Fhit down-regulation is an early event in pancreatic carcinogenesis

Abstract

Aberrant Fhit expression characterizes a large proportion of primary pancreatic ductal adenocarcinomas (PDACs), but fragmentary information is available on Fhit expression during the phenotypic changes of pancreatic ductal epithelium during multistep transformation. We assessed Fhit expression by immunohistochemistry in two different multistep pancreatic carcinogenic processes: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). We considered 105 surgically treated PDACs/IPMNs and selected 30 samples of non-neoplastic pancreatic parenchyma, 50 PanIN lesions, 30 IPMNs, 15 IPMNs with associated invasive carcinoma, and 60 adenocarcinomas. Normal pancreatic ducts and surrounding acinar cells consistently showed moderate to strong Fhit immunoreactivity. Significant down-regulation of Fhit expression was observed in association with increasing severity of dysplastia/neoplastia in both carcinogenic processes. This was further confirmed by studying multiple lesions obtained from the same surgical specimen. Of 60 PDACs, only 14 showed Fhit expression comparable to normal pancreatic ductal epithelium, while the remainder (77%) showed clearly negative or reduced Fhit expression. This study demonstrates that Fhit down-regulation is an early event in both multistep carcinogenic processes leading to PDAC.

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Correspondence to Matteo Fassan.

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The materials used have been collected under Program 853 protocol 298CE on 15 February 2002 and Program 1885 protocol 52438 on 23 November 2010. The protocols include informed consent of the patient and were approved by the local ethics committee of the Integrated University Hospital Trust of Verona. The first approval (prog. 853) regarded the collection of pancreas samples for use in molecular research studies. This was later updated (prog. 1885) for the creation of a coordinated biobank for the collection of samples from all cancer patients that included neoplastic and associated local and distant normal tissue. The approved programs include tissue processing and storage methods of FFPE tissues of both neoplastic and normal tissues.

Funding

This work was supported by AssociazioneItalianaRicercaCancro (AIRC grant n. 12182, to AS); Cam-Pac FP7 Grant no: 602783 (to AS); Italian Cancer Genome Project (FIRB RBAP10AHJB to AS); FIMP-Italian Ministry of Health (CUP_J33G13000210001 to AS), and USPHS National Cancer Institute grant CA120516 (to KH).

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The authors declare that they have no competing interests.

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Aldo Scarpa and Kay Huebner are co-last authors.

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Fassan, M., Rusev, B., Corbo, V. et al. Fhit down-regulation is an early event in pancreatic carcinogenesis. Virchows Arch 470, 647–653 (2017). https://doi.org/10.1007/s00428-017-2105-3

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Keywords

  • FHIT
  • Pancreatic cancer
  • Carcinogenesis
  • Biomarkers