Circulating Epstein-Barr virus DNA associated with hepatic impairment and its diagnostic and prognostic role in patients with gastric cancer.

Epstein-Barr virus (EBV) infection may affect all tissues and organs of the body. Little is known about the impact of this entity on its systematic incorporation in patients with gastric cancer (GC). This study enrolled a total of 113 GC patients with EBV infection (EBVaGC) and 167 GC patients without EBV infection (EBVnGC). It was found that the CRP levels (indicative of inflammatory status) were significantly increased in EBVaGC compared with those in EBVnGC (12.11 mg/L vs. 5.72 mg/L, P = 0.008), but WBC and neutrophils counts were similar in both groups (P > 0.05). Consistent elevations in the levels of liver enzymes, ALP and GGT, with incompatible alterations in ALT or AST were observed in EBVaGC. Slightly prolonged coagulation indices, PT and INR, and decreased albumin consistently suggested impaired synthesis capability of the liver in EBVaGC (all P < 0.05). The level of circulating EBV DNA was positively correlated with the level of GGT, tumor marker CA72-4 and the lymphocyte infiltration in tumor tissues (all P < 0.05). Of note, the EBV associated high-lymphocyte infiltrated tissues presented rich CD8 + T cells. Circulating EBV DNA further showed a predictive role in distinguishing EBVaGC from EBVnGC (AUC 0.79, 95% CI 0.73 to 0.85, P < 0.001), and was associated closely with better overall survival (HR 0.45, 95% CI 0.21 to 0.96, P = 0.039). EBV infection in patients with gastric cancer may be linked to hepatic impairment and immune response. Circulating cell-free EBV DNA is not only a biomarker for the screening of an EBV-related GC subtype but is also an independently prognosis factor for the long-term survival benefit in GC patients.

A diagnostic and predictive lncRNA lnc-MPEG1-1 promotes the proliferation and metastasis of papillary thyroid cancer cells by occupying miR-766-5p.

Long non-coding RNAs (lncRNAs) act as important biological regulators in human cancers. The purpose of this study was to identify promising biomarkers for improved diagnosis and prognosis of papillary thyroid cancer (PTC). We analyzed the lncRNA expression profile of PTC patients and identified five upregulated and three downregulated lncRNAs as diagnostic biomarkers for PTC in our cohorts, which were confirmed using The Cancer Genome Atlas (TCGA) data. Several lncRNAs have been linked with lymph node (LN) metastasis in patients with PTC. A nomogram combining two lncRNAs, lnc-MPEG1-1:1 and lnc-ABCA12-5:2, with age, T stage, histological type, and predicted LN metastasis was developed. The area under the curve of the developed nomogram was 0.77 (0.73-0.81) in the TCGA training cohort and 0.88 (0.79-0.96) in our validation cohort. In particular, in vivo and in vitro experiments showed that overexpression of lnc-MPEG1-1:1 in PTC cell lines promoted the proliferation and migration of PTC. lnc-MPEG1-1:1 is overexpressed in the cytoplasm of PTC cells and functionally promotes cellular proliferation and migration and functions as a competitive endogenous RNA (ceRNA) by competitively occupying the shared binding sequences of miR-766-5p. lnc-MPEG1-1:1 knockdown suppressed epithelial-mesenchymal transition by miR-766-5p in PTC cells. Collectively, these results revealed a lnc-MPEG1-1:1/miR-766-5p pathway for thyroid cancer progression and suggest that a nomogram effectively predicted the LN metastasis in PTC.

Inherited rare and common variants in PTCH1 and PTCH2 contributing to the predisposition to reproductive cancers.

PTCH1 and PTCH2 are associated with nevoid basal cell carcinoma syndrome and basal cell carcinoma. We determined the prevalence of their common and rare variants in 877 patients with various reproductive cancers and 296 healthy subjects. Using targeted next-generation sequencing, we found significantly statistical associations of the minor alleles at seven common variants of PTCH1 and PTCH2 with a decreased risk of reproductive cancers (P = 9.69 × 10-12). Among these variants, two haplotype blocks in high linkage disequilibrium were consisted of rs2277184, rs2066829 and rs2236405 sites at PTCH1 and rs3795720, rs11573590 and rs11211040 sites at PTCH2. Single marker and haplotype-based analysis consistently revealed a decreased risk of reproductive cancers especially breast and prostate cancers in the subjects carrying the minor alleles, and on the contrary, an increased risk for major alleles. Healthy control subjects showed a higher rate of rare variants than that of cancer patients (P = 0.017). Notably, two frameshift variants (p.Ser391* and p.Cys101Alafs*48) of PTCH2 with deleterious effects were found in only four cancer patients. Higher frequencies of variants of PTCH genes might have a protective role against the development of reproductive cancers, whereas rare deleterious variants of PTCH2 might predispose a carrier to reproductive cancers.

