different fuel sources, but particularly glucose, in overexpressing cells. We, therefore, propose that SGPL1-overexpressing ACC tumours reduce patient survival by increasing fuel usage for anabolism and energy production to facilitate growth and invasion.

Application of TFE3 Immunophenotypic and TFE3 mRNA Expressions in Diagnosis and Prognostication of Adrenal Cortical Neoplasms and Distinction From Kidney Tumors.

We explored the application of TFE3 immunostaining and TFE3 mRNA expression in the differential diagnosis and prognostication of adrenal cortical tumors and distinction of the latter from clear cell renal cell carcinoma (ccRCC) which show significant morphologic overlap. TFE3 immunostaining was performed on a large cohort of samples including 40 adrenal cortex tissues, 95 adrenocortical adenoma (ACA), 11 adrenocortical carcinoma (ACC), 53 ccRCC, and 18 pheochromocytomas. TFE3 was compared with other immunomarkers melan-A, inhibin-α, synaptophysin, chromogranin A, CAIX and CD10. One hundred percent normal adrenal cortices and 94% ACA were strongly and diffusely stained for TFE3 while no ACC showed diffuse staining. TFE3 is thus useful in distinguishing ACA from ACC. TFE3 is also useful in separating ACC from ccRCC as 64% ACC showed partial, while only 7% of ccRCC showed partial TFE3 staining. Only 1 pheochromocytoma showed focal weak TFE3 staining. Results also demonstrated superiority of TFE3 over other commonly used immunomarkers. TFE3 gene rearrangement testing by fluorescence in situ hybridization showed no rearrangement in 6 TFE3 positive adrenal tumors. TFE3 mRNA were analyzed by the Cancer Genome Atlas database and we found TFE3 mRNA expression correlated with overall patient survival in ACC. Our study showed usefulness of TFE3 in distinguishing ACA from ACC, and ACC from ccRCC. TFE3 is superior over other commonly used immunomarkers for adrenal tumors. In addition, decreased TFE3 immunoexpression and TFE3 mRNA expression may carry poor prognostic implication in adrenal tumors.

Multi-genomic analysis of 260 adrenocortical cancer patient tumors identifies novel network BIRC5-hsa-miR-335-5p-PAX8-AS1 strongly associated with poor survival

BackgroundAdrenocortical carcinoma is a rare endocrine cancer with poor overall survival. Linking survival outcomes to a common target across multiple genomic datasets incorporating microRNA-long non-coding RNA dysregulation have not been well described. We hypothesized that a multi-database analysis of microRNA-long noncoding RNA-messenger RNA regulatory networks associated with survival will identify novel biomarkers. MethodsSignificantly dysregulated genes or microRNA in adrenocortical carcinoma compared to normal adrenal was identified from sequencing data for 260 human adrenocortical carcinomas using GEO2R. The miRnet identified hub microRNA and genes and long noncoding RNA and microRNA associated with survival genes. The R2 generated Kaplan-Meier curves. The database miRTarBase linked genes associated with poor survival and dysregulated microRNA. ResultsAnalysis of genes and microRNAs differentially regulated in >50% of datasets revealed 75 genes and 12 microRNAs were upregulated, and 167 genes and 12 microRNAs were downregulated (bonf. P < .05). Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed cell cycle, P53 signaling, arachidonic acid and innate immune response, and PI3/Akt are altered in adrenocortical carcinoma. A microRNA-target interaction network of differentially regulated microRNAs identified upregulated miRNA107, 103a-3p and 27a-3p, 16-5p, and downregulated 335-5p to have the highest degree of interaction with upregulated (ie, TPX2, CDK1, BIRC5, PRC1, CCNB1, GINS1) and downregulated (ie, RSPO3, NR2F1, TLR4, HOXA5, USP53, SLC16A9) hub genes as well as hub long noncoding RNAs XIST, NEAT1, KCNQ1OT1, and PAX8-AS1. Survival analysis revealed that the hub genes are associated with poor overall survival (P < .05) of adrenocortical carcinoma in the Cancer Genome Atlas data. ConclusionA messenger RNA–microRNA–long noncoding RNA network analysis identified the BIRC5-miR335-5p-PAX8-AS1 network as one that was associated with poor overall survival in adrenocortical carcinoma, warranting further validation as a potential therapeutic target.

