TY - JOUR
T1 - Integrated genomic analysis of pancreatic ductal adenocarcinomas reveals genomic rearrangement events as significant drivers of disease
AU - Murphy, Stephen J.
AU - Hart, Steven N.
AU - Halling, Geoffrey C.
AU - Johnson, Sarah H.
AU - Smadbeck, James B.
AU - Drucker, Travis
AU - Lima, Joema Felipe
AU - Rohakhtar, Fariborz Rakhshan
AU - Harris, Faye R.
AU - Kosari, Farhad
AU - Subramanian, Subbaya
AU - Petersen, Gloria M.
AU - Wiltshire, Timothy D.
AU - Kipp, Benjamin R.
AU - Truty, Mark J.
AU - McWilliams, Robert R.
AU - Couch, Fergus J.
AU - Vasmatzis, George
N1 - Publisher Copyright:
© 2015 AACR. © 2016 American Association for Cancer Research.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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 lasercaptured 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.
AB - 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 lasercaptured 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.
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U2 - 10.1158/0008-5472.CAN-15-2198
DO - 10.1158/0008-5472.CAN-15-2198
M3 - Article
C2 - 26676757
AN - SCOPUS:84958212131
SN - 0008-5472
VL - 76
SP - 749
EP - 761
JO - Cancer research
JF - Cancer research
IS - 3
ER -