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Differentially Methylated CpG Sites (2173 Sites) in 24 Nasopharyngeal Carcinoma (NPC) Tissues and 24 Non-cancer Nasopharyngitis Biopsy Tissues (NCNBT)

Kaplan-Meier curves estimation of disease-free survival (DFS) and overall survival (OS) for patients with high or low methylation levels stratified by tumor stage or the receipt of concurrent chemotherapy.

Supplementary Table S1: Clinicopathological Characteristics of 24 NPC and 24 NCNBT Supplementary Table S2: Clinical Characteristics of Nasopharyngeal Carcinoma Patients According to Gene Methylation Panel in Training, Validation, and Independent Cohorts. Supplementary Table S3: Primer Sequences of 28 Genes and GAPDH Supplementary Table S4: Primer Used for Pyrosequencing Methylation Analysis of Candidate Genes Supplementary Table S6: Data Analysis with PubMeth and NCBI PubMed Supplementary Table S7: Correlation Analysis between Methylation of Six Genes in the Training Cohort

Representative Pyrograms of Methylation Analysis by Bisulfite Pyrosequencing.

Supplementary Table S1. Clinical characteristics of 534 NPC patients. Supplementary Table S2. Sequences used for shRNA construction and siRNAs. Supplementary Table S3. Primers used for real-time PCR. Supplementary Table S4. Association of SPINK6 expression with clinicopathological characteristics of NPC patients.

Supplementary Materials and Methods

Purpose: Metastatic colorectal cancer patients with low epidermal growth factor receptor (EGFR) gene copy number are unlikely to respond to anti-EGFR monoclonal antibody (mAb) treatment. The objective of this study was to investigate EGFR fluorescence in situ hybridization (FISH) patterns of chromosome 7 disomy with efficacy of cetuximab therapy in metastatic colorectal cancer patients.Experimental Design: We detected the EGFR FISH patterns and KRAS status in 74 tumors from cetuximab-treated metastatic colorectal cancer patients and analyzed with response rate (RR) and progression-free survival (PFS).Results: One of the 16 (6.25%) patients with chromosome 7 homogeneous disomy (defined as FISH negative) had objective response to cetuximab. A total of 53(76.8%) patients with chromosome 7 pattern of variable ratios of disomy versus polysomy (defined as FISH positive) had a significantly higher RR (37.7% versus 6.25%; P = 0.01), a trend towards longer PFS (4.5 versus 2.9 months; P = 0.07). Among 54 KRAS wild-type patients, EGFR FISH-positive patients had significantly higher RR (51.3% versus 9%; P = 0.01) and longer PFS (5.0 versus 2.3 months; P = 0.02) than EGFR FISH-negative patients. However, among 20 KRAS mutant-type patients, there was no difference in RR (0% versus 0%) and PFS (2.5 versus 3.8 months; P = 0.51) between EGFR FISH-positive and -negative patients.Conclusion: Our results show firstly that patients with EGFR FISH pattern of chromosome 7 disomy have a very low chance to benefit from cetuximab-based therapy. EGFR FISH pattern of chromosome 7 disomy may be as a negative predicative factor for cetuximab response in KRAS wild-type metastatic colorectal cancer patients. Clin Cancer Res; 17(2); 382–90. ©2011 AACR.

Supplementary Tables 1-4. Supplementary Table 1. Odds ratios (ORs) and 95% confidence intervals (CIs) of nasopharyngeal carcinoma (NPC) associated with oral health among ever smokers in southern China (2010-2014). Supplementary Table 2. Stratified odds ratios (ORs) and 95% confidence intervals (CIs) of nasopharyngeal carcinoma (NPC) associated with number of teeth lost after age 20 years.* Supplementary Table 3. Stratified odds ratios (ORs) and 95% confidence intervals (CIs)of nasopharyngeal carcinoma (NPC) associated with frequency of tooth brushing.* Supplementary Table 4. Odds ratios (ORs) and 95% confidence intervals (CIs) of nasopharyngeal carcinoma (NPC) associated with oral health in southern China - restricted to cases interviewed within 30 days of diagnosis (2010-2014).

Supplementary Fig. S1. Expression of SPINK6 in condition medium of NPC cells. Supplementary Fig. S2. Cellular growth of NPC cells. Supplementary Fig. S3. Wound-healing ability of NPC cells upon SPINK6 knockdown. Supplementary Fig. S4. Migration and invasion of NPC cells upon silencing of KLKs. Supplementary Fig. S5. Promoted motility of NPC cells by recombinant SPINK6. Supplementary Fig. S6. Interaction between SPINK6 and EGFR. Supplementary Fig. S7. Phosphorylation of EGFR and downstream signaling molecules in NPC cells. Supplementary Fig. S8. Wound-healing ability of NPC cells. Supplementary Fig. S9. The expression of E-cadherin and vimentin in NPC cells. Supplementary Fig. S10. The expression of EGF, EGFR and KLKs in NPC and NP tissues.

Nasopharyngeal carcinoma has the highest rate of metastasis among head and neck cancers, and distant metastasis is the major reason for treatment failure. The underlying molecular mechanisms of nasopharyngeal carcinoma metastasis are not fully understood. Here, we report the identification of serine protease inhibitor Kazal-type 6 (SPINK6) as a functional regulator of nasopharyngeal carcinoma metastasis via EGFR signaling. SPINK6 mRNA was upregulated in tumor and highly metastatic nasopharyngeal carcinoma cells. Immunohistochemical staining of 534 nasopharyngeal carcinomas revealed elevated SPINK6 expression as an independent unfavorable prognostic factor for overall, disease-free, and distant metastasis–free survival. Ectopic SPINK6 expression promoted in vitro migration and invasion as well as in vivo lymph node metastasis and liver metastasis of nasopharyngeal carcinoma cells, whereas silencing SPINK6 exhibited opposing effects. SPINK6 enhanced epithelial–mesenchymal transition by activating EGFR and the downstream AKT pathway. Inhibition of EGFR with a neutralizing antibody or erlotinib reversed SPINK6-induced nasopharyngeal carcinoma cell migration and invasion. Erlotinib also inhibited SPINK6-induced metastasis in vivo. Notably, SPINK6 bound to the EGFR extracellular domain independent of serine protease–inhibitory activity. Overall, our results identified a novel EGFR-activating mechanism in which SPINK6 has a critical role in promoting nasopharyngeal carcinoma metastasis, with possible implications as a prognostic indicator in nasopharyngeal carcinoma patients. Cancer Res; 77(2); 579–89. ©2016 AACR.

Background: The association between oral health and risk of nasopharyngeal carcinoma (NPC) is largely unknown. Further understanding could shed light on potential pathogenic mechanisms and preventive measures.Methods: We conducted a population-based case–control study in southern China between 2010 and 2014. We enrolled 2,528 incident NPC cases, aged 20–74 years, and 2,596 controls, randomly selected from the total population registers, with frequency matching to the 5-year age and sex distribution of the cases by geographic region. We interviewed subjects using a structured questionnaire inquiring about oral health indicators and potential confounding factors. We used unconditional logistic regression to estimate multivariate-adjusted ORs with 95% confidence intervals (CI).Results: A higher number of filled teeth was associated with an elevated risk of NPC. Individuals with 1 to 3 and more than 3 teeth filled versus none had adjusted ORs of 1.25 (95% CI, 1.06–1.49) and 1.55 (95% CI, 1.13–2.12), respectively (Ptrend = 0.002). Conversely, the adjusted OR for those who brushed teeth twice or more per day versus once or less per day was 0.62 (95% CI, 0.55–0.70). We detected a borderline significant positive association with earlier age at first adult tooth loss.Conclusion: Our study suggested a positive association between some indicators of poor oral health and risk of NPC. Further studies are needed to confirm whether the findings are causal and, if so, to further explain the underlying mechanisms.Impact: Improvement of oral hygiene might contribute to reducing NPC risk. Cancer Epidemiol Biomarkers Prev; 25(8); 1201–7. ©2016 AACR.

Supplementary Table S1.

