title: Integrated Genomic Analysis of Pancreatic Ductal Adenocarcinomas Reveals Genomic Rearrangement Events as Significant Drivers of Disease.
abstract: Many somatic mutations have been detected in pancreatic ductal adenocarcinoma (PDAC), leading to the identification of some key drivers of disease progression, but the involvement of large genomic rearrangements has often been overlooked. In this study, we performed mate pair sequencing (MPseq) on genomic DNA from 24 PDAC tumors, including 15 laser-captured microdissected PDAC and 9 patient-derived xenografts, to identify genome-wide rearrangements. Large genomic rearrangements with intragenic breakpoints altering key regulatory genes involved in PDAC progression were detected in all tumors. SMAD4, ZNF521, and FHIT were among the most frequently hit genes. Conversely, commonly reported genes with copy number gains, including MYC and GATA6, were frequently observed in the absence of direct intragenic breakpoints, suggesting a requirement for sustaining oncogenic function during PDAC progression. Integration of data from MPseq, exome sequencing, and transcriptome analysis of primary PDAC cases identified limited overlap in genes affected by both rearrangements and point mutations. However, significant overlap was observed in major PDAC-associated signaling pathways, with all PDAC exhibiting reduced SMAD4 expression, reduced SMAD-dependent TGFβ signaling, and increased WNT and Hedgehog signaling. The frequent loss of SMAD4 and FHIT due to genomic rearrangements strongly implicates these genes as key drivers of PDAC, thus highlighting the strengths of an integrated genomic and transcriptomic approach for identifying mechanisms underlying disease initiation and progression.
authors.affiliation: Department of Biomarker Discovery, Center for Individualized Medicine, Rochester, Minnesota. Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Murphy
authors.affiliation: Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hart
authors.affiliation: Department of Biomarker Discovery, Center for Individualized Medicine, Rochester, Minnesota. Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Halling
authors.affiliation: Department of Biomarker Discovery, Center for Individualized Medicine, Rochester, Minnesota. Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Johnson
authors.affiliation: Department of Biomarker Discovery, Center for Individualized Medicine, Rochester, Minnesota. Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: James B
authors.initials: JB
authors.lastname: Smadbeck
authors.affiliation: Department of Biomarker Discovery, Center for Individualized Medicine, Rochester, Minnesota.
authors.forename: Travis
authors.initials: T
authors.lastname: Drucker
authors.affiliation: Department of Biomarker Discovery, Center for Individualized Medicine, Rochester, Minnesota.
authors.forename: Joema Felipe
authors.initials: JF
authors.lastname: Lima
authors.affiliation: Medical Genomics Facility, Mayo Clinic, Rochester, Minnesota.
authors.forename: Fariborz Rakhshan
authors.initials: FR
authors.lastname: Rohakhtar
authors.affiliation: Department of Biomarker Discovery, Center for Individualized Medicine, Rochester, Minnesota. Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Faye R
authors.initials: FR
authors.lastname: Harris
authors.affiliation: Department of Biomarker Discovery, Center for Individualized Medicine, Rochester, Minnesota. Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Farhad
authors.initials: F
authors.lastname: Kosari
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Subbaya
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Wiltshire
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Kipp
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Truty
authors.affiliation: Department of Oncology, Mayo Clinic Rochester, Minnesota.
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
authors.affiliation: Health Sciences Research, Mayo Clinic, Rochester, Minnesota. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. vasmatzis.george@mayo.edu couch.fergus@mayo.edu.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Department of Biomarker Discovery, Center for Individualized Medicine, Rochester, Minnesota. Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota. vasmatzis.george@mayo.edu couch.fergus@mayo.edu.
authors.forename: George
authors.initials: G
authors.lastname: Vasmatzis
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D023281:Genomics / Q000379:methods; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction