Fhit down-regulation is an early event in pancreatic carcinogenesis

doi:10.1007/s00428-017-2105-3

. 2017 Jun;470(6):647-653.

doi: 10.1007/s00428-017-2105-3. Epub 2017 Mar 13.

Fhit down-regulation is an early event in pancreatic carcinogenesis

Matteo Fassan^{1

2}, Borislav Rusev³, Vincenzo Corbo³, Pierluigi Gasparini⁴, Claudio Luchini^{3

5

6}, Caterina Vicentini³, Andrea Mafficini³, Salvatore Paiella⁷, Roberto Salvia⁷, Ivana Cataldo³, Aldo Scarpa^{3

5}, Kay Huebner⁴

Affiliations

¹ ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy. matteo.fassan@unipd.it.
² Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Via Gabelli 61, 35121, Padua, Italy. matteo.fassan@unipd.it.
³ ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
⁴ Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
⁵ Department of Diagnostics and Public Health, Surgical Pathology Unit, University and Hospital Trust of Verona, Verona, Italy.
⁶ Department of Pathology, Santa Chiara Hospital, Trento, Italy.
⁷ Department of Surgery, Unit of General Surgery B, University and Hospital Trust of Verona, Verona, Italy.

PMID: 28289900
PMCID: PMC5568551
DOI: 10.1007/s00428-017-2105-3

Fhit down-regulation is an early event in pancreatic carcinogenesis

Matteo Fassan et al. Virchows Arch. 2017 Jun.

. 2017 Jun;470(6):647-653.

doi: 10.1007/s00428-017-2105-3. Epub 2017 Mar 13.

Authors

Affiliations

¹ ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy. matteo.fassan@unipd.it.
² Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Via Gabelli 61, 35121, Padua, Italy. matteo.fassan@unipd.it.
³ ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
⁴ Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
⁵ Department of Diagnostics and Public Health, Surgical Pathology Unit, University and Hospital Trust of Verona, Verona, Italy.
⁶ Department of Pathology, Santa Chiara Hospital, Trento, Italy.
⁷ Department of Surgery, Unit of General Surgery B, University and Hospital Trust of Verona, Verona, Italy.

PMID: 28289900
PMCID: PMC5568551
DOI: 10.1007/s00428-017-2105-3

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.

Keywords: Biomarkers; Carcinogenesis; FHIT; Pancreatic cancer.

PubMed Disclaimer

Conflict of interest statement

Conflict of interests: The authors declare that they have no competing interests.

Figures

**Figure 1. Fhit expression is down-regulated early in pancreatic carcinogenesis**
Immunohistochemical expression is represented as H-score values. PanIN= Pancreatic intraepithelial neoplasia; LG= low grade; HG= high grade. (A) Fhit expression distribution in the series of samples examined. (B) Fhit expression according to dysplasia grade of PanIN. (C) Matched PanIN-PDAC. (**D&E**) Distribution of Fhit H-score according to histotype and grade of IPMNs, respectively. (F) Fhit expression in matched dysplastic and invasive epithelia in 15 IPMNs with an associated invasive carcinoma. Boxplots are with wiskers from minimum to maximum of all data.

**Figure 2. Fhit expression is significantly down-regulated in pancreatic ductal adenocarcinoma (PDAC) and in PDAC-associated pancreatic intraepithelial neoplastic (PanIN) lesions**
(A) A low-grade PanIN lesion (asterisk) showing Fhit expression comparable to expression in normal surrounding pancreatic parenchyma. (B) A representative Fhit-negative adenocarcinoma intermingled with Fhit-positive pancreatic ductal epithelia. (C) A high-grade PanIN lesion (arrow heads) and coexisting PDAC, both showing negative/low Fhit expression. (Original magnifications, 4×, 10, and 20×).

**Figure 3. Down-regulation of Fhit expression in IPMNs**
(A and B) IPMNs (asterisks) with low-grade dysplasia showing negative/low Fhit expression in comparison to Fhit-positive adjacent pancreatic parenchyma. (C) A Fhit positive IPMN (arrow heads), showing down-regulation of Fhit expression in higher grade epithelia. (D) IPMN with low-grade dysplasia showing negative (arrow heads)/low Fhit expression in comparison to Fhit positive adjacent pancreatic parenchyma (asterisk). (E) Fhit-negative IPMN with high-grade dysplasia. (F) Mild to moderate Fhit expression in an IPMN with high-grade dysplasia and a coexisting Fhit-negative colloid adenocarcinoma (arrow heads). (Original magnifications, 4×, 10, and 20×).

See this image and copyright information in PMC

Cited by

Potential Role of the Fragile Histidine Triad in Cancer Evo-Dev.
Niu Z, Jiang D, Shen J, Liu W, Tan X, Cao G. Niu Z, et al. Cancers (Basel). 2023 Feb 10;15(4):1144. doi: 10.3390/cancers15041144. Cancers (Basel). 2023. PMID: 36831487 Free PMC article. Review.
WD repeat-containing protein 1 maintains β-Catenin activity to promote pancreatic cancer aggressiveness.
Li H, Liu X, Jiang S, Zhou X, Yao L, Di Y, Jiang Y, Gu J, Mao Y, Li J, Jin C, Yang P, Fu D. Li H, et al. Br J Cancer. 2020 Sep;123(6):1012-1023. doi: 10.1038/s41416-020-0929-0. Epub 2020 Jun 30. Br J Cancer. 2020. PMID: 32601462 Free PMC article.
Effect of interventional embolotherapy on FHIT and p16 expression in hepatocellular carcinoma patients.
Xu W, Qi X, Wang X, Sun J. Xu W, et al. Oncol Lett. 2019 Jan;17(1):871-876. doi: 10.3892/ol.2018.9648. Epub 2018 Oct 31. Oncol Lett. 2019. PMID: 30655841 Free PMC article.
The ubiquitous 'cancer mutational signature' 5 occurs specifically in cancers with deleted FHIT alleles.
Volinia S, Druck T, Paisie CA, Schrock MS, Huebner K. Volinia S, et al. Oncotarget. 2017 Nov 6;8(60):102199-102211. doi: 10.18632/oncotarget.22321. eCollection 2017 Nov 24. Oncotarget. 2017. PMID: 29254236 Free PMC article.

References

1. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–1617. - PubMed
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30. - PubMed
1. Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grutzmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM, Australian Pancreatic Cancer Genome Initiative. Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52. - PubMed
1. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Australian Pancreatic Cancer Genome Initiative. Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399–405. - PMC - PubMed
1. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–1806. - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions

Grants and funding

R01 CA120516/CA/NCI NIH HHS/United States

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Health Information

[1] Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–1617. - PubMed

[2] Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–1617. - PubMed

[3] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30. - PubMed

[4] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30. - PubMed

[5] Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grutzmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM, Australian Pancreatic Cancer Genome Initiative. Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52. - PubMed

[6] Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grutzmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM, Australian Pancreatic Cancer Genome Initiative. Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52. - PubMed

[7] Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Australian Pancreatic Cancer Genome Initiative. Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399–405. - PMC - PubMed

[8] Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Australian Pancreatic Cancer Genome Initiative. Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399–405. - PMC - PubMed

[9] Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–1806. - PMC - PubMed

[10] Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–1806. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Fhit down-regulation is an early event in pancreatic carcinogenesis

Affiliations

Fhit down-regulation is an early event in pancreatic carcinogenesis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical