HOXD8 hypermethylation as a fully sensitive and specific biomarker for biliary tract cancer detectable in tissue and bile samples

Background Biliary tract cancers (BTC) are rare but highly aggressive tumours with poor prognosis, usually detected at advanced stages. Herein, we aimed at identifying BTC-specific DNA methylation alterations. Methods Study design included statistical power and sample size estimation. A genome-wide...

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Bibliographic Details
Published in:British journal of cancer 2022-06, Vol.126 (12), p.1783-1794
Main Authors: Loi, Eleonora, Zavattari, Cesare, Tommasi, Alessandro, Moi, Loredana, Canale, Matteo, Po, Agnese, Sabato, Claudia, Vega-Benedetti, Ana Florencia, Ziranu, Pina, Puzzoni, Marco, Lai, Eleonora, Faloppi, Luca, Rullán, María, Carrascosa, Juan, Amat, Irene, Urman, Jesús M., Arechederra, Maria, Berasain, Carmen, Ferretti, Elisabetta, Casadei-Gardini, Andrea, Avila, Matías A., Alonso, Sergio, Scartozzi, Mario, Zavattari, Patrizia
Format: Article
Language:English
Subjects:
631/67/1504/1329
692/53/2421
Bile
Biliary tract
Biliary Tract Neoplasms - genetics
Biliary Tract Neoplasms - pathology
Biomarkers
Biomarkers, Tumor - genetics
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cholangiocarcinoma
Clinical trials
CpG islands
DNA Methylation
Drug Resistance
Epidemiology
Genomes
Homeodomain Proteins - genetics
Humans
Molecular Medicine
Mutation
Oncology
Transcription Factors - genetics
Tumors
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Summary:Background Biliary tract cancers (BTC) are rare but highly aggressive tumours with poor prognosis, usually detected at advanced stages. Herein, we aimed at identifying BTC-specific DNA methylation alterations. Methods Study design included statistical power and sample size estimation. A genome-wide methylation study of an explorative cohort (50 BTC and ten matched non-tumoral tissue samples) has been performed. BTC-specific altered CpG islands were validated in over 180 samples (174 BTCs and 13 non-tumoral controls). The final biomarkers, selected by a machine-learning approach, were validated in independent tissue (18 BTCs, 14 matched non-tumoral samples) and bile (24 BTCs, five non-tumoral samples) replication series, using droplet digital PCR. Results We identified and successfully validated BTC-specific DNA methylation alterations in over 200 BTC samples. The two-biomarker panel, selected by an in-house algorithm, showed an AUC > 0.97. The best-performing biomarker (chr2:176993479-176995557), associated with HOXD8 , a pivotal gene in cancer-related pathways, achieved 100% sensitivity and specificity in a new series of tissue and bile samples. Conclusions We identified a novel fully efficient BTC biomarker, associated with HOXD8 gene, detectable both in tissue and bile by a standardised assay ready-to-use in clinical trials also including samples from non-invasive matrices.
ISSN:0007-0920
1532-1827
DOI:10.1038/s41416-022-01738-1