Supplementary Tables 1-3 from Serglycin Is a Theranostic Target in Nasopharyngeal Carcinoma that Promotes Metastasis

Supplementary Figures 1-2 from Serglycin Is a Theranostic Target in Nasopharyngeal Carcinoma that Promotes Metastasis

Nasopharyngeal carcinoma (NPC) is known for its high-metastatic potential. Here we report the identification of the proteoglycan serglycin as a functionally significant regulator of metastasis in this setting. Comparative genomic expression profiling of NPC cell line clones with high- and low-metastatic potential revealed the serglycin gene (SRGN) as one of the most upregulated genes in highly metastatic cells. RNAi-mediated inhibition of serglycin expression blocked serglycin secretion and the invasive motility of highly metastatic cells, reducing metastatic capacity in vivo. Conversely, serglycin overexpression in poorly metastatic cells increased their motile behavior and metastatic capacity in vivo. Growth rate was not influenced by serglycin in either highly or poorly metastatic cells. Secreted but not bacterial recombinant serglycin promoted motile behavior, suggesting a critical role for glycosylation in serglycin activity. Serglycin inhibition was associated with reduced expression of vimentin but not other epithelial–mesenchymal transition proteins. In clinical specimens, serglycin expression was elevated significantly in liver metastases from NPC relative to primary NPC tumors. We evaluated the prognostic value of serglycin by immunohistochemical staining of tissue microarrays from 263 NPC patients followed by multivariate analyses. High serglycin expression in primary NPC was found to be an unfavorable independent indicator of distant metastasis-free and disease-free survival. Our findings establish that glycosylated serglycin regulates NPC metastasis via autocrine and paracrine routes, and that it serves as an independent prognostic indicator of metastasis-free survival and disease-free survival in NPC patients. Cancer Res; 71(8); 3162–72. ©2011 AACR.

Supplementary Materials and Methods from Serglycin Is a Theranostic Target in Nasopharyngeal Carcinoma that Promotes Metastasis

Supplementary Figures 1-5 from miR-125b Is Methylated and Functions as a Tumor Suppressor by Regulating the ETS1 Proto-oncogene in Human Invasive Breast Cancer

Background This study aimed to explore the prognostic value of tumor mutational burden (TMB) combined with smoking status in advanced non‐small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitor therapy (anti PD‐1/PD‐L1 therapy) combined with chemotherapy or anti‐angiogenesis therapy. Methods We conducted a retrospective analysis of NSCLC patients who underwent next‐generation sequencing test (either 295‐gene panel NGS or 1021‐gene panel NGS) from September 2017 to November 2020. The relationship between TMB and smoking status was investigated. Kaplan–Meier survival analysis was used to compare progression‐free survival (PFS) of the NSCLC patients who received combination immunotherapy grouped by TMB value and smoking status. Results We enrolled 323 cases and 388 cases of NSCLC patients in the 295‐gene panel cohort and 1021‐gene panel cohort, respectively. Positive correlation between TMB and smoking status was found in lung adenocarcinoma, but not in lung squamous cell carcinoma. Participants with both high TMB and smoking status who received immune checkpoint therapy combined with chemotherapy or anti‐angiogenesis therapy had longer PFS than other participants (p, The tumor mutational burden (TMB) value correlated with smoking status in lung adenocarcinoma patients, but not in lung squamous cell carcinoma patients in both NGS panels. The TMB value combined with smoking status might be used as a potential prognostic indicator for advanced non‐small cell lung cancer patients receiving immune checkpoint inhibitor combination therapy.

Background Inherited susceptibility accounts for nearly one‐third of colorectal cancer (CRC) predispositions and has an 80%‐100% lifetime risk of this disease. However, there are few data about germline mutations of hereditary CRC‐related genes in Chinese patients with CRC. This study aimed to assess the prevalence of gene mutations related to cancer susceptibility among Chinese patients with CRC, differences between Chinese and Western patients, and the phenotype‐genotype correlation. Methods We retrospectively collected tumor samples from 526 patients with CRC under 70 years old who underwent hereditary CRC genetic testing. A series of bioinformatic analyses, as well as statistical comparisons, were performed. Results We found that 77 patients (14.6%) harbored functional variants of the 12 genes. The mutation frequencies of the top 5 mutated genes were 6.5% for MutL homolog 1 (MLH1), 5.1% for MutS homolog 2 (MSH2), 1.0% for MSH6, 0.8% for PMS1 homolog 2 (PMS2), and 0.8% for APC regulator of the WNT signaling pathway (APC). Our data showed much higher rates of mutations of MSH6 and PMS2 genes among all mismatch repair (MMR) genes as compared with those in Western populations. Mutations in MLH1, MSH2, and MSH6 were found to be mutually exclusive. Patients with MLH1 or MSH2 mutations had higher frequencies of personal history of cancer (MLH1: 20.6% vs. 8.7%; MSH2: 25.9% vs. 8.6%) and family history of cancer than those without these mutations (MLH1: 73.5% vs. 48.4%; MSH2: 70.4% vs. 48.9%), and the lesions were more prone to occur on the right side of the colon than on the left side (MLH1: 73.5% vs. 29.3%; MSH2: 56.0% vs. 31.0%). The proportion of stage I/II disease was higher in patients with MLH1 mutations than in those without MLH1 mutations (70.6% vs. 50.7%), and the rate of polyps was higher in patients with APC mutations than in those with wild‐type APC (75.0% vs. 17.4%). Conclusion These results provide a full‐scale landscape of hereditary susceptibility over 12 related genes in CRC patients and suggest that a comprehensive multi‐gene panel testing for hereditary CRC predisposition could be a helpful analysis in clinical practice.

Zinc finger protein 154 (ZNF154) is hypermethylated at the promoter in many epithelial-derived solid tumors. However, its methylation status and function in esophageal squamous carcinoma (ESCC) are poorly understood. We found that the ZNF154 promoter is hypermethylated in ESCC and portends poor prognosis. In addition, ZNF154 functions as a tumor suppressor gene (TSG) in ESCC, and is downregulated by promoter hypermethylation. We established a targeted demethylation strategy based on CRISPR/dCas9 technology and found that the hypermethylation of ZNF154 promoter repressed ZNF154 induction, which in turn promoted the proliferation and migration of ESCC cells in vitro and in vivo. Finally, high-throughput CUT&Tag analysis, GEPIA software and qPCR were used to revealed the role of ZNF154 as a transcription factor to upregulate the expression of ESCC-associated tumor suppressor genes. Taken together, hypermethylation of the ZNF154 promoter plays an important role in the development of ESCC, and epigenetic editing is a promising tool for inhibiting ESCC cells with aberrant DNA methylation.

Background There is no satisfactory indicator for monitoring recurrence after resection of hepatocellular carcinoma (HCC). This retrospective study aimed to design and validate an HCC monitor recurrence (HMR) model for patients without metastasis after hepatectomy. Methods A training cohort was recruited from 1179 patients with HCC without metastasis after hepatectomy between February 2012 and December 2015. An HMR model was developed using an AdaBoost classifier algorithm. The factors included patient age, TNM staging, tumor size, and pre/postoperative dynamic variations of alpha-fetoprotein (AFP). The diagnostic efficacy of the model was evaluated based on the area under the receiver operating characteristic curves (AUCs). The model was validated using a cohort of 695 patients. Results In preoperative patients with positive or negative AFP, the AUC of the validation cohort in the HMR model was .8877, which indicated better diagnostic efficacy than that of serum AFP (AUC, .7348). The HMR model predicted recurrence earlier than computed tomography/magnetic resonance imaging did by 191.58 ± 165 days. In addition, the HMR model can predict the prognosis of patients with HCC after resection. Conclusions The HMR model established in this study is more accurate than serum AFP for monitoring recurrence after hepatectomy for HCC and can be used for real-time monitoring of the postoperative status in patients with HCC without metastasis.

