Zinc and ring finger 3 (ZNRF3) is a negative suppressor of Wnt signal and newly identified as an important regulator in tumorigenesis and development. However, the pan-cancer analysis of ZNRF3 has not been reported. We found that ZNRF3 was significantly decreased in six tumors including CESC, KIRP, KIRC, SKCM, OV, and ACC, but increased in twelve tumors, namely LGG, ESCA, STES, COAD, STAD, LUSC, LIHC, THCA, READ, PAAD, TGCT, and LAML. Clinical outcomes of cancer patients were closely related to ZNRF3 expression in ESCA, GBM, KIRC, LUAD, STAD, UCEC, LGG, and SARC. The highest genetic alteration frequency of ZNRF3 occurred in ACC. Abnormal expression of ZNRF3 could be attributed to the differences of copy number variation (CNV) and DNA methylation as well as ZNRF3-interacting proteins. Besides, ZNRF3 were strongly associated with tumor heterogeneity, tumor stemness, immune score, stromal score and ESTIMATE score in certain cancers. In terms of immune cell infiltration, ZNRF3 was positively correlated to infiltration of cancer-associated fibroblasts in CESC, HNSC, OV, PAAD, PRAD, and THYM, but negatively associated with infiltration of CD8 T cells in HNSC, KIRC, KIRP and THYM. Moreover, ZNRF3 expression was correlated with most immune checkpoint genes in SARC, LUSC, LUAD, PRAD, THCA, UVM, TGCT, and OV, and associated with overwhelming majority of immunoregulatory genes in almost all cancers. Most RNA modification genes were also remarkably related to ZNRF3 level in KIRP, LUAD, LUSC, THYM, UVM, PRAD, and UCEC, indicating that ZNRF3 might have an important effect on cancer epigenetic regulation. Finally, we verified the expression and role of ZNRF3 in clinical specimens and cell lines of renal cancer and liver cancer. This study provides a comprehensive pan-cancer analysis of ZNRF3 and reveals the complexity of its carcinogenic effect.

OBJECTIVE: Comprehensive genomic profiling is useful for patients with Thyroid carcinoma (TC) for whom standard treatment has become refractory. We analyzed the clinical and genomic characteristics of patients with TC using the Japanese nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database.
METHODS: This retrospective observational study used the data obtained from the C-CAT database. Genomic information has been accumulated on representative gene mutations associated with TC.
RESULTS: Among the 482 patients, 212 (44%) were male and 270 (56%) were female. According to histological type, 259 (54%), 46 (10%), 16 (3%), 51 (11%), and 110 (23%) patients had papillary TC (PTC), follicular TC, medullary TC, poorly differentiated TC, and anaplastic TC (ATC), respectively. Among the genomic profiling tests, FoundationOne CDx (n = 388; 80%) was the most frequently performed. The frequencies of BRAF, NRAS, HRAS, KRAS, and RET mutations were 259 (54%), 62 (13%), 13 (3%), 16 (3%), and 12 (2%), respectively. The BRAF V600E mutation (n = 257) was the predominant BRAF mutation. TERT promoter mutations, which are associated with tumor aggressiveness, were detected in 308 patients (64%).
CONCLUSIONS: PTC was the most common histologic type of TC for which genetic profiling was performed in Japan, followed by ATC. Since the most common targetable mutation is the BRAF mutation, practical application of BRAF-targeted therapy can be an important treatment option for Japanese patients with TC.

Penile cancer (PC) is a rare male malignant tumor, with early lymph node metastasis and poor prognosis. Human papillomavirus (HPV) plays a key role in the carcinogenesis of PC. This review aims to summarize the association between HPV infection and PC in terms of virus-host genome integration patterns (the disrupted regions in the HPV and PC genome), genetic alterations, and epigenetic regulation (methylation and microRNA modification) occurring in HPV and PC DNA, as well as tumor immune microenvironment reprogramming. In addition, the potential of HPV vaccination strategies for PC prevention and treatment is discussed. Understanding of the HPV-related multidimensional mechanisms and the application of HPV vaccines will promote rational and novel management of PC.

Being among the top 10 causes of adult deaths, tuberculosis (TB) disease is considered a major global public health concern to address. The human tuberculosis pathogen, Mycobacterium tuberculosis (Mtb), is an extremely competent and well-versed pathogen that promotes pathogenesis by evading the host immune systems through numerous tactics. Investigations revealed that Mtb could evade the host defense mechanisms by reconfiguring the host gene transcription and causing epigenetic changes. Although results indicate the link between epigenetics and disease manifestation in other bacterial infections, little is known regarding the kinetics of the epigenetic alterations in mycobacterial infection. This literature review discusses the studies in Mtb-induced epigenetic alterations inside the host and its contribution in the host immune evasion strategies. It also discusses how the Mtb-induced alterations could be used as \'epibiomarkers\' to diagnose TB. Additionally, this review also discusses therapeutic interventions to be enhanced through remodification by \'epidrugs\'.

