Andreas Schröck1, Annette Leisse1,2, Luka de Vos1, Heidrun Gevensleben2, Freya Dröge3, Alina Franzen1, Malin Wachendörfer1,2, Friederike Schröck1, Joerg Ellinger4, Marcus Teschke5, Timo Wilhelm-Buchstab6, Jennifer Landsberg7, Stefan Holdenrieder8, Gunther Hartmann9, John K Field10, Friedrich Bootz1, Glen Kristiansen2, Dimo Dietrich11. 1. Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany. 2. Institute of Pathology, University Hospital Bonn, Bonn, Germany. 3. Ear, Nose and Throat Clinic, University Hospital Essen, Essen, Germany. 4. Department of Urology, University Hospital Bonn, Bonn, Germany. 5. Department of Oral and Maxillofacial Surgery, University Hospital Bonn, Bonn, Germany. 6. Department of Radiology, University Hospital Bonn, Bonn, Germany. 7. Department of Dermatology, Bonn, University Hospital Bonn, Germany. 8. German Heart Centre Munich, Munich, Germany. 9. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany. 10. University of Liverpool Cancer Research Center, Liverpool, UK. 11. Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany; dimo.dietrich@gmail.com.
Abstract
BACKGROUND: Circulating cell-free DNA methylation testing in blood has recently received regulatory approval for screening of colorectal cancer. Its application in other clinical settings, including staging, prognosis, prediction, and recurrence monitoring is highly promising, and of particular interest in head and neck squamous cell carcinomas (HNSCCs) that represent a heterogeneous group of cancers with unsatisfactory treatment guidelines. METHODS: Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) DNA methylation in plasma from 649 prospectively enrolled patients (training study: 284 HNSCC/122 control patients; testing study: 141 HNSCC/102 control patients) was quantified before treatment and longitudinally during surveillance. RESULTS: In the training study, 59% of HNSCC patients were methylation-positive at 96% specificity. Methylation levels correlated with tumor and nodal category (P < 0.001). Initially increased methylation levels were associated with a higher risk of death [SEPT9: hazard ratio (HR) = 5.27, P = 0.001; SHOX2: HR = 2.32, P = 0.024]. Disease recurrence/metastases were detected in 47% of patients up to 377 days earlier compared to current clinical practice. The onset of second cancers was detected up to 343 days earlier. In the testing study, sensitivity (52%), specificity (95%), prediction of overall survival (SEPT9: HR = 2.78, P = 0.022; SHOX2: HR = 2.50, P = 0.026), and correlation with tumor and nodal category (P <0.001) were successfully validated. CONCLUSIONS: Methylation testing in plasma is a powerful diagnostic tool for molecular disease staging, risk stratification, and disease monitoring. Patients with initially high biomarker levels might benefit from intensified treatment and posttherapeutic surveillance. The early detection of a recurrent/metastatic disease or a second malignancy could lead to an earlier consecutive treatment, thereby improving patients' outcomes.
BACKGROUND: Circulating cell-free DNA methylation testing in blood has recently received regulatory approval for screening of colorectal cancer. Its application in other clinical settings, including staging, prognosis, prediction, and recurrence monitoring is highly promising, and of particular interest in head and neck squamous cell carcinomas (HNSCCs) that represent a heterogeneous group of cancers with unsatisfactory treatment guidelines. METHODS: Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) DNA methylation in plasma from 649 prospectively enrolled patients (training study: 284 HNSCC/122 control patients; testing study: 141 HNSCC/102 control patients) was quantified before treatment and longitudinally during surveillance. RESULTS: In the training study, 59% of HNSCC patients were methylation-positive at 96% specificity. Methylation levels correlated with tumor and nodal category (P < 0.001). Initially increased methylation levels were associated with a higher risk of death [SEPT9: hazard ratio (HR) = 5.27, P = 0.001; SHOX2: HR = 2.32, P = 0.024]. Disease recurrence/metastases were detected in 47% of patients up to 377 days earlier compared to current clinical practice. The onset of second cancers was detected up to 343 days earlier. In the testing study, sensitivity (52%), specificity (95%), prediction of overall survival (SEPT9: HR = 2.78, P = 0.022; SHOX2: HR = 2.50, P = 0.026), and correlation with tumor and nodal category (P <0.001) were successfully validated. CONCLUSIONS: Methylation testing in plasma is a powerful diagnostic tool for molecular disease staging, risk stratification, and disease monitoring. Patients with initially high biomarker levels might benefit from intensified treatment and posttherapeutic surveillance. The early detection of a recurrent/metastatic disease or a second malignancy could lead to an earlier consecutive treatment, thereby improving patients' outcomes.
Authors: Holli A Loomans-Kropp; Yurong Song; Manish Gala; Aparna R Parikh; Emily E Van Seventer; Rocio Alvarez; Megan P Hitchins; Robert H Shoemaker; Asad Umar Journal: Cancer Res Commun Date: 2022-02-11
Authors: Vasudha Mishra; Alka Singh; Xiangying Chen; Ari J Rosenberg; Alexander T Pearson; Alex Zhavoronkov; Peter A Savage; Mark W Lingen; Nishant Agrawal; Evgeny Izumchenko Journal: Br J Cancer Date: 2021-12-07 Impact factor: 7.640
Authors: Luka de Vos; Heidrun Gevensleben; Andreas Schröck; Alina Franzen; Glen Kristiansen; Friedrich Bootz; Dimo Dietrich Journal: Clin Epigenetics Date: 2017-12-01 Impact factor: 6.551
Authors: Julia Bergheim; Alexander Semaan; Heidrun Gevensleben; Susanne Groening; Andreas Knoblich; Jörn Dietrich; Julia Weber; Jörg C Kalff; Friedrich Bootz; Glen Kristiansen; Dimo Dietrich Journal: Br J Cancer Date: 2018-04-03 Impact factor: 7.640