Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer

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 circulat...

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Vydáno v:Cancer biology & therapy Ročník 18; číslo 3; s. 158 - 165
Hlavní autoři: 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
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Taylor & Francis 04.03.2017
Témata:
Case-Control Studies
Cell Line, Tumor
Circulating exosomal DNA
digital PCR
DNA - blood
DNA - genetics
DNA, Neoplasm - blood
DNA, Neoplasm - genetics
exosome
Exosomes - genetics
Humans
KRAS
liquid biopsy
Mutation
pancreatic cancer
Pancreatic Neoplasms - blood
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Polymerase Chain Reaction - methods
Proto-Oncogene Proteins p21(ras) - genetics
Research Paper
TP53
Tumor Suppressor Protein p53 - genetics
pancreatic cancer
Circulating exosomal DNA
digital PCR
KRAS
TP53
exosome
liquid biopsy
ISSN:1538-4047, 1555-8576, 1555-8576
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Shrnutí: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 KRAS G 12 D and TP53 R 273 H 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 KRAS G 12 D mutation in 39.6% of cases, and TP53 R 273 H mutation in 4.2% of cases. KRAS G 12 D and TP53 R 273 H mutations were also detected in exosomal DNA from IPMN patients (2 out of 7 with KRAS G 12 D , one of which also co-presented with TP53 R 273 H mutation). Circulating exosomal DNA in 5 out of 9 CP patients enabled the detection of KRAS G 12 D mutation. In 114 healthy subject-derived circulating exosomal DNA, 2.6% presented with KRAS G 12 D mutation and none with TP53 R 273 H 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.
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Supplemental data for this article can be accessed on the publisher's website.
These authors contributed equally to this work.
ISSN:1538-4047
1555-8576
1555-8576
DOI:10.1080/15384047.2017.1281499