Background: Differences between the features of primary cancer and matched metastatic cancer have recently drawn attention in research. This study investigated the concordance in microsatellite instability (MSI) and mismatch repair (MMR) status between primary and corresponding metastatic colorectal cancer (CRC). Methods: Consecutive patients with metastatic CRC who had both primary and metastatic tumors diagnosed at our institution in January 2008 through December 2016 were identified. Immunohistochemistry was used to test the MMR status of both primary and matched metastatic tumors, and PCR analysis was performed to test MSI in patients with deficient MMR (dMMR) status. Results: A total of 369 patients were included. Of the 46 patients with MSI-high primary tumors, 37 (80.4%) also had MSI-high metastatic tumors, whereas 9 (19.6%) had microsatellite stable (MSS) metastatic tumors. A high concordance was found in patients with liver, lung, or distant lymph node metastases. Interestingly, the discrepancy was more likely to be limited to peritoneal (5/20) or ovarian (4/4) metastasis (chi-square test, PP=.008). However, the change did not influence survival; the median overall survival of MSI-high and MSS metastatic tumors was 21.3 and 21.6 months, respectively (P=.774). The discrepancy rate was 1.6% for patients with proficient MMR primary tumors. Conclusions: For patients with dMMR primary tumors, the concordance of MSI and MMR status in primary CRC and corresponding metastatic cancer is potentially organ-specific. High concordance is found in liver, lung, and distant lymph node metastases, whereas discrepancy is more likely to occur in peritoneal or ovarian metastasis. Rebiopsy to evaluate MSI-high/dMMR status might be needed during the course of anti–PD-1 therapy in cases of peritoneal or ovarian metastasis.

Objectives: Anaplastic lymphoma kinase (ALK) is one of the leading therapeutic targets in patients with non-small cell lung cancer (NSCLC). However, the clinical importance that the percentage of A...

Background: The goal of this study was to explore the value of adding neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy (ACT) to concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma (NPC) with different risks of treatment failure. Patients and Methods: A total of 2,263 eligible patients with stage III–IVb NPC treated with CCRT ± NACT or ACT were included in this retrospective study. Distant metastasis–free survival (DMFS), overall survival, and progression-free survival were calculated using the Kaplan-Meier method and differences were compared using the log-rank test. Results: Patients in the low-risk group (stage N0–1 disease and Epstein-Barr virus [EBV] DNA P= .008). Multivariate analyses also demonstrated that additional NACT was the only independent prognostic factor for DMFS (hazard ratio, 0.42; 95% CI, 0.22–0.80; P=.009). In both the intermediate-risk group (stage N0–1 disease and EBV DNA ≥4,000 copies/mL and stage N2–3 disease and EBV DNA Conclusions: The addition of NACT to CCRT could reduce distant failure in patients with low risk of treatment failure.

Background: Genetic factors play an important role in colorectal cancer (CRC) risk, yet the prevalence and spectrum of germline cancer susceptibility gene mutations among unselected Chinese CRC patients is largely undetermined. Methods: We performed next-generation sequencing with a 73-genes panel and analyzed the prevalence and spectrum of germline mutations in 618 unselected Chinese CRC patients. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations. Clinical characteristics were assessed by age and mutation status. Protein expressions and interactions of MLH1 missense variants were evaluated by western blot and co- immunoprecipitation. Results: Overall, 112 (18.1%) of 618 unselected Chinese CRC patients were found to carry at least one pathogenic or likely pathogenic variant (totaling 97 variants), including 70 (11.3%) Lynch syndrome (LS) mutation carriers and 42 (6.8%) non-LS mutation carriers. LS mutation carriers were significantly younger at CRC diagnosis and were more likely to have right-sided, poorly differentiated, early stage, high-frequency microsatellite instability (MSI-H) or dMMR CRC and a family history of cancer compared with noncarriers. Non-LS mutation carriers were more likely to be proficient mismatch repair (pMMR) than noncarriers (p=0.039). We found four clinical variables (gender, tumor histological stage, cancer stage and mutation status) that showed significant differences between patients younger and older than 50 years old. Higher mutation rates were found in patients under 50 years old (p=0.017). Thirty-three novel variants were discovered and evaluated as pathogenic mutations by our study. Conclusion: Given the high frequency and wide spectrum of mutations, genetic testing with a multigene panel should be considered for all Chinese CRC patients under 50 years old and is also needed to determine whether a gene is associated with CRC susceptibility and to promote clinical translation.

