Elucidating the clinical and immunological value of m6A regulatormediated methylation modification patterns in adrenocortical carcinoma

N6-methyladenosine methylation(m6A)is a common type of epigenetic alteration that prominently affects the prognosis of tumor patients.However,it is unknown how the m6A regulator affects the tumor microenvironment(TME)cell infiltration in adrenocortical carcinoma(ACC)and how it affects the prognosis of ACC patients yet.The m6A alteration patterns of 112 ACC patients were evaluated,furthermore,the association with immune infiltration cell features was investigated.The unsupervised clustering method was applied to typify the m6A alteration patterns of ACC patients.The principal component analysis(PCA)technique was taken to create the m6A score to assess the alteration pattern in specific malignancies.We found two independent patterns of m6A alteration in ACC patients.The TME cell infiltration features were significantly in accordance with phenotypes of tumor immune-inflamed and immune desert in both patterns.The m6Ascore also served as an independent predictive factor in ACC patients.The somatic copy number variation(CNV)and patients prognosis can be predicted by m6A alteration patterns.Moreover,the ACC patients with high m6A scores had better overall survival(OS)and higher efficiency in immune checkpoint blockade therapy.Our work demonstrated the significance of m6A alteration to the ACC patients immunotherapy.The individual m6A alteration patterns analysis might contribute to ACC patients prognosis prediction and immunotherapy choice.

Multidisciplinary team therapy for left giant adrenocortical carcinoma: A case report

BACKGROUND Adrenocortical carcinoma(ACC)is a rare malignant epithelial tumor originating from adrenocortical cells that carries a very poor prognosis.Metastatic or inoperable diseases are often considered incurable,and treatment remains a challenge.Especially for advanced cases such as ACC complicated with renal venous cancer thrombus,there are few cumulative cases in the literature.CASE SUMMARY The patient in this case was a 39-year-old middle-aged male who was admitted to the hospital for more than half a month due to dizziness and chest tightness.Computed tomography(CT)findings after admission revealed a left retroperitoneal malignant space-occupying lesion,but the origin of the formation of the left renal vein cancer thrombus remained to be determined.It was speculated that it originated from the left adrenal gland,perhaps a retroperitoneal source,and left adrenal mass+left nephrectomy+left renal vein tumor thrombus removal+angioplasty were performed under general anesthesia.Postoperative pathology results indicated a diagnosis of ACC.Postoperative steroid therapy was administered.At 3 mo after surgery,abdominal CT reexamination revealed multiple enlarged retroperitoneal lymph nodes and multiple low-density shadows in the liver,and palliative radiotherapy and mitotane were administered,considering the possibility of metastasis.The patient is currently being followed up.CONCLUSION ACC is a highly malignant tumor.Even if the tumor is removed surgically,there is still the possibility of recurrence.Postoperative mitotane and adjuvant chemoradiotherapy have certain benefits for patients,but they cannot fully offset the poor prognosis of this disease.

Rare complication of acute adrenocortical dysfunction in adrenocortical carcinoma after transcatheter arterial chemoembolization:A case report

BACKGROUND Adrenocortical carcinoma(ACC)is a rare and highly invasive endocrine malignant tumor with a poor prognosis.Although surgical resection is the main treatment for ACC,postoperative recurrence and metastasis have become the important factors of death.Transcatheter arterial chemoembolization(TACE)is an important option for the treatment of advanced ACC with liver metastasis.However,due to the small number of patients treated for ACC,the safety of the operation is not completely clear and needs to be further studied.CASE SUMMARY A 47-year-old patient with ACC after surgery was admitted for reexamination by abdominal computerized tomography suggesting liver metastasis.Because the patient expressed reluctance to undergo surgery again,we treated her with TACE for the liver lesions.After treatment,symptoms of acute adrenal dysfunction such as decreased blood pressure,anorexia,and fatigue appeared,which were relieved after hydrocortisone treatment.To date,the patient's liver lesion is well controlled and no other metastases are observed.CONCLUSION We report a rare case of acute adrenal hypofunction after TACE.Glucocorticoid supplementation can alleviate the symptoms.

Giant androgen-producing adrenocortical carcinoma with atrial flutter: A case report and review of the literature

BACKGROUND Adrenocortical carcinoma(ACC),the second most aggressive malignant tumor,lacks epidemiological data worldwide;therefore,every new case can improve the understanding of the pathology and treatment of this malignancy.CASE SUMMARY We present the case of a 66-year-old Caucasian woman with a giant androgenproducing ACC(21 cm×17 cm×12 cm;2100 g),without metastases,which unusually presented with an acute onset of atrial flutter and congestive heart failure.The cardiac complications observed in our case support the hypothesis that androgen excess in women is a cardiovascular risk factor.Androgen excess in women can be a rare cause of reversible dilated cardiomyopathy,therefore a comprehensive approach to the patient is essential to improve the recognition of androgen-secreting ACC.The atrial flutter was remitted after initiation of drug treatment during admission.The severe heart failure was totally remitted at 6 mo after radical open surgery to remove the giant ACC.CONCLUSION Radical open surgery to remove a giant androgen-producing ACC was the firstline treatment to cure the excess of androgen,which determined the total remission of cardiac complications at 6 mo after surgery in the women of this case report.

Screening of biomarkers for the diagnosis and prognosis of adrenocortical carcinoma based on bioinformatics analysis

Objective:To explore the gene biomarkers related to the diagnosis and prognosis of adrenocortical carcinoma(ACC)by bioinformatics.Methods:GEPIA online analysis tool was used to screen differentially expressed genes for sequencing data from patients with ACC and normal adrenal cortex.The overall survival rate and disease-free survival method were used to conduct batch survival analysis on differentially expressed genes,and the top 100 genes with HR values calculated by the two methods were obtained respectively.The intersection method is used to obtain core genes that play a key role in both overall survival and disease-free survival.GEPIA online analysis tool was used again to explore the relationship between the above-mentioned survival-related genes and the pathological stage of ACC.Use UALCAN online analysis tool to verify the survival-related genes again and draw the Kaplan-Meier survival curve.Finally,GSE33371 chip dataset of the GEO database was used to evaluate the diagnostic value of the above-mentioned survival-related genes.Results:514 differentially expressed genes were obtained by limma method.Batch analysis of differential genes was performed to obtain the top 100 genes most related to overall survival and disease-free survival,of which 13 genes were closely related to overall survival and disease-free survival.9 hub genes including TP73,SNHG1,PDE6D,GPC2,SUV39H2,HELLS,CLK2,COPS7B and CEP164 were finally obtained by exploring the relationship between their expression levels and pathological stage and resurvival analysis.At the same time,the results of ROC analysis suggest that the above hub genes have high diagnostic value for patients with adrenocortical carcinoma.Conclusion:By using GEPIA,UALCAN and the gene chip retrieved from GEO database,combined with the bioinformatics method,we analyzed and verified the new biomarkers that can be used to evaluate the prognosis of patients with ACC and to differential diagnosis of ACC,and provided the theoretical support of bioinformatics for exploring the occurrence,development of molecular mechanism and potential target of treatment of ACC.

A nomogram for individualized estimation of survival among adult patients with adrenocortical carcinoma after surgery:a retrospective analysis and multicenter validation study

Background:Clinical outcome of adrenocortical carcinoma(ACC)varies because of its heterogeneous nature and reliable prognostic prediction model for adult ACC patients is limited.The objective of this study was to develop and externally validate a nomogram for overall survival(OS)prediction in adult patients with ACC after surgery.Methods:Based on the data from the Surveillance Epidemiology,and End Results(SEER)database,adults patients diagnosed with ACC between January 1988 and December 2015 were identified and classified into a training set,comprised of 404 patients diagnosed between January 2007 and December 2015,and an internal validation set,com-prised of 318 patients diagnosed between January 1988 and December 2006.The endpoint of this study was OS.The nomogram was developed using a multivariate Cox proportional hazards regression algorithm in the training set and its performance was evaluated in terms of its discriminative ability,calibration,and clinical usefulness.The nomogram was then validated using the internal SEER validation,also externally validated using the Cancer Genome Atlas set(TCGA,82 patients diagnosed between 1998 and 2012)and a Chinese multicenter cohort dataset(82 patients diag-nosed between December 2002 and May 2018),respectively.Results:Age at diagnosis,T stage,N stage,and M stage were identified as independent predictors for OS.A nomo-gram incorporating these four predictors was constructed using the training set and demonstrated good calibration and discrimination(C-index 95%confidence interval[CI],0.715[0.679-0.751]),which was validated in the internal validation set(C-index[95%CI],0.672[0.637-0.707]),the TCGA set(C-index[95%CI],0.810[0.732-0.888])and the Chi-nese multicenter set(C-index[95%CI],0.726[0.633-0.819]),respectively.Encouragingly,the nomogram was able to successfully distinguished patients with a high-risk of mortality in all enrolled patients and in the subgroup analyses.Decision curve analysis indicated that the nomogram was clinically useful and applicable.Conclusions:The study presents a nomogram that incorporates clinicopathological predictors,which can accurately predict the OS of adult ACC patients after surgery.This model and the corresponding risk classification system have the potential to guide therapy decisions after surgery.

Systematic Genome-Wide Profiles Reveal Alternative Splicing Landscape and Implications of Splicing Regulator DExD-Box Helicase 21 in Aggressive Progression of Adrenocortical Carcinoma

Alternative splicing(AS)in the tumor biological process has provided a novel perspective on carcinogenesis.However,the clinical significance of individual AS patterns of adrenocortical carcinoma(ACC)has been underestimated,and in-depth investigations are lacking.We selected 76 ACC samples from the Cancer Genome Atlas(TCGA)SpliceSeq and SpliceAid2 databases,and 39 ACC samples from Fudan University Shanghai Cancer Center(FUSCC).Prognosis-related AS events(PASEs)and survival analysis were evaluated based on prediction models constructed by machine-learning algorithm.In total,23,984 AS events and 3,614 PASEs were detected in the patients with ACC.The predicted risk score of each patient suggested that eight PASEs groups were significantly correlated with the clinical outcomes of these patients(p<0.001).Prognostic models produced AUC values of 0.907 in all PASEs’groups.Eight splicing factors(SFs),including BAG2,CXorf56,DExD-Box Helicase 21(DDX21),HSPB1,MBNL3,MSI1,RBMXL2,and SEC31B,were identified in regulatory networks of ACC.DDX21 was identified and validated as a novel clinical promoter and therapeutic target in 115 patients with ACC from TCGA and FUSCC cohorts.In conclusion,the strict standards used in this study ensured the systematic discovery of profiles of AS events using genome-wide cohorts.Our findings contribute to a comprehensive understanding of the landscape and underlying mechanism of AS,providing valuable insights into the potential usages of DDX21 for predict-ing prognosis for patients with ACC.