UNASSIGNED: We evaluated he effects of molecular guided-targeted therapy for intractable cancer. Also, the epidemiology of druggable gene alterations in Chinese population was investigated.
UNASSIGNED: The Long March Pathway (ClinicalTrials.gov identifier: NCT03239015) is a non-randomized, open-label, phase II trial consisting of several basket studies examining the molecular profiles of intractable cancers in the Chinese population. The trial aimed to 1) evaluate the efficacy of targeted therapy for intractable cancer and 2) identify the molecular epidemiology of the tier II gene alterations among Chinese pan-cancer patients.
UNASSIGNED: In the first stage, molecular profiles of 520 intractable pan-cancer patients were identified, and 115 patients were identified to have tier II gene alterations. Then, 27 of these 115 patients received targeted therapy based on molecular profiles. The overall response rate (ORR) was 29.6% (8/27), and the disease control rate (DCR) was 44.4% (12/27). The median duration of response (DOR) was 4.80 months (95% CI, 3.33-27.2), and median progression-free survival (PFS) was 4.67 months (95% CI, 2.33-9.50). In the second stage, molecular epidemiology of 17,841 Chinese pan-cancer patients demonstrated that the frequency of tier II gene alterations across cancer types is 17.7%. Bladder cancer had the most tier-II alterations (26.1%), followed by breast cancer (22.4%), and non-small cell lung cancer (NSCLC; 20.2%).
UNASSIGNED: The Long March Pathway trial demonstrated a significant clinical benefit for intractable cancer from molecular-guided targeted therapy in the Chinese population. The frequency of tier II gene alterations across cancer types supports the feasibility of molecular-guided targeted therapy under basket trials.

UNASSIGNED: This study sought to explore the biological significance of genetic variation in RAS wild-type metastatic colorectal cancer (mCRC) in the real world, the difference in the efficacy of cetuximab in the treatment of mCRC with different genetic variants and identify clinical features and new predictors of efficacy.
UNASSIGNED: A retrospective analysis of the data of 60 patients with stage IV mCRC who received cetuximab at The First and Second Affiliated Hospital of Soochow University from 2016 to 2020 was conducted. The patients were divided into the following 3 groups according to the genetic test results: (I) group A (the all-RAS wild-type group); (II) group B (the all-RAS wild-type group with the tumor suppressor gene mutation); and (III) group C (the all-RAS wild-type group with the oncogenic driver gene mutation). A subgroup analysis was conducted to examine left CRC and local intervention, and the progression-free survival (PFS) and overall survival (OS) of the patients were observed.
UNASSIGNED: The all-RAS wild-type mCRC patients were divided into group A (n=10), group B (including the TP53, APC, PTEN, BRCA2, and SMAD4 variants) (n=42), and group C (including the ERBB2, BRAF, PIK3CA, and RET variants) (n=8). The median PFS of groups A, B, and C were 15.0, 12.0, and 3.0 months, respectively (P=0.007). Fitting sex as a stratified variable to the Cox survival analysis model showed that only the PFS of groups B and C differed significantly (P=0.011). In the left-sided mCRC patients, the median PFS of groups A, B, C were 3.0, 13.0, and 3.0 months, respectively (P=0.009). Among the patients in group B, the median PFS of the metastatic local intervention subgroup was 14.0 months, and the non-local intervention subgroup was 12.0 months (P=0.55). Only the type of combined gene mutation was an independent factor affecting PFS.
UNASSIGNED: The PFS and OS of mCRC patients with all-RAS wild-type and no combined mutations treated with cetuximab were not better than those of patients with combined mutations. Compared to mCRC patients with all-RAS wild-type and oncogenic driver gene mutations, cetuximab significantly prolonged the PFS of all-RAS wild-type patients with the tumor suppressor gene mutations.

Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma characterized by an unbalanced translocation, resulting in ASPSCR1-TFE3 fusion that transcriptionally upregulates MET expression. The European Organization for Research and Treatment of Cancer (EORTC) 90101 \"CREATE\" phase II trial evaluated the MET inhibitor crizotinib in ASPS patients, achieving only limited antitumor activity. We performed a comprehensive molecular analysis of ASPS tissue samples collected in this trial to identify potential biomarkers correlating with treatment outcome. A tissue microarray containing 47 ASPS cases was used for the characterization of the tumor microenvironment using multiplex immunofluorescence. DNA isolated from 34 available tumor samples was analyzed to detect recurrent gene copy number alterations (CNAs) and mutations by low-coverage whole-genome sequencing and whole-exome sequencing. Pathway enrichment analysis was used to identify diseased-associated pathways in ASPS sarcomagenesis. Kaplan-Meier estimates, Cox regression, and the Fisher\'s exact test were used to correlate histopathological and molecular findings with clinical data related to crizotinib treatment, aiming to identify potential factors associated with patient outcome. Tumor microenvironment characterization showed the presence of PD-L1 and CTLA-4 in 10 and 2 tumors, respectively, and the absence of PD-1 in all specimens. Apart from CD68, other immunological markers were rarely expressed, suggesting a low level of tumor-infiltrating lymphocytes in ASPS. By CNA analysis, we detected a number of broad and focal alterations. The most common alteration was the loss of chromosomal region 1p36.32 in 44% of cases. The loss of chromosomal regions 1p36.32, 1p33, 1p22.2, and 8p was associated with shorter progression-free survival. Using whole-exome sequencing, 13 cancer-associated genes were found to be mutated in at least three cases. Pathway enrichment analysis identified genetic alterations in NOTCH signaling, chromatin organization, and SUMOylation pathways. NOTCH4 intracellular domain dysregulation was associated with poor outcome, while inactivation of the beta-catenin/TCF complex correlated with improved outcome in patients receiving crizotinib. ASPS is characterized by molecular heterogeneity. We identify genetic aberrations potentially predictive of treatment outcome during crizotinib therapy and provide additional insights into the biology of ASPS, paving the way to improve treatment approaches for this extremely rare malignancy.

The central nervous system is the main target of MeHg toxicity and glial cells are the first line of defense; however, their true role remains unclear. This study aimed to identify the global map of human glial-like (U87) cells transcriptome after exposure to a non-toxic and non-lethal MeHg concentration and to investigate the related molecular changes. U87 cells were exposed upon 0.1, 0.5, and 1 µM MeHg for 4 and 24 h. Although no changes were observed in the percentage of viable cells, the metabolic viability was significantly decreased after exposure to 1 µM MeHg for 24 h; thus, the non-toxic concentration of 0.1 µM MeHg was chosen to perform microarray analysis. Significant changes in U87 cells transcriptome were observed only after 24 h. The expression of 392 genes was down regulated while 431 genes were up-regulated. Gene ontology showed alterations in biological processes (75%), cellular components (21%), and molecular functions (4%). The main pathways showed by KEGG and Reactome were cell cycle regulation and Rho GTPase signaling. The complex mechanism of U87 cells response against MeHg exposure indicates that even a low and non-toxic concentration is able to alter the gene expression profile.

BACKGROUND: Surgery is the standard treatment for patients with stage I non-small cell lung cancer (NSCLC). However, postoperative recurrence leads to a poor prognosis of patients. Currently, there is no effective prognostic biomarker and perioperative treatment for patients with stage I NSCLC.
METHODS: One hundred thirty stage I NSCLC patients who had surgical resection were enrolled, including 69 patients who had recurrence within three years and 61 patients who had no recurrence (follow up more than five years). Whole exome sequencing was performed to evaluate gene mutation, copy number variation, and tumor mutation burden (TMB). Immunohistochemistry was carried out to assess the expression of PD-L1 and the level of CD3+ and CD8+ tumor-infiltrating lymphocytes (TILs). Tumor mutation score (TMS) was constructed with the recurrence-associated genes identified by Lasso regression. Immunoscore (IS) was built based on the location and density of CD3+ and CD8+ TILs. Logistic regression was performed to build a prediction model. Seventy percent of patients were included in the training cohort and 30% patients in the testing cohort. P<0.05 was considered to be statistically significant.
RESULTS: Univariate analysis showed that lung adenocarcinoma (LUAD), MUC4 mutation, and high TMB were related to early recurrence (P=0.008, 0.0008, and <0.0001, respectively). CD3+ and CD8+ TILs within tumor center and invasive margin significantly negatively correlated with recurrence. EGFR mutation and PD-L1 expression had no association with recurrence. Early recurrence group had significantly higher TMS and lower IS (P<0.0001 and P=0.0003, respectively). Multivariate analysis showed that high TMS and low IS were independent predictors for early recurrence (P<0.0001 and P=0.001, respectively). Integrating TMS and IS, we built a recurrence-model with great discrimination and calibration in the training cohort (AUC =0.935; HL test, P=0.2885) and testing cohort (AUC =0.932; HL test, P=0.5515).
CONCLUSIONS: High TMS and low IS were both poor prognostic factors for recurrence in stage I NSCLC. The integrated recurrence-model helps identify patients with high recurrence risk, which provides evidence for future research about perioperative treatment.

Glandular cancers have a significant share of the total cancer patients all over the world. In the case of adrenocortical carcinomas (ACCs), although the benign form is more frequent and common, the malignant form provides a very less percentage of patients with five or more than five years of survival rate. There are gene alterations that are involved as a crucial factor behind the occurrence of ACCs. Out of these, the most prominent genetic alterations (PRKAR-1A, CTNNB1, ZNRF3, TP53, CCNE1 and TERF2 genes) are linked with a glycolytic enzyme pyruvate kinase M2 (PKM2), which converts phosphoenolpyruvate (PEP) to pyruvate in the glycolytic pathway. The involvementof PKM2 renders a cumulative effect through different pathways that may result in the onset of ACCs. Thus, this review aims to establish a link between ACCs, alterations of specific genes and PKM2.