The aim of this study was to use whole‐exome sequencing to derive a molecular classifier for nasopharyngeal carcinoma (NPC) and evaluate its clinical performance. We performed whole‐exome sequencing on 82 primary NPC tumors from Sun Yat‐sen University Cancer Center (Guangzhou cohort) to obtain somatic single‐nucleotide variants, indels, and copy number variants. A novel molecular classifier was then developed and validated in another NPC cohort (Hong Kong cohort, n = 99). Survival analysis was estimated by the Kaplan‐Meier method and compared using the log‐rank test. Cox proportional hazards model was adopted for univariate and multivariate analyses. We identified three prominent NPC genetic subtypes: RAS/PI3K/AKT (based on RAS, AKT1, and PIK3CA mutations), cell‐cycle (based on CDKN2A/CDKN2B deletions, and CDKN1B and CCND1 amplifications), and unclassified (based on dominant mutations in epigenetic regulators, such as KMT2C/2D, or the Notch signaling pathway, such as NOTCH1/2). These subtypes differed in survival analysis, with good, intermediate, and poor progression‐free survival in the unclassified, cell‐cycle, and RAS/PI3K/AKT subgroups, respectively, among the Guangzhou, Hong Kong, and combined cohorts (n = 82, P = 0.0342; n = 99, P = 0.0372; and n = 181, P = 0.0023; log‐rank test). We have uncovered genetic subtypes of NPC with distinct mutations and/or copy number changes, reflecting discrete paths of NPC tumorigenesis and providing a roadmap for developing new prognostic biomarkers and targeted therapies.

Next-generation sequencing (NGS) technology is capable of sequencing millions or billions of DNA molecules simultaneously. Therefore, it represents a promising tool for the analysis of molecular targets for the initial diagnosis of disease, monitoring of disease progression, and identifying the mechanism of drug resistance. On behalf of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology (CSCO) and the China Actionable Genome Consortium (CAGC), the present expert group hereby proposes advisory guidelines on clinical applications of NGS technology for the analysis of cancer driver genes for precision cancer therapy. This group comprises an assembly of laboratory cancer geneticists, clinical oncologists, bioinformaticians, pathologists, and other professionals. After multiple rounds of discussions and revisions, the expert group has reached a preliminary consensus on the need of NGS in clinical diagnosis, its regulation, and compliance standards in clinical sample collection. Moreover, it has prepared NGS criteria, the sequencing standard operation procedure (SOP), data analysis, report, and NGS platform certification and validation.

Background. At present, the diagnostic accuracy of alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) surveillance is insufficient. It remains controversial whether prothrombin induced by vitamin K absence II (PIVKA-II) has a better diagnostic value than AFP for HCC patients. Objective. To investigate the diagnostic role of PIVKA-II alone or in combination with AFP in Chinese HCC patients. Methods. Serum AFP and PIVKA-II levels were detected and analyzed in 308 HCC afflicted patients and 120 unafflicted controls. The receiver operator curve (ROC) and area under the curve (AUC) were conducted to evaluate the clinical value of AFP and PIVKA-II for diagnosing HCC and early HCC. Results. In the whole HCC cohort, the diagnostic values of PIVKA-II were better than that of AFP. The AUC of PIVKA-II and AFP was 0.90 (95% CI 0.87-0.94) and 0.79 (95% CI 0.74-0.84), respectively. “AFP + PIVKA-II” yielded a high sensitivity of 95.1% and a specificity of 83.3%, with the AUC 0.89 (95% CI 0.85-0.93). In the early stage HCC group, the diagnostic accuracy of PIVKA-II was also better than that of AFP. The AUC of PIVKA-II and AFP was 0.83 (95% CI 0.77-0.89) and 0.75 (95% CI 0.68-0.81), respectively. “AFP + PIVKA-II” achieved the sensitivity of 83.3% and specificity of 89.1%, with an AUC of 0.86 (95% CI 0.81-0.91). Moreover, for AFP-negative HCC patients, serum PIVKA-II showed good diagnostic performance, with an AUC of 0.804 (95% CI 0.720-0.887). Besides, elevated PIVKA-II level was a strong independent risk factor for HCC patients with portal vein tumor thrombus (PVTT) ( OR = 4.890 , P = 0.020 ). Conclusion. PIVKA-II is superior to AFP in HCC screening, and AFP in combination with PIVKA-II significantly improves the diagnostic value for Chinese HCC patients. PIVKA-II could effectively indicate HCC accompanied by PVTT and help to optimize the therapeutic strategy.

