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Background: RUNX3 is hypermethylated in multiple cancers. TIMP2 also functions as a regulator of tumors. However, there are only very few reports on the association of methylation of RUNX3 and TIMP2 with lung cancer (LC) in peripheral blood. Methods: 426 LC patients and 428 age- and sex-matched healthy controls were recruited. DNA methylation in blood was semi-quantitively assessed by mass spectrometry. For the association analysis, binary logistic regression analysis adjusted covariant was applied, and ORs were presented as per +10% methylation. Results: Hypermethylation of CpG_1, CpG_5 and CpG_8 in RUNX3 was significantly associated with LC (ORs = 1.45, 1.35 and 1.35, respectively, adjusted p < 0.05), and even stage I LC. The association between the three RUNX3 CpG sites and LC was enhanced by increased age (> 55 years, ORs ranged from 1.43 to 1.75, adjusted p < 0.05), male gender (ORs ranged from 1.47 to 1.59, adjusted p < 0.05) and tumor stage (stage II&III&IV, ORs ranged from 1.86 to 3.03, adjusted p < 0.05). Conclusions: This study suggests a significant association between blood-based RUNX3 hypermethylation and LC, especially in elder people, in males and in LC patients with advanced stage. Clinical significance: The blood-based RUNX3 hypermethylation is associated with LC, especially stage I LC. LC-associated blood RUNX3 hypermethylation is increased with age. More LC-associated RUNX3 hypermethylation are found in males. [ABSTRACT FROM AUTHOR]

Previous work has shown that DNA methylation in peripheral blood may be associated with malignancy; however, these studies have mainly been conducted within Caucasian populations. Here, we investigated the association between blood-based methylation of S100 calcium-binding protein P gene (S100P) and hyaluronoglucosaminidase 2 gene (HYAL2) and breast cancer (BC) via mass spectrometry in two independent case-control studies of the Chinese population with a total of 351 BC cases and 427 cancer-free female controls. In Study I, in which subjects had an average of 45 years, hypomethylation of S100P showed a protective effect for women ≤45 years (six out of nine CpG sites, p < 0.05) but not for women >45 years. In contrast, hypomethylation of HAYL2 was not correlated with BC in women ≤45 years but was a risk factor for women >45 years (three out of four CpG sites, p < 0.05). We proposed an age-dependent correlation between BC and methylation of S100P and HYAL2 and performed further validation in Study II with older subjects (average age = 52.5 years), where hypomethylation of both S100P and HYAL2 was a risk factor for BC (p < 0.05 for 10 CpG sites) as reported in Caucasians who develop BC around 55 years old. Together with the observation that Chinese cancer-free females having variant basal methylation levels comparing to Caucasians, we assumed that blood-based methylation might be modified by ethnic background, hormone status, and lifestyle. Here, we highlighted that the epigenetic biomarkers warrant validations when its application in variant ethnic groups is considered. [ABSTRACT FROM AUTHOR]

• MALDI-TOF mass spectrometry was applied to detect RPTOR methylation level. • RPTOR hypomethylation in peripheral blood was associated with LC even in very early stage, such as LC with tumor length ≤1 cm. • RPTOR methylation pattern showed differences between different age groups or genders. • Blood-based hypomethylation of RPTOR showed correlations with some clinical characteristics of LC cases. Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Novel biomarkers for LC detection are urgently needed. Here we aimed to investigate the association between RPTOR methylation in peripheral blood and LC. The methylation levels were measured by mass spectrometry in two independent case-control studies (159 LC cases vs. 188 controls in Study I, 413 LC cases vs. 687 controls in Study II). Logistic regression and Bonferroni correction were conducted to analyze the association. RPTOR hypomethylation was discovered in Study I and validated in Study II. Combining the two studies, RPTOR_CpG_2 and RPTOR_CpG_8 showed significantly lower methylation levels in stage I cases (ORs per −10% methylation = 1.22 and 1.27, respectively, both P -values < 0.005). The significance kept between RPTOR_CpG_8 and LC cases with tumor length ≤ 1 cm (OR per −10% methylation = 1.39, P = 0.001). Moreover, methylation levels of all CpG sites were lower in cases at stage II & III than in those at stage I (all P -values less than 0.017). Our study disclosed the association between RPTOR hypomethylation in peripheral blood and LC even in very early stage, suggesting the feasibility of blood-based DNA methylation for LC early detection. [ABSTRACT FROM AUTHOR]