Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer
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Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer. / Yang, Sujuan; Che, Sara P Y; Kurywchak, Paul; Tavormina, Jena L; Gansmo, Liv B; Correa de Sampaio, Pedro; Tachezy, Michael; Bockhorn, Maximilian; Gebauer, Florian; Haltom, Amanda R; Melo, Sonia A; LeBleu, Valerie S; Kalluri, Raghu.
in: CANCER BIOL THER, Jahrgang 18, Nr. 3, 04.03.2017, S. 158-165.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer
AU - Yang, Sujuan
AU - Che, Sara P Y
AU - Kurywchak, Paul
AU - Tavormina, Jena L
AU - Gansmo, Liv B
AU - Correa de Sampaio, Pedro
AU - Tachezy, Michael
AU - Bockhorn, Maximilian
AU - Gebauer, Florian
AU - Haltom, Amanda R
AU - Melo, Sonia A
AU - LeBleu, Valerie S
AU - Kalluri, Raghu
PY - 2017/3/4
Y1 - 2017/3/4
N2 - Pancreatic cancer presents with a dismal mortality rate and is in urgent need of methods for early detection with potential for timely intervention. All living cells, including cancer cells, generate exosomes. We previously discovered double stranded genomic DNA in exosomes derived from the circulation of pancreatic cancer patients, which enabled the detection of prevalent mutations associated with the disease. Here, we report a proof-of-concept study that demonstrates the potential clinical utility of circulating exosomal DNA for identification of KRASG12D and TP53R273H mutations in patients with pancreas-associated pathologies, including pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP) and intraductal papillary mucinous neoplasm (IPMN), and in healthy human subjects. In 48 clinically annotated serum samples from PDAC patients, digital PCR analyses of exosomal DNA identified KRASG12D mutation in 39.6% of cases, and TP53R273H mutation in 4.2% of cases. KRASG12D and TP53R273H mutations were also detected in exosomal DNA from IPMN patients (2 out of 7 with KRASG12D, one of which also co-presented with TP53R273H mutation). Circulating exosomal DNA in 5 out of 9 CP patients enabled the detection of KRASG12D mutation. In 114 healthy subject-derived circulating exosomal DNA, 2.6% presented with KRASG12D mutation and none with TP53R273H mutation. This study highlights the value of circulating exosomal DNA for a rapid, low-cost identification of cancer driving mutations. The identification of mutations in IPMN patients and healthy subjects suggests that liquid biopsies may allow potential assessment of cancer risk but with a cautionary note that detection of clinical cancer cannot be assumed.
AB - Pancreatic cancer presents with a dismal mortality rate and is in urgent need of methods for early detection with potential for timely intervention. All living cells, including cancer cells, generate exosomes. We previously discovered double stranded genomic DNA in exosomes derived from the circulation of pancreatic cancer patients, which enabled the detection of prevalent mutations associated with the disease. Here, we report a proof-of-concept study that demonstrates the potential clinical utility of circulating exosomal DNA for identification of KRASG12D and TP53R273H mutations in patients with pancreas-associated pathologies, including pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP) and intraductal papillary mucinous neoplasm (IPMN), and in healthy human subjects. In 48 clinically annotated serum samples from PDAC patients, digital PCR analyses of exosomal DNA identified KRASG12D mutation in 39.6% of cases, and TP53R273H mutation in 4.2% of cases. KRASG12D and TP53R273H mutations were also detected in exosomal DNA from IPMN patients (2 out of 7 with KRASG12D, one of which also co-presented with TP53R273H mutation). Circulating exosomal DNA in 5 out of 9 CP patients enabled the detection of KRASG12D mutation. In 114 healthy subject-derived circulating exosomal DNA, 2.6% presented with KRASG12D mutation and none with TP53R273H mutation. This study highlights the value of circulating exosomal DNA for a rapid, low-cost identification of cancer driving mutations. The identification of mutations in IPMN patients and healthy subjects suggests that liquid biopsies may allow potential assessment of cancer risk but with a cautionary note that detection of clinical cancer cannot be assumed.
KW - Case-Control Studies
KW - Cell Line, Tumor
KW - DNA/blood
KW - DNA, Neoplasm/blood
KW - Exosomes/genetics
KW - Humans
KW - Mutation
KW - Pancreatic Neoplasms/blood
KW - Polymerase Chain Reaction/methods
KW - Proto-Oncogene Proteins p21(ras)/genetics
KW - Tumor Suppressor Protein p53/genetics
U2 - 10.1080/15384047.2017.1281499
DO - 10.1080/15384047.2017.1281499
M3 - SCORING: Journal article
C2 - 28121262
VL - 18
SP - 158
EP - 165
JO - CANCER BIOL THER
JF - CANCER BIOL THER
SN - 1538-4047
IS - 3
ER -