Key Points Question Could a prognostic nomogram that integrates the TNM staging system with other critical variables accurately predict overall survival and guide treatment in patients with nonmetastatic nasopharyngeal carcinoma? Findings In this cohort study of 8093 patients with nasopharyngeal carcinoma, a nomogram was developed and validated to reliably estimate overall survival, which provided significantly better discrimination than the TNM staging system. This nomogram identified 4 risk groups with differential OS rates; these 4 risk groups were associated with the efficacy of different treatment regimens. Meaning These finding suggest that this nomogram could enable individualized prognostication of overall survival and guide risk-adapted treatment for patients with nonmetastatic nasopharyngeal carcinoma., This cohort study evaluates a comprehensive nomogram to estimate individualized overall survival among patients with nometastatic nasopharyngeal carcinoma and explores stratified treatment regimens for risk subgroups., Importance Because of tumor heterogeneity, overall survival (OS) differs significantly among individuals with nasopharyngeal carcinoma (NPC), even among those with the same clinical stage. Relying solely on TNM staging to guide treatment remains imperfect. Objectives To establish a comprehensive nomogram to estimate individualized OS and to explore stratified treatment regimens for risk subgroups in nonmetastatic NPC. Design, Setting, and Participants This cohort study included 8093 patients diagnosed with NPC at a single center in China from April 2009 to December 2015. The sample was split into a training cohort (5398 participants [66.7%]) and validation cohort (2695 [33.3%]). Data were analyzed in May 2020. Exposures Age, T stage, N stage, Epstein-Barr virus (EBV) DNA level, serum lactate dehydrogenase (LDH) levels, and albumin (ALB) levels. Main Outcomes and Measures The primary end point was OS. The nomogram for estimating OS was generated based on multivariate Cox proportional hazards regression. The performance of the nomogram was quantified using Harrell concordance index (C index), the area under the curve (AUC) of the receiver operating characteristic curve, and a calibration curve. OS rates were established using the Kaplan-Meier method, and intersubgroup differences were examined by the log-rank test. Results Among the 8093 participants, 5688 (70.3%) were men, and the median age at diagnosis was 45 years (range, 7-85 years). Six variables (age, T stage, N stage, EBV DNA levels, LDH levels, and ALB levels) were identified through multivariate Cox regression and incorporated into a nomogram to estimate OS. The resulting nomogram showed excellent discriminative ability and significantly outperformed the eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control TNM staging system for estimating OS (C index, 0.716 [95% CI, 0.698-0.734] vs 0.643 [95% CI, 0.624-0.661]; P

Background: Early failure of cancer treatment generally indicates a poor prognosis. Here, we aim to develop and validate a pre-treatment nomogram to predict early metachronous metastasis (EMM) in nasopharyngeal carcinoma (NPC). Methods: From 2009 to 2015, a total of 9461 patients with NPC (training cohort: n = 7096; validation cohort: n = 2365) were identified from an institutional big-data research platform. EMM was defined as time to metastasis within 2 years after treatment. Early metachronous distant metastasis-free survival (EM-DMFS) was the primary endpoint. A nomogram was established with the significant prognostic factors for EM-DMFS determined by multivariate Cox regression analyses in the training cohort. The Harrell Concordance Index (C-index), area under the receiver operator characteristic curve (AUC), and calibration curves were applied to evaluate this model. Results: EMM account for 73.5% of the total metachronous metastasis rate and is associated with poor long-term survival in NPC. The final nomogram, which included six clinical variables, achieved satisfactory discriminative performance and significantly outperformed the traditional tumor–node–metastasis (TNM) classification for predicting EM-DMFS: C-index: 0.721 versus 0.638, p Conclusion: Our established nomogram can reliably predict EMM in patients with NPC and might aid in formulating risk-adapted treatment decisions and personalized patient follow-up strategies.