Higher SUVmax on FDG-PET is associated with shorter survival in adrenocortical carcinoma

BackgroundAdrenocortical carcinoma (ACC) is an aggressive, rare malignancy. 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography (FDG-PET) assesses tumor metabolism and glucose utilization. We hypothesized that higher maximum standard uptake value (SUVmax) is associated with decreased survival. MethodsWe performed a retrospective analysis of patients with ACC. Included patients (n = 26) had an FDG-PET scan available with a documentable SUVmax. Patients were dichotomized into “High” (≥8.4, n = 12) and “Low” (<8.4, n = 14) SUVmax. Univariate analysis and survival analysis were performed to compare groups. ResultsDemographics between groups were equivalent. The high SUVmax cohort demonstrated lower survival (median 479 days or 15.7 months) compared to the low group (median 1490 days or 48.6 months, p = .01). Log-Rank curve confirmed differences in survival (p = .007). ConclusionsHigher SUVmax was associated with significantly worse survival in ACC and may reflect a more aggressive phenotype. FDG-PET may provide clinically useful information to determine prognosis and treatment. Further studies should prospectively evaluate using FDG-PET/CT in ACC.

Impact of sweet, umami, and bitter taste receptor (TAS1R and TAS2R) genomic and expression alterations in solid tumors on survival

Originally identified on the tongue for their chemosensory role, the receptors for sweet, umami, and bitter taste are expressed in some cancers where they regulate important cellular processes including apoptosis and proliferation. We examined DNA mutations (n = 5103), structural variation (n = 7545), and expression (n = 6224) of genes encoding sweet or umami receptors (TAS1Rs) and bitter receptors (TAS2Rs) in 45 solid tumors subtypes compared to corresponding normal tissue using The Cancer Genome Atlas and the Genotype Tissue Expression Project databases. Expression of TAS1R and TAS2R genes differed between normal and cancer tissue, and nonsilent mutations occurred in many solid tumor taste receptor genes (~ 1–7%). Expression levels of certain TAS1Rs/TAS2Rs were associated with survival differences in 12 solid tumor subtypes. Increased TAS1R1 expression was associated with improved survival in lung adenocarcinoma (mean survival difference + 1185 days, p = 0.0191). Increased TAS2R14 expression was associated with worse survival in adrenocortical carcinoma (−1757 days, p < 0.001) and esophageal adenocarcinoma (−640 days, p = 0.0041), but improved survival in non-papillary bladder cancer (+ 343 days, p = 0.0436). Certain taste receptor genes may be associated with important oncologic pathways and could serve as biomarkers for disease outcomes.

ASO Author Reflections: The Impact of Oncocytic Histology on Survival in Adrenocortical Carcinoma.

ASO Author Reflections: The Impact of Oncocytic Histology on Survival in Adrenocortical Carcinoma.

Pan-cancer analysis of oncogenic role of Programmed Cell Death 2 Like (PDCD2L) and validation in colorectal cancer

BackgroundProgrammed Cell Death 2 Like (PDCD2L) correlates with cell proliferation, apoptosis and mouse embryonic development. However, the role of PDCD2L in human cancers is unclear.MethodsMultiple bioinformatic methods, in vitro function experiments and validation were performed to clarify the oncogenic role of PDCD2L in human cancers.ResultsOur study found that PDCD2L was aberrantly expressed in multiple types of human cancers, and associated with clinical stage and molecular subtype. Furthermore, overexpression of PDCD2L predicted poor overall survival in adrenocortical carcinoma(ACC), kidney chromophobe(KICH), acute myeloid leukemia(LAML), brain lower grade glioma(LGG),liver hepatocellular carcinoma(LIHC), mesothelioma(MESO), uveal melanoma(UVM) and poor diseases free survival in ACC, bladder urothelial carcinoma(BLCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), kidney renal clear cell carcinoma(KIRC), kidney renal papillary cell carcinoma(KIRP), LGG, LIHC, and UVM. PDCD2L expression was negatively associated with cancer associated fibroblast in breast invasive carcinoma (BRCA), lung squamous cell carcinoma (LUSC), sarcoma (SARC), stomach adenocarcinoma (STAD) and testicular germ cell tumors (TGCT). Mechanically, we found that PDCD2L expression was associated with apoptosis, invasion and cell cycle by investigating single cell sequencing data. For further validation, PDCD2Lwas highly expressed in colorectal cancer (CRC) cell lines and tissue samples compared with the normal colon cell line and non-tumor adjacent colorectal mucosa tissues. PDCD2L knockdown induced the apoptosis and proliferation of CRC cells.ConclusionsOur study shows that the oncogenic role of PDCD2L in various cancers and PDCD2L could be served as a biomarker of CRC.

A comprehensive investigation on pan-cancer impacts of constitutive centromere associated network gene family by integrating multi-omics data: A CONSORT-compliant article.

Background:The constitutive centromere associated network (CCAN) complex played a critical role in connecting the centromere with the mitotic spindle during mitosis and meiosis. Many studies have indicated that CCAN is related to the tumorigenesis and cancer development. Nonetheless, the overview of CCAN gene family in pan-cancer remain incompletely understood.Methods:We performed a comprehensive investigation on pan-cancer impacts of CCAN by integrating multi-omics data. We comprehensively investigated the expression profile, kyoto encyclopedia of genes and genomes (kegg) pathway, mutation, copy number variation, tumor microenvironment, immune cells infiltration, and drug sensitivity of CCAN in pan-cancer. MRNA expression profiles were collected from the cancer genome atlas, oncomine and ccle, the differential expression and various relevance analysis were performed with R or Perl.Results:The results showed that the expression of CCAN was different in 33 tumors. Intriguingly, the poor survival in adrenocortical carcinoma, cholangiocarcinoma, kidney chromophobe, mesothelioma, kidney renal clear cell carcinoma, brain lower grade glioma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, thyroid carcinoma, uveal melanoma was most likely related to the kegg single transduction pathway including one carbon pool by folate, proteasome, arachidonic acid metabolism and so on. CENPC, ITGB3BP, APITD1, CENPU, and CENPW were more involved in tumor microenvironment, which more likely related to NK cells resting, T cells follicular helper, T cells CD8, neutrophils, macrophages M0, T cells CD4 memory activated. The relationship of CCAN expression with drug sensitivity showed that chelerythrine, nelarabine, and hydroxyurea maybe be potential drugs.Conclusions:This multidimensional study provides a valuable resource to assist mechanism research and clinical utility about CCAN.

Adrenocortical Carcinoma: The Value of Lymphadenectomy

Adrenocortical carcinoma (ACC) staging does not account for the number of positive nodes. The prognostic value of quantitative metastatic nodal burden is unknown. The National Cancer Database was retrospectively queried from 2004-2016 to identify patients with Stage I-III ACC undergoing adrenalectomy. Patients who underwent lymphadenectomy (LAD) were further studied. Demographics, TNM staging, tumor characteristics, and surgical approach were analyzed. 386 LADs were identified. The median number of nodes examined was 2 (IQR 2-6), with no difference by surgical approach '[laparoscopic, 3 (1-3); robotic, 1.5 (1-4.5); open, 2 (1-7), p = 0.493]. In LADs with cN0 disease, positive nodes were seen in 17.5% of patients; an average of 6 (1-12) nodes were examined in patients who upstaged to pN1 disease compared with an average of 2 (1-6) nodes in those who remained pN0. Median survival was incrementally worse for patients with more positive nodes (62.8 vs. 21.9 vs. 13.7 vs. 11.3 vs. 10.7 months for 0, 1, 2, 3, and ≥4 positive nodes, respectively, p < 0.01). On multivariate analysis, significant prognostic factors for poor survival included older age, ≥2 comorbidities, pT3, and pT4. The strongest prognostic factor for poor survival was the number of positive nodes (1 node, hazards ratio [HR] 2.3, 95% confidence interval [CI] 1.5-3.6; 2 nodes, HR 1.3, 95% CI 0.6-3.0; 3 nodes, HR 3.0, 95% CI 1.1-8.0; ≥4 nodes, HR 4.0, 95% CI 2.5-6.2). Lymphadenectomy was associated with improved survival (HR 0.82, 95% CI 0.67-0.99). Higher quantitative metastatic nodal burden is a robust prognostic factor for worse survival in ACC.

Expression of the Chemokine Receptor CCR7 in the Normal Adrenal Gland and Adrenal Tumors and Its Correlation with Clinical Outcome in Adrenocortical Carcinoma.

Simple SummaryThe chemokine receptor CCR7 plays an important role in immune function and lymphoid trafficking and has been shown to be expressed in several malignant tumors with evidence for a role in tumor cell progression and clinical outcome. Here, we investigated the expression of CCR7 in normal adrenal glands, adrenocortical adenomas, and adrenocortical carcinomas. CCR7 was expressed across all adrenal tissues. However, CCR7 protein or mRNA expression did not significantly influence patient survival in adrenocortical carcinoma, but it could play a role in adrenocortical homeostasis.Background: The chemokine receptor CCR7 is crucial for an intact immune function, but its expression is also associated with clinical outcome in several malignancies. No data exist on the expression of CCR7 in adrenocortical tumors. Methods: CCR7 expression was investigated by qRT-PCR and immunohistochemistry in 4 normal adrenal glands, 59 adrenocortical adenomas, and 181 adrenocortical carcinoma (ACC) samples. Results: CCR7 is highly expressed in the outer adrenocortical zones and medulla. Aldosterone-producing adenomas showed lower CCR7 protein levels (H-score 1.3 ± 1.0) compared to non-functioning (2.4 ± 0.5) and cortisol-producing adenomas (2.3 ± 0.6), whereas protein expression was variable in ACC (1.8 ± 0.8). In ACC, CCR7 protein expression was significantly higher in lymph node metastases (2.5 ± 0.5) compared to primary tumors (1.8±0.8) or distant metastases (2.0 ± 0.4; p < 0.01). mRNA levels of CCR7 were not significantly different between ACCs, normal adrenals, and adrenocortical adenomas. In contrast to other tumor entities, neither CCR7 protein nor mRNA expression significantly impacted patients’ survival. Conclusion: We show that CCR7 is expressed on mRNA and protein level across normal adrenals, benign adrenocortical tumors, as well as ACCs. Given that CCR7 did not influence survival in ACC, it is probably not involved in tumor progression, but it could play a role in adrenocortical homeostasis.

Gene Regulation Network of Prognostic Biomarker YAP1 in Human Cancers: An Integrated Bioinformatics Study.

Background: Yes-associated protein 1 (YAP1) is the main downstream effector of the Hippo signaling pathway, which is involved in tumorigenesis. This study aimed to comprehensively understand the prognostic performances of YAP1 expression and its potential mechanism in pan-cancers by mining databases. Methods: The YAP1 expression was evaluated by the Oncomine database and GEPIA tool. The clinical significance of YAP1 expression was analyzed by the UALCAN, GEPIA, and DriverDBv3 database. Then, the co-expressed genes with YAP1 were screened by the LinkedOmics, and annotated by the Metascape and DAVID database. Additionally, by the MitoMiner 4.0 v tool, the YAP1 co-expressed genes were screened to obtain the YAP1-associated mitochondrial genes that were further enriched by DAVID and analyzed by MCODE for the hub genes. Results: YAP1 was differentially expressed in human cancers. Higher YAP1 expression was significantly associated with poorer overall survival and disease-free survival in adrenocortical carcinoma (ACC), brain Lower Grade Glioma (LGG), and pancreatic adenocarcinoma (PAAD). The LinkedOmics analysis revealed 923 co-expressed genes with YAP1 in adrenocortical carcinoma, LGG and PAAD. The 923 genes mainly participated in mitochondrial functions including mitochondrial gene expression and mitochondrial respiratory chain complex I assembly. Of the 923 genes, 112 mitochondrial genes were identified by MitoMiner 4.0 v and significantly enriched in oxidative phosphorylation. The MCODE analysis identified three hub genes including CHCHD1, IDH3G and NDUFAF5. Conclusion: Our findings showed that the YAP1 overexpression could be a biomarker for poor prognosis in ACC, LGG and PAAD. Specifically, the YAP1 co-expression genes were mainly involved in the regulation of mitochondrial function especially in oxidative phosphorylation. Thus, our findings provided evidence of the carcinogenesis of YAP1 in human cancers and new insights into the mechanisms underlying the role of YAP1 in mitochondrial dysregulation.

Reassessing the impact of tumor size on operative approach in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is often a contraindication to minimally invasive adrenalectomy (MIA). We used an administrative data set to analyze postoperative outcomes. We hypothesized that small tumors would have better short- and long-term outcomes, independent of the operative approach. The National Cancer Database (2010-2016) identified patients with ACC who underwent adrenalectomy. Tumors were grouped:<5 cm (n = 125), 5-10 cm (n = 431), and>10 cm (n = 443). The primary and secondary outcomes were margin positivity and overall survival, respectively. Nine hundred and ninety-ninepatients were analyzed: 37% MIA and 63% open adrenalectomy (OA). As the size increased, the rate of attempted MIA decreased. Larger tumors were associated with conversion to open. Althoughtumors with local invasion and those which required conversion to open were associated with an increased likelihood of a positive margin, tumor size was not. Although "complete" MIA (vs. OA) and tumor size were not associated with differences in survival, conversion (HR = 1.83, p = .02), positive margins (HR = 1.54, p = .01), and local invasion (HR = 1.84, p < .001) were associated with poor survival. Positive margins are associated with poor survival in ACC. Tumors ≥ 5 cm were associated with an increased conversion rate and subsequent increase in margin positivity. MIA may be considered for select patients with small tumors but adequate oncologic resection is critical.

Prognostic Implications of Pan-Cancer CMTM6 Expression and Its Relationship with the Immune Microenvironment.

CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) reportedly stabilizes programmed death-ligand 1 (PD-L1) and enhances the efficacy of immunotherapy. However, correlations between CMTM6 expression and the immune microenvironment and its prognostic value remain unknown in a variety of tumors. CMTM6 expression data were obtained from The Cancer Genome Atlas (TCGA) for 33 cancer types classified into high and low expression subgroups according to the median CMTM6 expression value. Pan-cancer analysis of CMTM6 protein expression in 20 tumor types was performed using a cohort from the Human Protein Atlas (HPA). PD-L1 protein expression data were obtained from The Cancer Proteome Atlas (TCPA) for 32 cancer types. Frequencies of CMTM6 copy number alterations and mutations were analyzed using cBioPortal. MANTIS was employed to estimate microsatellite instability in the TCGA cohort. CIBERSORT and the ESTIMATE algorithm were applied to estimate the relative fractions of infiltrating immune cell types and immune scores, respectively. Kaplan–Meier survival curve analysis was performed to assess the pan-cancer prognostic value of CMTM6.CMTM6 is heterogeneously expressed in diverse cancers. Further, the results revealed low CMTM6 mutation frequencies in multiple cancers. Among them, CMTM6 mutation frequency was the highest in uterine cancer. Additionally, CMTM6 expression was related to PD-L1 protein expression in breast invasive carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, glioblastoma multiforme (GBM), head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma, sarcoma (SARC), stomach adenocarcinoma, and uterine carcinosarcoma. Increased CMTM6 expression may be associated with increased infiltration of neutrophils in some types of cancer. Finally, pan-cancer analysis indicated that CMTM6 expression was closely related to overall survival in adrenocortical carcinoma, GBM, acute myeloid leukemia, liver hepatocellular carcinoma, mesothelioma, SARC, thymoma, and uveal melanoma. Taken together, these findings highlight that CMTM6 plays an important role in the tumor immune microenvironment, and CMTM6 has been identified to have prognostic value in some types of cancers. Thus, CMTM6 is a potential target for cancer immunotherapy and effective prognostic biomarker.

PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma

ABSTRACTAdrenocortical carcinomas (ACCs) are heterogeneous cancers associated with a very poor prognosis. The improvement of prognostic tools and systemic therapy are urgently needed. Targeting the immune system using checkpoint inhibitors such as PD1/PDL1 inhibitors is an attractive novel therapeutic strategy for poor-prognosis tumors. Multiple clinical trials are ongoing, including in advanced ACC. However, PDL1 expression has been studied in ACC in only one heterogeneous series of 28 clinical samples. Here, we have retrospectively analyzed PDL1 mRNA expression in 146 clinical ACC samples and searched for correlations between expression and biological and clinicopathological data, including post-operative disease-free survival (DFS). PDL1 mRNA expression was heterogeneous across samples. “PDL1-high” tumors were not associated with the classical prognostic variables but were associated with longer DFS in both uni- and multivariate analyses. High PDL1 mRNA expression was associated with biological signs of the cytotoxic local immune response. Supervised analysis between “PDL1-high” and “PDL1-low” tumors identified a robust 370-gene signature whose ontology analysis suggested the existence in “PDL1-high” tumors of a cytotoxic T-cell response, however, associated with some degree of T-cell exhaustion. In conclusion, PDL1 mRNA expression refines the prognostication in ACC and high expression is associated with longer DFS. Clinical validation at the protein level and functional validation are required to fully understand the role of PDL1 in ACC. Reactivation of dormant tumor-infiltrating lymphocytes by PDL1-inhibitors could represent a promising strategy in “PDL1-high” ACCs, supporting the ongoing clinical trials.

Adjuvant Radiation Improves Recurrence-Free Survival and Overall Survival in Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy with high rates of recurrence and poor prognosis. The role of radiotherapy (RT) in localized ACC has been controversial, and RT is not routinely offered. To evaluate the benefit of adjuvant RT on outcomes in ACC. This is a retrospective propensity-matched analysis. All patients were seen through the University of Michigan's Endocrine Oncology program, and all those who underwent RT were treated at the University of Michigan. Of 424 patients with ACC, 78 were selected; 39 patients underwent adjuvant radiation. Adjuvant RT to the tumor bed and adjacent lymph nodes. Time to local failure, distant failure, or death. Median follow-up time was 4.21 years (95% CI, 2.79 to 4.94). The median radiation dose was 55 Gy (range, 45 to 60). The 3-year overall survival estimate for patients improved from 48.6% for patients without RT (95% CI, 29.7 to 65.2) to 77.7% (95% CI, 56.3 to 89.5) with RT, with a hazard ratio (HR) of 3.59 (95% CI, 1.60 to 8.09; P = 0.002). RT improved local recurrence-free survival (RFS) from 34.2% (95% CI, 18.8 to 50.3) to 59.5% (95% CI, 39.0 to 75.0), with an HR of 2.67 (95% CI, 1.38 to 5.19; P = 0.0035). RT improved all RFS from 18.3% (95% CI, 6.7 to 34.3) to 46.7% (95% CI, 26.9 to 64.3), with an HR 2.59 (95% CI, 1.40 to 4.79; P = 0.0024). In the largest single institution study to date, adjuvant RT after gross resection of ACC improved local RFS, all RFS, and overall survival in this propensity-matched analysis. Adjuvant RT should be considered a part of multidisciplinary management for patients with ACC.