Genetic profiling and pharmacogenetics

The high rate of genetic alterations and chromosomal instability in core signaling pathways are a major cause for the intrinsic aggressiveness of PDAC as well as of the inefficacy of currently available therapeutic strategies, which has been partly attributed to the high rate of genetic alterations affecting multiple pathways, whose multilevel cross-stimulation can overcome drug activity.

Identification of prognostic genetic biomarkers may provide important insights into the selection of the optimal therapeutic strategy to be used for any given patient, resulting in the highest likelihood of improving clinical outcome while minimizing useless and toxic treatments.

We evaluated the association of genomic imbalances and clinical outcome using high-resolution array comparative genomic hybridization (aCGH) technology in a cohort of paraffin embedded samples from 44 radically resected patients, which represents the largest series of PDACs ever investigated by aCGH. In this series we observed a significant correlation between shorter survival and loss of the small cytoband 18q22.3. More recently, we further explored the clinical relevance of this discovery by screening the expression of the genes included in this cytoband in two independent cohorts of radically-resected patients, demonstrating that PDACs are more aggressive if they have low expression of the microsomal protein CYB5A, which therefore represents a promising new tool for prognostic purposes.

Finally, we are performing several pharmacogenetic studies, towards the identification of molecular markers that are predictive of drug sensitivity/toxicity and are helpful in the selection of chemotherapeutic agents best suited to the individual patient.

Our main articles related to this project

1. Vasile E, Tibaldi C, Leon GL, D’Incecco A, Giovannetti E.
   Cytochrome P450 1B1 (CYP1B1) polymorphisms are associated with clinical outcome of docetaxel in non-small cell lung cancer (NSCLC) patients.
   J Cancer Res Clin Oncol. 2015 Jul;141(7):1189-94
2. Giovannetti E, Wang Q, Avan A, Funel N, Lagerweij T, Lee JH, Caretti V, van der Velde A, Boggi U, Wang Y, Vasile E, Peters GJ, Wurdinger T, Giaccone G.
   Role of CYB5A in pancreatic cancer prognosis and autophagy modulation
   J Natl Cancer Inst. 2014 Jan;106(1):djt346
   Link: www.ncbi.nlm.nih.gov/pubmed/24301457
3. Giovannetti E, Giaccone G.
   CYB5A and autophagy-mediated cell death in pancreatic cancer
   Autophagy. 2014 Apr;10(4):697-8
   Link: www.ncbi.nlm.nih.gov/pubmed/24448000
4. Robert J, Le Morvan V, Giovannetti E, Peters GJ; PAMM Group of EORTC.
   On the use of pharmacogenetics in cancer treatment and clinical trials
   Eur J Cancer. 2014 Oct;50(15):2532-2543
   Link: www.ncbi.nlm.nih.gov/pubmed/25103456
5. Avan A, Avan A, Le Large TY, Mambrini A, Funel N, Maftouh M, Ghayour-Mobarhan M, Cantore M, Boggi U, Peters GJ, Pacetti P, Giovannetti E.
   AKT1 and SELP Polymorphisms Predict the Risk of Developing Cachexia in Pancreatic Cancer Patients
   PLoS One. 2014 Sep 19;9(9):e108057
   Link: www.ncbi.nlm.nih.gov/pubmed/25238546
   Free pdf: click here
6. Maftouh M, Avan A, Funel N, Paolicchi E, Vasile E, Pacetti P, Vaccaro V, Faviana P, Campani D, Caponi S, Mambrini A, Boggi U, Cantore M, Milella M, Peters GJ, Reni M, Giovannetti E.
   A polymorphism in the promoter is associated with EZH2 expression but not with outcome in advanced pancreatic cancer patients
   Pharmacogenomics. 2014 Apr;15(5):609-18
   Link: www.ncbi.nlm.nih.gov/pubmed/24798718
7. Avan A, Caretti V, Funel N, Galvani E, Maftouh M, Honeywell RJ, Lagerweij T, Van Tellingen O, Campani D, Fuchs D, Verheul HM, Schuurhuis GJ, Boggi U, Peters GJ, Würdinger T, Giovannetti E.
   Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma
   Cancer Res. 2013 Nov 15;73(22):6745-56
   Link: www.ncbi.nlm.nih.gov/pubmed/24085787
8. Avan A, Pacetti P, Reni M, Milella M, Vasile E, Mambrini A, Vaccaro V, Caponi S, Cereda S, Peters GJ, Cantore M, Giovannetti E.
   Prognostic factors in gemcitabine-cisplatin polychemotherapy regimens in pancreatic cancer: XPD-Lys751Gln polymorphism strikes back
   Int J Cancer. 2013 Aug 15;133(4):1016-22
   Link: www.ncbi.nlm.nih.gov/pubmed/23390054
9. Frampton AE, Krell J, Giovannetti E, Krell D, Stebbing J, Castellano L, Jiao LR.
   Defining a prognostic molecular profile for ductal adenocarcinoma of the pancreas highlights known key signaling pathways
   Expert Rev Anticancer Ther. 2012 Oct;12(10):1275-8
   Link: www.ncbi.nlm.nih.gov/pubmed/23176615
10. Lee JH, Giovannetti E, Hwang JH, Petrini I, Wang Q, Voortman J, Wang Y, Steinberg SM, Funel N, Meltzer PS, Wang Y, Giaccone G.
    Loss of 18q22.3 involving the carboxypeptidase of glutamate-like gene is associated with poor prognosis in resected pancreatic cancer
    Clin Cancer Res. 2012 Jan 15;18(2):524-33
    Link: www.ncbi.nlm.nih.gov/pubmed/22128300
    Free pdf: click here
11. Giovannetti E, Pacetti P, Reni M, Leon LG, Mambrini A, Vasile E, Ghidini M, Funel N, Lucchesi M, Cereda S, Peters GJ, Cantore M.
    Association between DNA-repair polymorphisms and survival in pancreatic cancer patients treated with combination chemotherapy
    Pharmacogenomics. 2011 Dec;12(12):1641-52
    Link: www.ncbi.nlm.nih.gov/pubmed/22026922
12. Funel N, Giovannetti E, Pollina LE, del Chiaro M, Mosca F, Boggi U, Campani D.
    Critical role of laser microdissection for genetic, epigenetic and proteomic analyses in pancreatic cancer
    Expert Rev Mol Diagn. 2011 Sep;11(7):695-701
    Link: www.ncbi.nlm.nih.gov/pubmed/21902531
13. Funel N, Vasile E, Del Chiaro M, Boggi U, Falcone A, Campani D, Scarpa A, Giovannetti E.
    Correlation of basal EGFR expression with pancreatic cancer grading but not with clinical outcome after gemcitabine-based treatment
    Ann Oncol. 2011 Feb;22(2):482-4
    Link: www.ncbi.nlm.nih.gov/pubmed/21196439
14. Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, Orlandini C, Boggi U, Campani D, Del Chiaro M, Iannopollo M, Bevilacqua G, Mosca F, Danesi R.
    Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine
    Cancer Res. 2006 Apr 1;66(7):3928-35
    Link: www.ncbi.nlm.nih.gov/pubmed/16585222