International guidelines recommend BRCA testing for patients with breast and ovarian cancer. Little is known about the genetic testing practices of BRCA1/2 mutations in laboratories across China. This study was designed to assess the discrepancies in genetic testing procedures of BRCA1/2 mutations across China. An online survey was developed for depicting the BRCA1/2 testing landscape in China. Our results show that there were several variations among the laboratories in technologies adopted, large genomic rearrangement detection, probe design, quality control, variant of uncertain significance interpretation, and disposition of variants in public databases. The discrepancies observed in our study would affect the authenticity of results, thus necessitating the formulation of proper national and international guidelines for optimal BRCA1/2 testing clinical practice for efficient management and patient care of this population.

Presently, there is a lack of effective blood-based biomarkers facilitating the diagnosis of hepatocellular carcinoma (HCC). Thus, we aimed to investigate novel methylation markers for HCC diagnosis, and explore relationships between biomarker methylation and clinicopathology of HCC. The methylation status of the SCAN domain containing three (SCAND3) and myosin 1g (Myo1g) genes in HCC cell lines and tissues were detected by digital droplet PCR. The serum SCAND3 and Myo1g methylation levels were analyzed in HCC-afflicted patients and unafflicted controls. The results indicated SCAND3 and Myo1g methylation were abnormally high in the HCC cell lines and tissues. The values of serum SCAND3, Myo1g, and SCAND3 + Myo1g methylation with respect to facilitating the detection, and early detection of HCC were better than for alpha-fetoprotein (AFP) alone. Furthermore, when we combined SCAND3 + Myo1g with AFP, a high sensitivity and specificity resulted. Notably, in the AFP-negative HCC group, the methylation of SCAND3 and Myo1g also showed an excellent diagnostic performance. Besides this, a high serum SCAND3 methylation level was an independent risk factor for predicting portal vein tumor thrombus (PVTT) in HCC patients (OR = 4.746, p = 0.013). Finally, SCAND3 and Myo1g enhanced the HCC diagnostics as noninvasive serum methylation biomarkers, and the SCAND3 methylation status effectively indicated HCC accompanied by PVTT.

The efficacy of susceptible variants derived from genome-wide association studies (GWAs) optimizing discriminatory accuracy of colorectal cancer (CRC) in Chinese remains unclear. In the present validation study, we assessed 75 recently identified variants from GWAs. A risk predictive model combining 19 variants using the least absolute shrinkage and selection operator (LASSO) statistics offered certain clinical advantages. This model demonstrated an area under the receiver operating characteristic (AUC) of 0.61 during training analysis and yielded robust AUCs from 0.59 to 0.61 during validation analysis in three independent centers. The individuals carrying the highest quartile of risk score revealed over 2-fold risks of CRC (ranging from 2.12 to 2.90) compared with those who presented the lowest quartile of risk score. This genetic model offered the possibility of partitioning risk within the average risk population, which might serve as a first step toward developing individualized CRC prevention strategies in China.

Objective. To investigate methylation of the adenomatosis polyposis coli homologue (APC2) promoter and its correlation with prognostic implications in Chinese colorectal cancer (CRC). Methods. The mRNA expression of APC2 in colorectal tissues was evaluated using the database of The Cancer Genome Atlas (TCGA). Methylation analysis of APC2 in tumor (n=66) and corresponding adjacent formalin-fixed and paraffin-embedded (FFPE) tissues (n=44) was performed by Sequenom EpiTYPER® and verified by cloning-based bisulfite sequencing analysis. Demethylation and retrieval of APC2 expression in cell lines HT29, HCT116, and SW480 were treated with 5-aza-2′-deoxycytidine (5-AZC). Results. Analysis of TCGA showed that APC2 mRNA was significantly downregulated in primary tumors when compared to normal tissues (p<0.05). APC2 methylation was upregulated (43.93% vs 7.31%, p<0.05) in tumors compared to adjacent FFPE tissues. In vitro experiments demonstrated that 5-AZC downregulated the methylation of APC2 and retrieved its expression of mRNA and protein levels (p<0.05). Multivariate Cox regression indicated that APC2_CPG_14 was an independent risk factor for overall survival (HR = 6.38, 95% CI: 1.59–25.64, p<0.05). Conclusion. This study indicates that APC2 is hypermethylated and may be a tumorigenesis biomarker for Chinese CRC patients.