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Title: Accurate diagnosis of mismatch repair deficiency in colorectal cancer using high-quality DNA samples from cultured stem cells
Authors: Yamaura, Tadayoshi
Miyoshi, Hiroyuki
Maekawa, Hisatsugu
Morimoto, Tomonori
Yamamoto, Takehito
Kakizaki, Fumihiko  kyouindb  KAKEN_id
Higasa, Koichiro
Kawada, Kenji
Matsuda, Fumihiko
Sakai, Yoshiharu
Taketo, M. Mark
Author's alias: 山浦, 忠能
三好, 弘之
前川, 久継
森本, 智紀
山本, 健人
柿崎, 文彦
日笠, 幸一郎
河田, 健二
松田, 文彦
坂井, 義治
武藤, 誠
Keywords: colorectal cancer
spheroid
cancer stem cell
molecular oncology
immunotherapy
Issue Date: 25-Dec-2018
Publisher: Impact Journals, LLC
Journal title: Oncotarget
Volume: 9
Issue: 101
Start page: 37534
End page: 37548
Abstract: Mismatch repair (MMR)-deficient or microsatellite instability (MSI) colorectal cancer includes two subtypes; Lynch syndrome and sporadic MSI cancer, both of which generate multiple neoantigens due to unrepaired mutations. Although such patients respond very well to immune checkpoint therapy, their diagnosis can be confused by low quality DNA samples owing to formalin fixation and/or low cancer cell content. Here we prepared high-quality DNA samples from in vitro-cultured cancer spheroids that consisted of the pure cell population. We evaluated their diagnostic power by on-chip electrophoresis, mutational burden assessment, and direct sequencing. Because formalin-fixed paraffin-embedded (FFPE) tissues are widely used as the DNA source, we compared such samples with spheroid DNA. Additionally, we performed immunohistochemistry (IHC) for MMR proteins on spheroids as well as primary tumor sections. Of 111 cases of colorectal cancer patients, we found seven MSI-high cases in which all diagnostic results agreed on spheroid-based assays, whereas the results with the FFPE DNA were less reliable though analyzable. Importantly, there was an MSS case that appeared as MSI by IHC on primary tumor sections. Based on these results, we propose to employ cultured cancer spheroids as the source of both DNA and IHC specimens for more reliable clinical diagnosis.
Rights: Yamaura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
URI: http://hdl.handle.net/2433/235914
DOI(Published Version): 10.18632/oncotarget.26495
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