TOP1 gene copy numbers are increased in cancers of the bile duct and pancreas

Abstract

Background. Bile duct and pancreatic cancer (PC) have poor prognoses and treatment options for inoperable patients are scarce. In order to improve outcome for these patients, there is an urgent need for biomarkers predictive of treatment effect. Irinotecan is a topoisomerase 1 (Top1) poison. Top1 protein, TOP1 gene copy number and mRNA expression, respectively, have been proposed as predictive biomarkers of response to irinotecan in other cancers. Here we investigate the occurrence of TOP1 gene aberrations in cancers of the bile ducts and pancreas. Material and methods. TOP1 and centromere 20 (CEN-20) numbers were investigated by fluorescence in situ hybridization analyses in tumor tissue from 226 patients. The frequencies of aberration in the TOP1 gene copy number, the CEN-20 copy number and the TOP1/CEN-20 ratio were analyzed. As TOP1 is located on chromosome 20, the CEN-20 probe was included to distinguish between chromosomal and gene amplifications. Results. In PC, 29.8% had an increased TOP1 copy number (≥3.5n gene copies per cell) and 10.8% had a TOP1/CEN-20 ratio >1.5. In bile duct cancer, 12.8 % had an increased TOP1 copy number and 6.4% had a TOP1/CEN-20 ratio >1.5. Neither the TOP1 copy number nor the TOP1/CEN-20 ratios could predict overall survival. Conclusion. We here report that a substantial number of patients with bile duct or PC have increased TOP1 copy number and increased TOP1/CEN-20 ratio making further analyses on the association between TOP1 gene copy number and irinotecan efficacy clinically relevant.

Key Words:

• bile duct cancer
• biomarkers
• pancreatic cancer
• prediction
• topoisomerase-1

Acknowledgement

The authors greatly acknowledge and are truly grateful for the corporation-willingness from all of the BIOPAC study group, in particular Professor, MD, DMSc Julia S. Johansen and consultant, MD Benny V. Jensen, Department of Oncology, Herlev Hospital, University of Copenhagen. Also thanks to Signe Lykke Nielsen, Section of Molecular Disease Biology, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, for all her work and technical support. Thanks to those that financed the study: The Oncological Research Fund and Department of Oncology, Rigshospitalet and the Danish Cancer Research Fund.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.