Key woRDSglobal genomic hypomethylation, epigenetics of hepatocarcinogenesis, epigenetic biomarkers for early detection, molecular cancer screening technology, epigenetic approaches to cancer epidemiology ABStRActBackground: Global genomic DNA hypomethylation is a feature of genomic DNA derived from solid and hematologic tumors in animal models and human carcinogenesis. Global genomic DNA hypomethylation may be the earliest epigenetic change from a normal to a pre-malignant cell.Objectives: To test if global hypomethylation is a good marker for early detection of cancer we used a novel quantification method of 2'-deoxynucleosides to evaluate DNA methylation in liver cancer cases and controls.Methods: Frozen tissue from liver cancer patients and controls were obtained from the Cooperative Human Tissue Network. DNA was extracted using standard methods. Genomic DNA samples were boiled and treated with nuclease P1 and alkaline phosphatase. Global genomic DNA methylation patterns were obtained using HPLC for fraction separation and mass spectrometry for quantification. A two-sample t-test was performed using Welch's approximation for samples with unequal variances. A Wilcoxon rank sum test was also performed.Results: A global genomic DNA methylation index measuring methylated cytidine relative to global cytidine in the genome was significantly lower (p value = 0.001) for all cases, mean = 2.43 (95% CI, 2.08, 2.78), when compared to controls, mean = 3.55 (95% CI, 3.16, 3.93).Discussion: A correlation between global genomic DNA methylation patterns and type of liver tissue was observed. These results add to the accumulating body of evidence suggesting that global DNA hypomethylation may be a useful biomarker to distinguish between liver cancer cases and controls.

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months. Among patients who discontinued brigatinib, 100 (59.9%) received subsequent ALK-TKIs. Lorlatinib was the most common next ALK TKI (57.0%), followed by brigatinib retreatment (16.0%), alectinib (13.0%), ceritinib (10.0%), and crizotinib (4.0%). The median (95% CI) TTD of the post-brigatinib ALK TKI was 7.2 (3.9-13.8) months. In patients who received crizotinib then brigatinib, the median (95% CI) TTD of the post-brigatinib ALK TKI was 6.7 (3.7-22.2) months. In patients who received lorlatinib after brigatinib was discontinued, median (95% CI) lorlartinib TTD was 8.0 (3.9-not reached) months.Conclusions: These results indicate that brigatinib has real-world durable clinical effects for patients. Treatment with subsequent TKIs, can still bring benefit to patients after discontinuing brigatinib. More formalized prospective data are needed to establish sequencing recommendations.

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