BACKGROUND:Parathyroid carcinoma (PC), often misdiagnosed as a parathyroid adenoma (PA), is prone to local relapse due to the initial surgery being restricted to parathyroid lesions instead of en bloc resection of parathyroid lesions with negative incision margins. However, it is very challenging to distinguish PC from PA preoperatively; hence, this study investigated an effective biomarker for increasing accuracy in PC diagnosis.METHOD:First, the differentially expressed circular RNAs between three PC tissues and three PA tissues were screened by high-throughput circular RNA sequencing, and the expression of hsa_circ_0005729 was verified by qRT-PCR in 14 patients with PC and 40 patients with PA. Secondly, the receiver operating characteristic curve and the area under the curve (AUC) were used to analyze the diagnostic efficiency of hsa_circ_0005729 in PC by combining with laboratory data. Thirdly, RNF138mRNA, the corresponding linear transcript of hsa_circ_0005729, was measured, and the relationship between hsa_circ_0005729 and RNF138 mRNA was analyzed in patients with PA and patients with PC.RESULTS:Hsa_circ_0005729 expression was significantly higher in patients with PC than in patients with PA. Serum calcium (P = 0.045), alkaline phosphatase (ALP) (P = 0.048), and creatinine levels (P = 0.036) were significantly higher in patients with PC than in patients with PA. The AUC increased to 0.86 when hsa_circ_0005729 combined with serum calcium, creatinine, and ALP. In addition, hsa_circ_0005729 was positively correlated with RNF138 mRNA in patients with PA but not in patients with PC.CONCLUSION:The novel circular RNA hsa_circ_0005729 was found to have a higher expression in patients with PC, indicating its usefulness for distinguishing PC from PA.

Nuclear factor erythroid-2 related factor-2 (NFE2L2 or NRF2) is a frequently mutated gene in esophageal squamous cell carcinoma (ESCC). However, the roles of NFE2L2 alterations in ESCC remain elusive. In order to elucidate this issue, 130 ESCC patients who underwent esophagectomy were enrolled. The majority of tumor tissues were positive for NRF2, which was significantly enriched in the nucleus of the primary tumor tissues compared with the noncancerous mucosae. Primary ESCC tumors positive for NRF2 tended to be positive for NAD(P)H quinone oxidoreductase 1 (NQO1) as the downstream target of NRF2. There was a positive correlation between NRF2 and NQO1 expression level in primary tumors. NQO1 staining in primary tumors with NRF2 nuclear expression was significantly stronger than that with NRF2 cytoplasmic expression. In addition, high concordance for the status of NRF2 expression between primary tumors and corresponding metastatic lesions was observed. Next, we found high expression of nuclear NRF2 (the proportion of nuclear NRF2 expression >20% or nuclear NRF2 immunohistochemistry score >20) predicted shorter overall survival in patients with dual-positive expression of NRF2 and NQO1. Captured-based targeted sequencing revealed that NFE2L2 somatic alterations were observed in 52.8% of ESCC patients with dual-positive expression of NRF2 and NQO1. NFE2L2 amplification and mutations within the DLG/ETGE motifs were seen more frequently in ESCC tumors with nuclear or nucleocytoplasmic expression of NRF2 compared with those with cytoplasmic expression of NRF2. We also found high expression of nuclear NRF2 plus the status of NFE2L2 alteration exhibited high performance in predicting prognosis of ESCC patients. Our study demonstrated that high nuclear NRF2 expression and NFE2L2 alterations were associated with poor prognosis of ESCC patients. These findings suggest that NRF2 signaling pathway might play vital roles in ESCC malignancy and the aberrant activation of NRF2 pathway predicts unfavorable prognosis in ESCC.

Alpha-fetoprotein-producing gastric cancer (AFPGC) is associated with high invasion and poor prognosis, but has not been well-documented due to its rarity. To develop the understanding of AFPGC, and further facilitate its clinical decision-making and treatment, we performed clinicopathological and molecular characterization of AFPGC and its two major subtypes, namely, gastric adenocarcinoma with enteroblastic differentiation (GAED) and hepatoid adenocarcinoma (HAC). The clinicopathological and molecular characteristics of AFPGC patients (n = 54) were mainly investigated by immunohistochemistry and next-generation sequencing (NGS) approaches. AFPGC exhibited a higher incidence of lymphatic and vascular invasion than conventional gastric adenocarcinoma (CGA). Despite various morphological patterns, there was mostly no evident difference in clinicopathological characteristics between the GAED and HAC subtypes. Target-enriched NGS profiling of disease mutation landscapes discovered 17 differentially mutated genes between AFPGC and CGA. The AFPGC patients carrying ZNF217 mutations had poorer overall survival than the ZNF217 wildtype. Furthermore, ATR showed a significantly higher mutation rate in GAED than in HAC. Overall, our study of clinicopathological characteristics shed light on the differences between CGA and AFPGC, as well as the relationships between the GAED and HAC subtypes of AFPGC. Furthermore, mutation landscape profiling revealed potential diagnostic and prognostic markers for AFPGC and its two subtypes.

Purpose: Early onset gastric carcinoma (EOGC) is thought to be developed by a distinct molecular genetic profile of gastric carcinoma occurring at an older age. The aim of this study was to compare clinicopathological features and expression patterns of programmed death-1 (PD-1) and its ligand PD-L1 in young and older GC patients. Methods: Consecutive cases of GC presented to our hospital between 2007-2016 were collected. Clinicopathological features and overall survival data of EOGC patients (initially diagnosed at 40 years old or younger) were retrospectively reviewed from hospital records and compared with data of GC in the elderly (GC-E) (age ≥60 years). We investigated expression of PD-1 and PD-L1 by immunohistochemistry in both GC groups. Staining results were correlated with clinicopathological characteristics and overall survival. We then compared expression of PD-1 and PD-L1 with EOGC and GC-E. Results: Two thousands one hundred and forty five GC cases were collected. All 109 EOGC cases and 116 randomly selected GC-E cases were enrolled in the current study. Compared to GC-E patients, EOGC had a significantly higher proportion of female and gastric body location, a larger diameter, a higher proportion of low adhesive adenocarcinoma or diffuse gastric carcinoma, and a higher proportion of poorly differentiated tumors. PD-L1 was positively expressed in tumor cells in 43.6% (98/225) of GC cases and was weak to medium positive in most positive cases. The intensity of PD-L1 expression in tumor cells was significantly higher in EOGC (P=0.02). The positive rate of PD-L1 expression in tumor cells was significantly higher in EOGC than in GC-E (P=0.02). Conclusion: Clinicopathological characteristics of EOGC were distinctive from GC-E patients. EOGC had poorer prognosis compared to the older age group. Expression of PD-L1 in EOGC was significantly higher than in GC-E.