LINE-1 hypomethylation in gastric cancer, detected by bisulfite pyrosequencing, is associated with poor prognosis

BACKGROUND: Genome-wide DNA hypomethylation plays an important role in genomic instability and carcinogenesis. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level. In some types of human neoplasms, LINE-1 methylation level is attracting interest as a predictive marker for patient prognosis. However, the prognostic significance of LINE-1 hypomethylation in gastric cancer remains unclear. METHODS: Using 203 resected gastric cancer specimens, we quantified LINE-1 methylation using bisulfite-pyrosequencing technology. A Cox proportional hazards model was used to calculate the hazard ratio (HR), adjusted for the clinical and pathological variables. RESULTS: Gastric cancers showed significantly lower LINE-1 methylation levels compared to matched normal gastric mucosa (p < 0.0001; n = 74). Tumoral LINE-1 methylation range was 11.6–97.5 on a 0–100 scale (n = 203; mean 71.4, median 74.4, standard deviation 12.9). LINE-1 hypomethylation was significantly associated with shorter overall survival [log-rank p = 0.029; univariate HR 2.01, 95 % confidence interval (CI) 1.09–3.99, p = 0.023; stage-matched HR 1.88, 95 % CI 1.02–3.74, p = 0.041; multivariate HR 1.98, 95 % CI 1.04–4.04, p = 0.036]. No significant effect modification was observed by any of the covariates in survival analysis (all p interaction >0.25). CONCLUSIONS: LINE-1 hypomethylation in gastric cancer is associated with shorter survival, suggesting that it has potential for use as a prognostic biomarker

Successful esophageal bypass surgery in a patient with a large tracheoesophageal fistula following endotracheal stenting and chemoradiotherapy for advanced esophageal cancer: case report

A 63-year-old man with esophageal achalasia for more than 20 years complained of respiratory distress. He was admitted as an emergency to the referral hospital three months previously. Computed tomography revealed tracheobronchial stenosis due to advanced esophageal cancer with tracheal invasion. He underwent tracheobronchial stenting and chemoradiotherapy. A large tracheoesophageal fistula (TEF) developed after irradiation (18 Gy) and chemotherapy, and he was unable to eat. Thereafter, he was referred to our hospital, where we performed esophageal bypass surgery using a gastric conduit. A percutaneous cardiopulmonary support system was prepared due to the risk of airway obstruction during anesthesia. A small-diameter tracheal tube inserted into the stent achieved ordinary respiratory management. No anesthesia-related problems were encountered. Oral intake commenced on postoperative day 9. He was discharged on postoperative day 23 and was able to take in sustenance orally right up to the last moment of his life. Esophageal bypass under general anesthesia can be performed in patients with large TEF with sufficient preparation for anesthetic management

Epigenomic Diversity of Colorectal Cancer Indicated by LINE-1 Methylation in a Database of 869 Tumors

Background: Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. LINE-1 (L1 retrotransposon) constitutes a substantial portion of the human genome, and LINE-1 methylation correlates with global DNA methylation status. LINE-1 hypomethylation in colon cancer has been strongly associated with poor prognosis. However, whether LINE-1 hypomethylators constitute a distinct cancer subtype remains uncertain. Recent evidence for concordant LINE-1 hypomethylation within synchronous colorectal cancer pairs suggests the presence of a non-stochastic mechanism influencing tumor LINE-1 methylation level. Thus, it is of particular interest to examine whether its wide variation can be attributed to clinical, pathologic or molecular features.Design Utilizing a database of 869 colorectal cancers in two prospective cohort studies, we constructed multivariate linear and logistic regression models for LINE-1 methylation (quantified by Pyrosequencing). Variables included age, sex, body mass index, family history of colorectal cancer, smoking status, tumor location, stage, grade, mucinous component, signet ring cells, tumor infiltrating lymphocytes, CpG island methylator phenotype (CIMP), microsatellite instability, expression of TP53 (p53), CDKN1A (p21), CTNNB1 (β-catenin), PTGS2 (cyclooxygenase-2), and FASN, and mutations in KRAS, BRAF, and PIK3CA. Results: Tumoral LINE-1 methylation ranged from 23.1 to 90.3 of 0-100 scale (mean 61.4; median 62.3; standard deviation 9.6), and distributed approximately normally except for extreme hypomethylators [LINE-1 methylation < 40; N = 22 (2.5%), which were far more than what could be expected by normal distribution]. LINE-1 extreme hypomethylators were significantly associated with younger patients (p = 0.0058). Residual plot by multivariate linear regression showed that LINE-1 extreme hypomethylators clustered as one distinct group, separate from the main tumor group. The multivariate linear regression model could explain 8.4% of the total variability of LINE-1 methylation (R-square = 0.084). Multivariate logistic regression models for binary LINE-1 hypomethylation outcomes (cutoffs of 40, 50 and 60) showed at most fair predictive ability (area under receiver operator characteristics curve < 0.63). Conclusions: LINE-1 extreme hypomethylators appear to constitute a previously-unrecognized, distinct subtype of colorectal cancers, which needs to be confirmed by additional studies. Our tumor LINE-1 methylation data indicate enormous epigenomic diversity of individual colorectal cancers