Comparison of the diagnostic performances of US-guided fine needle aspiration cytology and thyroglobulin measurement for lymph node metastases in patients with differentiated thyroid carcinoma: a meta-analysis.

OBJECTIVES: Ultrasound (US)-guided fine needle aspiration cytology (FNAC) and thyroglobulin measurement (FNA-Tg) are two common methods for confirming lymph node metastases (LNM) in patients with differentiated thyroid carcinoma (DTC). This study aimed at comparing the diagnostic performance of FNAC, FNA-Tg alone, and in combination by means of a meta-analysis. METHODS: Eligible articles were selected according to predefined criteria, and their quality was evaluated as per the QUADAS-2 checklist. We calculated pooled sensitivity (Se), specificity (Sp), positive/negative likelihood ratio, and diagnostic odds ratio (DOR), and plotted the summary receiver operating characteristic (SROC) curve using the Meta-DiSc1.4 software. RESULTS: Twenty-one studies pooling 1662 malignant and 1279 benign LNs from 2712 patients with DTC were included. The results showed that FNAC was more specific (pooled Sp, 0.98) while FNA-Tg was more sensitive (pooled Se, 0.94). FNAC and FNAC+FNA-Tg performed better postoperatively than FNA-Tg, while FNA-Tg performed better preoperatively. The combination of FNAC and FNA-Tg could achieve a better diagnostic performance than each alone (DOR 446.00, area under the curve [AUC] 0.9862), no matter preoperatively (DOR 378.14, AUC 0.9879) or postoperatively (DOR 788.72, AUC 0.9930). Besides, the combination of FNAC and FNA-Tg/serum-Tg ratio obtained a higher Sp (0.98) than the combination of FNAC and FNA-Tg. CONCLUSION: The addition of FNA-Tg, especially the FNA-Tg/serum-Tg ratio, to FNAC could increase the diagnostic performance of LNM in both preoperative and postoperative patients with DTC. Since one test or test combinations could perform differently according to the clinical situation, the best-fitting test should be chosen accordingly. KEY POINTS: • FNAC is more specific than FNA-Tg while FNA-Tg is more sensitive than FNAC. • The combination of FNAC and FNA-Tg could achieve a better diagnostic performance than either alone, no matter preoperatively or postoperatively. • The combination of FNAC and FNA-Tg/serum-Tg ratio could reach a higher Sp than the combination of FNAC and FNA-Tg.

A 10-Year Study on Larynx Preservation Compared With Surgical Resection in Patients With Locally Advanced Laryngeal and Hypopharyngeal Cancers.

BACKGROUND: Few reports from China provide confirmed evidence of the effectiveness of the larynx preservation strategy compared with surgery on the treatment of laryngeal and hypopharyngeal cancers. This study assessed the clinical outcomes of patients with locally advanced laryngeal and hypopharyngeal cancers treated with larynx preservation and determined the optimal larynx preservation procedure. METHODS: Data of 1,494 patients treated with total laryngectomy or larynx preservation between 2006 and 2014 were retrieved from the database of Sun-Yat Sen University Cancer Center in Guangzhou, China, and 366 eligible patients were selected for final analysis. The clinical outcomes of 228 patients received total laryngectomy and 138 patients received larynx preservation treatments, which comprises induction followed by radiotherapy and concurrent radio-chemotherapy, were compared. RESULTS: There was no statistical difference in the 3-, 5-, and 10-year PFS and OS in patients received larynx preservation compared with patients treated with laryngectomy. With respect to T stage, a better overall OS in T2-stage disease (P = 0.036) but poorer PFS (P = 0.005) in T3-stage disease was observed in the larynx preservation group compared with the surgery group in Univariate analysis. T3-stage disease had poorer PFS in multivariable analysis (P = 0.022). With larynx preservation intent, induction chemotherapy followed by radiotherapy showed no advantage in the control of disease progression and survival compared with concurrent chemoradiotherapy. The patient subpopulations who received efficacy assessment after induction chemotherapy exhibited significantly longer PFS and OS compared with those without efficacy assessment. CONCLUSIONS: This is the largest sample size study on larynx preservation treatment for laryngeal and hypopharyngeal cancers in China. Our results indicated that larynx preservation treatments did not jeopardize the survival of patients with advanced resectable laryngeal or hypopharyngeal cancers. Efficacy assessment should be emphasized in induction chemotherapy.

Polymorphisms in matricellular SPP1 and SPARC contribute to susceptibility to papillary thyroid cancer.

There is a compelling need to identify novel genetic variants for papillary thyroid cancer (PTC) susceptibility. The Cancer Genome Atlas (TCGA) data showed associations between SPP1 and SPARC mRNA overexpression and aggressive behaviors of PTC, which prompted us to assess potential associations between genetic variants in these genes and PTC risk. Three highly linked SPARC loci (rs1054204, rs3210714, and rs3549) contributed to reduced PTC risk under a codominant model (odds ratio [OR], 0.79-0.80). Variant CAG alleles at these loci significantly enhanced SPARC transcription activation upon cotransfection with miR-29b and miR-495 when compared to the common alleles GGC (all P < 0.05). The three SPARC polymorphisms interacted with SPP1 rs4754, with elevated joint ORs of 2.43, 2.52, and 2.52, respectively. Additionally, interaction between SPP1 rs2358744 and SPARC rs2304052 was observed. Our study revealed associations between SPP1 and SPARC polymorphisms that, individually or in combination, are involved in PTC susceptibility.

lncRNA GAS8-AS1 genetic alterations in papillary thyroid carcinoma and their clinical significance.

The long non-coding RNA (lncRNA) GAS8-AS1 is the second-most frequently altered gene, following the BRAF gene, in papillary thyroid carcinoma (PTC). We aimed to study the specificity and significance of genetic alterations in GAS8-AS1 in PTC. In this study, we reported the prevalence of genetic alterations of GAS8-AS1 in tissues of 48 nodular goiter, 573 papillary thyroid cancer, 95 colorectal cancer, 101 non-small cell lung cancer, 92 glioma, and 69 gastrointestinal stromal tumor patients, and in peripheral white blood cells of 286 healthy volunteers. We observed that the genomic sequence of GAS8-AS1 had a high frequency of genetic alterations in addition to the previously reported c.713A>G/714T>C substitution. Substitution of c.713A>G was completely linked with four other loci at c.714T>C, c.728A>G, c.737G>A, and c.752G>A. Two novel substitutions at c.749G>A and c.826A>G were also found. Interestingly, evidence from different samples indicated that these variations were not unique variants for PTC; they were also found in other malignant tissues and white blood cells of healthy volunteers. The c.713A>G substitution was associated with the T stage of PTC, while c.749G>A was more likely to occur in younger patients with PTC. PTC patients carrying heterozygous variants at the c.749 and c.826 loci had a higher risk of developing multiple lesions. These associations were also observed in patients with PTC and concomitant benign thyroid disease. Notably, the rare homozygous GG at the c.826 site conferred a higher risk of developing T2 PTC without benign thyroid disease, and a lower risk of developing T2 PTC with benign thyroid disease. Alterations of c.749G>A and c.826A>G had higher levels of serum TSH (thyroid stimulating hormone) in PTC subjects. Our study provides evidence that the detection of GAS8-AS1 genetic alterations would be useful in diagnostic screening and prognostic assessment of PTC.

Classification of gastric cancer by EBV status combined with molecular profiling predicts patient prognosis.

PURPOSE: To identify how Epstein-Barr virus (EBV) status combined with molecular profiling predicts the prognosis of gastric cancer patients and their associated clinical actionable biomarkers. EXPERIMENTAL DESIGN: A next-generation sequencing assay targeting 295 cancer-related genes was performed in 73 EBV-associated gastric cancer (EBVaGC) and 75 EBV-negative gastric cancer (EBVnGC) specimens and these results were compared with overall survival (OS). RESULTS: PIK3CA, ARID1A, SMAD4, and PIK3R1 mutated significantly more frequently in EBVaGC compared with their corresponding mutation rate in EBVnGC. As the most frequently mutated gene in EBVnGC (62.7%), TP53 also displayed a mutation rate of 15.1% in EBVaGC. PIK3R1 was revealed as a novel mutated gene (11.0%) associated almost exclusively with EBVaGC. PIK3CA, SMAD4, PIK3R1, and BCOR were revealed to be unique driver genes in EBVaGC. ARID1A displayed a significantly large proportion of inactivated variants in EBVaGC. A notable finding was that integrating the EBV status with tumor mutation burden (TMB) and large genomic instability (LGI) categorized the tumors into four distinct molecular subtypes and optimally predicted patient prognosis. The corresponding median OSs for the EBV+/TMB-high, EBV+/TMB-low, EBV-/LGI-, and EBV-/LGI+ subtypes were 96.2, 75.3, 44.4, and 20.2 months, respectively. The different subtypes were significantly segregated according to distinct mutational profiles and pathways. CONCLUSIONS: Novel mutations in PIK3R1 and TP53 genes, driver genes such as PIK3CA, SMAD4, PIK3R1, BCOR, and ARID1A, and distinguished genomic profiles from EBVnGC were identified in EBVaGC tumors. The classification of gastric cancer by EBV, TMB, and LGI could be a good prognostic indicator, and provides distinguishing, targetable markers for treatment.