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T. Wang



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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-097 - Genome-Wide Methylome Alterations in Lung Cancer (ID 3117)

      09:30 - 09:30  |  Author(s): T. Wang

      • Abstract

      Background:
      DNA cytosine methylation profiles are important features of malignancy. This study was designed to identify 5-methyl cytosines on a genome-wide scale in non-small cell lung cancers (NSCLC) relative to paired non-tumor lung which, analyzed alone or coupled to transcriptome data, could suggest methylome-deregulated loci.

      Methods:
      Twenty-four NSCLC tumor (T) – non-tumor (NT) pairs were interrogated for 1.2 million CCGG-bounded fragments across all genomic compartments, using a methylation-sensitive restriction enzyme based HELP-microarray assay. Expression microarrays were also employed, from specimens from the same lung resections.

      Results:
      We found: (i) Good correlation (r[2] =0.52, p=0.0006) between HELP and the reference quantitative methylation assay MassArray ®; (ii) Wide distribution of differential methylation (DM) among 32,037 promoters (PR, 26% of array-represented loci), 248,721 gene bodies (GB, 39 %), and 171,996 intergenic (IG, 48%) loci; (iii) In PR CpG island (CGI) hypermethylation exceeded CGI hypomethylation; (iv) DM hypermethylation in adenocarcinoma specifically was observed in many unexpected PR [e.g., RASL12; SPTAN1, mir-26a,] and GB [e.g., AKAP13, ANK family, PRKCE, ROS1] regions; (v) Overlay of DMxDE (differential expression) for adenocarcinoma yielded loci with canonical DM:DE patterns (e.g. PR hyper/hypo-methylation:mRNA down/up-regulated n=80; GB hyper/hypo-methylated:mRNA up/down-regulated GB n=3,136). (vi) Examples in adenocarcinoma hypermethylated PR loci with reduced expression included: HBEGF, DPT, AGER, SPARCL1, PTPRM; GB hypermethylated loci with upregulated expression included FERMT1, SLC7A5, FAP, TFAP2a genes. (vii) IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identifying familiar lung cancer nodes [tP53, Akt] and less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR].Figure 1



      Conclusion:
      Methylome sampling, alone and combined with transcriptome data, yields new loci, as well as previously recognized ones, distributed throughout the genome that are deregulated in NSCLC.