Frédéric Fina, Dominique Figarella-Branger, Marc Bartoli, Françoise Silvy, Eric Mas, Dominique Lombardo, Emmanuelle Martinez, Fabrice Barlesi, René Laugier, Martin Krahn, Juan L. Iovanna, Mehdi Ouaissi, Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Service d'Hepato-gastroentérologie, Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and MAS, Eric
// Emmanuelle Martinez 1, 2 , Francoise Silvy 1, 2 , Frederic Fina 1, 2, 3 , Marc Bartoli 4 , Martin Krahn 4, 5 , Fabrice Barlesi 1, 2, 6 , Dominique Figarella-Branger 1, 2, 7 , Juan Iovanna 8, 9, 10 , Rene Laugier 11 , Mehdi Ouaissi 1, 2, 12 , Dominique Lombardo 1, 2 , Eric Mas 1, 2 1 Aix-Marseille Universite, CRO2, Centre de Recherche en Oncologie biologique et Oncopharmacologie, F-13005, Marseille, France 2 INSERM, UMR_S 911, F-13005, Marseille, France 3 LBM- Assistance Publique Hopitaux de Marseille, Hopital Nord, Service de Transfert d’Oncologie Biologique, F-13015, Marseille, France 4 Aix-Marseille Universite, INSERM, UMR 910, F-13005, Marseille, France 5 Assistance Publique Hopitaux de Marseille, Hopital de la Timone-Enfants, Departement de Genetique Medicale, F-13005, Marseille, France 6 Assistance Publique Hopitaux de Marseille, Hopital Nord, Service d’Oncologie Multidisciplinaire & Innovation Therapeutique, F-13915, Marseille, France 7 Assistance Publique Hopitaux de Marseille, Hopital de la Timone, Service d’Anatomopathologie, F-13005, Marseille, France 8 Aix-Marseille Universite, CRCM, Centre de Recherche en Cancerologie de Marseille, F-13009, Marseille, France 9 INSERM, UMR_S 1068, F-13009, Marseille, France 10 CNRS, UMR 7258, F-13009, Marseille, France 11 Assistance Publique Hopitaux de Marseille, Hopital de la Timone, Service de Gastroenterologie, F-13005, Marseille, France 12 Assistance Publique Hopitaux de Marseille, Hopital de la Timone, Service de Chirurgie Digestive et Viscerale, F-13005, Marseille, France Correspondence to: Eric Mas, e-mail: eric.mas@univ-amu.fr Dominique Lombardo, e-mail: dominique.lombardo@univ-amu.fr Keywords: SNP, rs488087, pancreatic cancer Abbreviations: BSDL, bile-salt-dependent lipase; PDAC, pancreatic ductal adenocarcinoma; PC, pancreatic cancers Received: June 23, 2015 Accepted: October 05, 2015 Published: October 16, 2015 ABSTRACT Pancreatic cancer (PC) is a devastating disease progressing asymptomatically until death within months after diagnosis. Defining at-risk populations should promote its earlier diagnosis and hence also avoid its development. Considering the known involvement in pancreatic disease of exon 11 of the bile salt-dependent lipase (BSDL) gene that encodes variable number of tandem repeat (VNTR) sequences, we hypothesized upon the existence of a genetic link between predisposition to PC and mutations in VNTR loci. To test this, BSDL VNTR were amplified by touchdown-PCR performed on genomic DNA extracted from cancer tissue or blood samples from a French patient cohort and amplicons were Sanger sequenced. A robust method using probes for droplet digital (dd)-PCR was designed to discriminate the C/C major from C/T or T/T minor genotypes. We report that the c.1719C > T transition (SNP rs488087) present in BSDL VNTR may be a useful marker for defining a population at risk of developing PC (occurrence: 63.90% in the PC versus 27.30% in the control group). The odds ratio of 4.7 for the T allele was larger than those already determined for other SNPs suspected to be predictive of PC. Further studies on tumor pancreatic tissue suggested that a germline T allele may favor Kras G12R/G12D somatic mutations which represent negative prognostic factors associated with reduced survival. We propose that the detection of the T allele in rs488087 SNP should lead to an in-depth follow-up of patients in whom an association with other potential risk factors of pancreatic cancer may be present.