High prevalence of mutantKRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients

Allenson, Kelvin; Castillo, Jonathan; Lucas, F Anthony San; Scélo, Ghislaine; Kim, D. U.; Bernard, Vincent; Davis, Gerard; Kumar, T.; Katz, Matthew H.G.; Overman, Michael J.; Foretová, Lenka; Fabiánovà, Eleonóra; Holcátová, Ivana; Janout, Vladimí­r; Meric‐Bernstam, Funda; Gascoyne, Peter R. C.; Wistuba, Ignacio I.; Varadhachary, Gauri R.; Brennan, Paul; Hanash, Samir M.; Li, D.; Maitra, Anirban; Alvarez, Hector A.

doi:10.1093/annonc/mdx004

Cited by 408 publications

(360 citation statements)

References 32 publications

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“…Most studies focus on the presence of ccfDNA mutations in one or two genes to compare their presence to clinical outcome [19, 20]. In our study, we sought to assess the mutation patterns in a broad set of genes to highlight tumor heterogeneity and demonstrate clonal evolution over the course of disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…Mutant KRAS ccfDNA was, however, found by others in 10 of 34 pancreatic patients (29%) [22] or in 136 of 188 (72.3%) of patients with metastatic PDAC [23]. Another study showed that mutant KRAS ccfDNA was detected in 14.8%, 45.5%, 30.8%, and 57.9% of age-matched controls, localized, locally advanced, and metastatic PDAC patients, respectively [20]. In circulating exosomal DNA the percentages of mutant KRAS in these groups were even higher, i.e.…”

Section: Discussionmentioning

confidence: 99%

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Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer

et al. 2017

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Cancer is a heterogeneous disease harboring diverse subclonal populations that can be discriminated by their DNA mutations. Environmental pressure selects subclones that ultimately drive disease progression and tumor relapse. Circulating cell-free DNA (ccfDNA) can be used to approximate the mutational makeup of cancer lesions and can serve as a marker for monitoring disease progression at the molecular level without the need for invasively acquired samples from primary or metastatic lesions. This potential for molecular analysis makes ccfDNA attractive for the study of clonal evolution and for uncovering emerging therapeutic resistance or sensitivity. We assessed ccfDNA from colon and pancreatic adenocarcinoma patients using next generation sequencing of 56 cancer-associated genes at the time of primary resectable disease and metastatic progression and compared this to the mutational patterns of the primary tumor. 28%-47% of non-synonymous mutations in the primary tumors were also detected in the ccfDNA whilst 71%-78% mutations found in ccfDNA were not detected in the primary tumors. ccfDNA collected at the time of progression harbored 3-5 new mutations not detected in ccfDNA at the earlier collection time points. We conclude that incorporation of ccfDNA analysis provides crucial insights into the changing molecular makeup of progressive colon and pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer

et al. 2017

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“…Allenson and coworkers, who compared exosome-derived DNA to cfDNA in liquid biopsies of patients with pancreatic ductal adenocarcinoma, found higher percentage of detectable KRAS mutations in exosome DNA than previously reported for cfDNA. They isolated exosomes using serial ultracentrifugation and characterized them with electron microscopy, flow cytometry and particle analysis [141]. Concerns of contamination of protein/RNA/membrane aggregates arising from similarities in sedimentation properties during high-speed ultracentrifugation, have prompted some protocols to use sucrose density gradients or adjusting the centrifugation duration in a "swinging bucket" or "fixedangle" rotor for efficient separation of the exosomes from the protein-or lipid-aggregates [142,143].…”

Section: Methods To Isolate and Identify Exosomesmentioning

confidence: 99%

Liquid biopsy - emergence of a new era in personalized cancer care

2018

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The most successful treatment for cancer involves identifying druggable, biological markers for targeted therapy. In the clinical setting, surgical removal of tumors is the only procedure for identifying such targetable molecules. Shed from tumor cells, these markers are also present in circulating blood, albeit in very negligible amounts. Liquid biopsy is a procedure performed on a blood sample to look for such circulating cancer markers cells or pieces of nucleic acid from the tumor. The procedure shows promise in revolutionizing personalized cancer treatments. Here we briefly review the technique, characterization, and its utilization in clinics.

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“…A well-established example is non-small-cell lung cancer where liquid biopsy can help in guiding the choice of suitable therapeutic regimens and are already included in the portfolio of routine clinical algorithms as of to date [90,91]. Apart from these applications, in pancreatic cancer, liquid biopsy techniques are thought to carry great potential for early detection and secondary prophylaxis [92,93,94]. …”

Section: Liquid Biopsymentioning

confidence: 99%

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

Feldmann¹

2018

Oncol Res Treat

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Pancreatic ductal adenocarcinoma (PDAC, pancreatic cancer) carries one of the poorest overall prognoses of all human malignancies known to date. Despite the introduction of novel therapeutic regimens, the outcome has not markedly improved over the past decades, the incidence rates are almost identical to the mortality rates, and PDAC is projected to soon become the second most common cause of cancer-related mortality in Western countries. Despite this clear medical need to develop novel therapeutic strategies against this dire malady, this need has so far not been addressed with sufficient institutional attention and support in terms of research funding and strategical programs. Given the still growing life expectancy and projected demographic changes with a growing proportion of senior citizens in many European societies, this discrepancy is likely to become even more pressing in the future. This article provides a brief overview of ongoing preclinical efforts to identify novel targets and, based on this, to develop novel strategies to treat advanced pancreatic cancer and improve survival and the quality of life of patients suffering from this malignancy.

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High prevalence of mutantKRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients

Cited by 408 publications

References 32 publications

Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer

Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer

Liquid biopsy - emergence of a new era in personalized cancer care

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

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