Epigenomic diversity of colorectal cancer indicated by LINE-1 methylation in a database of 869 tumors

<p>Abstract</p> <p>Background</p> <p>Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. LINE-1 (L1 retrotransposon) constitutes a substantial portion of the human genome, and LINE-1 methylation correlates with global DNA methylation status. LINE-1 hypomethylation in colon cancer has been strongly associated with poor prognosis. However, whether LINE-1 hypomethylators constitute a distinct cancer subtype remains uncertain. Recent evidence for concordant LINE-1 hypomethylation within synchronous colorectal cancer pairs suggests the presence of a non-stochastic mechanism influencing tumor LINE-1 methylation level. Thus, it is of particular interest to examine whether its wide variation can be attributed to clinical, pathologic or molecular features.</p> <p>Design</p> <p>Utilizing a database of 869 colorectal cancers in two prospective cohort studies, we constructed multivariate linear and logistic regression models for LINE-1 methylation (quantified by Pyrosequencing). Variables included age, sex, body mass index, family history of colorectal cancer, smoking status, tumor location, stage, grade, mucinous component, signet ring cells, tumor infiltrating lymphocytes, CpG island methylator phenotype (CIMP), microsatellite instability, expression of TP53 (p53), CDKN1A (p21), CTNNB1 (β-catenin), PTGS2 (cyclooxygenase-2), and FASN, and mutations in <it>KRAS, BRAF</it>, and <it>PIK3CA</it>.</p> <p>Results</p> <p>Tumoral LINE-1 methylation ranged from 23.1 to 90.3 of 0-100 scale (mean 61.4; median 62.3; standard deviation 9.6), and distributed approximately normally except for extreme hypomethylators [LINE-1 methylation < 40; N = 22 (2.5%), which were far more than what could be expected by normal distribution]. LINE-1 extreme hypomethylators were significantly associated with younger patients (p = 0.0058). Residual plot by multivariate linear regression showed that LINE-1 extreme hypomethylators clustered as one distinct group, separate from the main tumor group. The multivariate linear regression model could explain 8.4% of the total variability of LINE-1 methylation (R-square = 0.084). Multivariate logistic regression models for binary LINE-1 hypomethylation outcomes (cutoffs of 40, 50 and 60) showed at most fair predictive ability (area under receiver operator characteristics curve < 0.63).</p> <p>Conclusions</p> <p>LINE-1 extreme hypomethylators appear to constitute a previously-unrecognized, distinct subtype of colorectal cancers, which needs to be confirmed by additional studies. Our tumor LINE-1 methylation data indicate enormous epigenomic diversity of individual colorectal cancers.</p

Differences among epitopes recognized by neutralizing antibodies induced by SARS-CoV-2 infection or COVID-19 vaccination

SARS-CoV-2 has gradually acquired amino acid substitutions in its S protein that reduce the potency of neutralizing antibodies, leading to decreased vaccine efficacy. Here, we attempted to obtain mutant viruses by passaging SARS-CoV-2 in the presence of plasma samples from convalescent patients or vaccinees to determine which amino acid substitutions affect the antigenicity of SARS-CoV-2. Several amino acid substitutions in the S2 region, as well as the N-terminal domain (NTD) and receptor-binding domain (RBD), affected the neutralization potency of plasma samples collected from vaccinees, indicating that amino acid substitutions in the S2 region as well as those in the NTD and RBD affect neutralization by vaccine-induced antibodies. Furthermore, the neutralizing potency of vaccinee plasma samples against mutant viruses we obtained or circulating viruses differed among individuals. These findings suggest that genetic backgrounds of vaccinees influence the recognition of neutralizing epitopes

Changes in expression levels of ERCC1, DPYD, and VEGFA mRNA after first-line chemotherapy of metastatic colorectal cancer: results of a multicenter study

Our previous study showed that administering oxaliplatin as first-line chemotherapy increased ERCC1 and DPD levels in liver colorectal cancers (CRCs) metastases. Second, whether the anti-VEGF monoclonal antibody bevacizumab alters tumoral VEGFA levels is unknown. We conducted this multicenter observational study to validate our previous findings on ERCC1 and DPD, and clarify the response of VEGFA expression to bavacizumab administration. 346 CRC patients with liver metastases were enrolled at 22 Japanese institutes. Resected liver metastases were available for 175 patients previously treated with oxaliplatin-based chemotherapy (chemotherapy group) and 171 receiving no previous chemotherapy (non-chemotherapy group). ERCC1, DPYD, and VEGFA mRNA levels were measured by real-time RT-PCR. ERCC1 mRNA expression was significantly higher in the chemotherapy group than in the non-chemotherapy group (P = 0.033), and were significantly correlated (Spearman\u27s correlation coefficient = 0.42; P < 0.0001). VEGFA expression level was higher in patients receiving bevacizumab (n = 51) than in those who did not (n = 251) (P = 0.007). This study confirmed that first-line oxaliplatin-based chemotherapy increases ERCC1 and DPYD expression levels, potentially enhancing chemosensitivity to subsequent therapy. We also found that bevacizumab induces VEGFA expression in tumor cells, suggesting a biologic rationale for extending bevacizumab treatment beyond first progression