Characterization of a multiple epigenetic marker panel for lung cancer detection and risk assessment in plasma

Abstract

BACKGROUND.Methylation patterns may be useful biomarkers of cancer detection and risk assessment.METHODS.The methylation status of 6 genes, including a candidate tumor suppressor gene (BLU), the cadherin 13 gene (CDH13), the fragile histidine triad gene (FHIT), the cell cycle control gene p16, the retinoic acid receptor β gene (RARβ), and the Ras association domain family 1 gene (RASSF1A), was examined in plasma samples, corresponding tumor tissues, and normal lung tissues from a group of 63 patients with lung cancer and in plasma samples from 36 cancer‐free individuals. The detection rate of the p16 gene was validated in a test group of 20 patients with lung cancer.RESULTS.The concordance of methylation in tumor tissues and plasma samples was 86%, 87%, 80%, 75%, 76%, and 84% for the BLU, CDH13, FHIT, p16, RARβ, and RASSF1A genes, respectively. The test group showed a similar concordance for p16 methylation detection. Multiple logistic regression analysis showed that the odds ratio for having lung cancer was 10.204 for individuals with p16 methylation (P = .013) and 9.952 for individuals with RASSFIA methylation (P = .019). After several trial tests, the authors established that methylation for ≥2 of the 6 markers met the criterion for an elevated risk of cancer. Comparisons yielded a sensitivity of 73%, a specificity of 82%, and a concordance of 75% between the methylation patterns in tumor tissues and in corresponding plasma samples. The detection rate was relatively high in cigarette smokers with advanced squamous cell lung cancer.CONCLUSIONS.The current results indicated that multiple epigenetic markers in the plasma, especially the p16 and RASSF1A genes, can be used for lung cancer detection. This methylation marker panel should improve the detection of cancer or the risk assessment for lung cancer in combination with conventional diagnostic tools. Cancer 2007. © 2007 American Cancer Society.

Clinicopathological significance of RASSF1A reduced expression and hypermethylation in hepatocellular carcinoma

“…It has been suggested that RASSF1A methylation is one of the most common aberrations so far identified in human cancers and that the loss of the functional protein may promote the development of many human tumors. Hypermethylation of the RASSF1A has been detected frequently in the tissues of different cancers [10][11][12][13][14][15][16][17], while in the body fluid, methylation of RASSF1A promoter has also been documented in 50% sputum and 84% serum from lung cancer [30], 35% urine from bladder cancer [15], 56-60% serum from breast caner [31][32][33], and 5% serum from undifferentiated nasopharyngeal carcinoma [34], which indicated the value of RASSF1A methylation in DNA for the early-stage diagnosis of tumors. Detection of methylated DNA has then been suggested as a potential biomarker for early detection of cancer.…”

Associations Between RASSF1A Promoter Methylation and NSCLC: A Meta-analysis of Published Data

“…To date, the prevalence of RASSF1A methylation is exhibited in 30-40% of NSCLC, and is mainly detected by methylation-specific PCR (MSP) analysis Toyooka et al, 2003;Guo et al, 2004;Wang et al, 2004;Choi et al, 2005;Dammann et al, 2005;Ito et al, 2005;Chen et al, 2006;Hsu et al, 2007;Yanagawa et al, 2007;Yang et al, 2007;Liu et al, 2008;Lin et al, 2009;Peng et al, 2010;Zhang et al, 2010;Kang et al, 2011;Song et al, 2011;. However, association of RASSF1A promoter methylation with NSCLC have mostly been investigated in studies with small sample sizes or other limitations in study design, leading to conflicting results, especially in the relationship between RASSF1A promoter methylation and clinicopathologic features among NSCLC.…”

“…Moreover, one was excluded as a duplicate publication . Ultimately, 19 publications met the inclusion criteria (Figure 1) Toyooka et al, 2003;Guo et al, 2004;Wang et al, 2004;Choi et al, 2005;Dammann et al, 2005;Ito et al, 2005;Chen et al, 2006;Hsu et al, 2007;Kim et al, 2007;Yanagawa et al, 2007;Yang et al, 2007;Liu et al, 2008;Lin et al, 2009;Peng et al, 2010;Zhang et al, 2010;Kang et al, 2011;Song et al, 2011;Li et al, 2012) and were included in the meta-analysis. Detailed characteristics of the 19 studies are listed in Table 1.…”

“…Detailed characteristics of the 19 studies are listed in Table 1. Overall, 5 of the included articles were published in Chinese Peng et al, 2010;Zhang et al, 2010;Kang et al, 2011;Song et al, 2011), and the others were published in English Toyooka et al, 2003;Guo et al, 2004;Wang et al, 2004;Choi et al, 2005;Dammann et al, 2005;Ito et al, 2005;Chen et al, 2006;Hsu et al, 2007;Yanagawa et al, 2007;Liu et al, 2008;Li et al, 2012). The aforementioned 19 studies provided data regarding RASSF1A promoter methylation in 2063 cases of NSCLC tissues and 1184 controls of non-tumor tissues, with a total sample size of 3247 cases.…”

“…Controls were mainly matched for sex and age. Among the controls, 14 studies were autogenous (tissues from corresponding adjacent normal tissues) Toyooka et al, 2003;Wang et al, 2004;Choi et al, 2005;Dammann et al, 2005;Ito et al, 2005;Chen et al, 2006;Hsu et al, 2007;Kim et al, 2007;Yanagawa et al, 2007;Liu et al, 2008;Song et al, 2011), and 5 were heterogeneous (tissues from non-cancerous respiratory diseases) (Lin et …”