title: Validation of SCT Methylation as a Hallmark Biomarker for Lung Cancers.
abstract: BACKGROUND
  The human secretin gene (SCT) encodes secretin, a hormone with limited tissue distribution. Analysis of the 450k methylation array data in The Cancer Genome Atlas (TCGA) indicated that the SCT promoter region is differentially hypermethylated in lung cancer. Our purpose was to validate SCT methylation as a potential biomarker for lung cancer.
  
  
  METHODS
  We analyzed data from TCGA and developed and applied SCT-specific bisulfite DNA sequencing and quantitative methylation-specific polymerase chain reaction assays.
  
  
  RESULTS
  The analyses of TCGA 450K data for 801 samples showed that SCT hypermethylation has an area under the curve (AUC) value greater than 0.98 that can be used to distinguish lung adenocarcinomas or squamous cell carcinomas from nonmalignant lung tissue. Bisulfite sequencing of lung cancer cell lines and normal blood cells allowed us to confirm that SCT methylation is highly discriminative. By applying a quantitative methylation-specific polymerase chain reaction assay, we found that SCT hypermethylation is frequently detected in all major subtypes of malignant non-small cell lung cancer (AUC = 0.92, n = 108) and small cell lung cancer (AUC = 0.93, n = 40) but is less frequent in lung carcinoids (AUC = 0.54, n = 20). SCT hypermethylation appeared in samples of lung carcinoma in situ during multistage pathogenesis and increased in invasive samples. Further analyses of TCGA 450k data showed that SCT hypermethylation is highly discriminative in most other types of malignant tumors but less frequent in low-grade malignant tumors. The only normal tissue with a high level of methylation was the placenta.
  
  
  CONCLUSIONS
  Our findings demonstrated that SCT methylation is a highly discriminative biomarker for lung and other malignant tumors, is less frequent in low-grade malignant tumors (including lung carcinoids), and appears at the carcinoma in situ stage.
authors.forename: Yu-An
authors.initials: YA
authors.lastname: Zhang
authors.forename: Xiaotu
authors.initials: X
authors.lastname: Ma
authors.forename: Adwait
authors.initials: A
authors.lastname: Sathe
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Wang
authors.forename: Victor
authors.initials: V
authors.lastname: Stastny
authors.forename: Boning
authors.initials: B
authors.lastname: Gao
authors.forename: Jill E
authors.initials: JE
authors.lastname: Larsen
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liu
authors.forename: Kai
authors.initials: K
authors.lastname: Song
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.forename: Neda
authors.initials: N
authors.lastname: Kalhor
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.forename: Michael Q
authors.initials: MQ
authors.lastname: Zhang
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012633:Secretin / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D014408:Biomarkers, Tumor; D012633:Secretin
keywords: Cancer biomarker; FFPE DNA SCT qMSP; Lung cancer; SCT methylation; Secretin