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Background  Biliary tract carcinoma (BTC) is a fatal malignancy which aggressiveness contrasts sharply with its relatively mild and late clinical presentation. Novel molecular markers for early diagnosis and precise treatment are urgently needed. The purpose of this study was to evaluate the diagnostic and prognostic value of promoter hypermethylation of the  SHOX2  and  SEPT9  gene loci in BTC.    Methods  Relative DNA methylation of  SHOX2  and  SEPT9  was quantified in tumor specimens and matched normal adjacent tissue (NAT) from 71 BTC patients, as well as in plasma samples from an independent prospective cohort of 20 cholangiocarcinoma patients and 100 control patients. Receiver operating characteristic (ROC) curve analyses were performed to probe the diagnostic ability of both methylation markers. DNA methylation was correlated to clinicopathological data and to overall survival.    Results    SHOX2  methylation was significantly higher in tumor tissue than in NAT irrespective of tumor localization ( p  < 0.001) and correctly identified 71% of BTC specimens with 100% specificity (AUC = 0.918; 95% CI 0.865–0.971).  SEPT9  hypermethylation was significantly more frequent in gallbladder carcinomas compared to cholangiocarcinomas ( p  = 0.01) and was associated with large primary tumors ( p  = 0.01) as well as age ( p  = 0.03). Cox proportional hazard analysis confirmed microscopic residual tumor at the surgical margin (R1-resection) as an independent prognostic factor, while  SHOX2  and  SEPT9  methylation showed no correlation with overall survival. Elevated DNA methylation levels were also found in plasma derived from cholangiocarcinoma patients.  SHOX2  and  SEPT9  methylation as a marker panel achieved a sensitivity of 45% and a specificity of 99% in differentiating between samples from patients with and without cholangiocarcinoma (AUC = 0.752; 95% CI 0.631–0.873).    Conclusions    SHOX2  and  SEPT9  are frequently methylated in biliary tract cancers. Promoter hypermethylation of  SHOX2  and  SEPT9  may therefore serve as a minimally invasive biomarker supporting diagnosis finding and therapy monitoring in clinical specimens.    Electronic supplementary material  The online version of this article (doi:10.1186/s13148-016-0299-x) contains supplementary material, which is available to authorized users.

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract