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Research Papers:

Target amplicon exome-sequencing identifies promising diagnosis and prognostic markers involved in RTK-RAS and PI3K-AKT signaling as central oncopathways in primary central nervous system lymphoma

Yasuo Takashima, Yasushi Sasaki, Azusa Hayano, Jumpei Homma, Junya Fukai, Yasuo Iwadate, Koji Kajiwara, Shin Ishizawa, Hiroaki Hondoh, Takashi Tokino and Ryuya Yamanaka _

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Oncotarget. 2018; 9:27471-27486. https://doi.org/10.18632/oncotarget.25463

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Abstract

Yasuo Takashima1, Yasushi Sasaki2, Azusa Hayano1, Jumpei Homma3, Junya Fukai4, Yasuo Iwadate5, Koji Kajiwara6, Shin Ishizawa7, Hiroaki Hondoh3, Takashi Tokino8 and Ryuya Yamanaka1

1Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

2Center for Medical Education, Sapporo Medical University, Sapporo, Japan

3Department of Neurosurgery, Toyama Prefectural Central Hospital, Toyama, Japan

4Department of Neurological Surgery, Wakayama Medical University School of Medicine, Wakayama, Japan

5Department of Neurosurgery, Graduate School of Medical Sciences, Chiba University, Chiba, Japan

6Department of Neurosurgery, Graduate School of Medical Sciences, Yamaguchi University, Ube, Yamaguchi, Japan

7Department of Pathology, Toyama Prefectural Central Hospital, Toyama, Japan

8Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan

Correspondence to:

Ryuya Yamanaka, email: ryaman@koto.kpu-m.ac.jp

Keywords: primary central nervous system lymphoma; somatic mutation; copy number variation; RAS signaling; prognosis

Received: February 21, 2018    Accepted: May 02, 2018    Published: June 08, 2018

ABSTRACT

Exome-sequencing for somatic mutation detection and copy number variation analysis are effective and valid methods for evaluating human cancers in current molecular medicine. We conducted target amplicon exome-sequencing analyses using PCR target enrichment and next-generation sequencing on Ion Proton semiconductor sequencers. Twenty-seven primary central nervous system lymphoma (PCNSL) specimens and their corresponding noncancerous tissues were used for multiplex PCR amplification to obtain targeted coverages of the entire coding regions of 409 cancer-related genes. The average of the total numbers of somatic mutations including single-nucleotide variations and insertion/deletion mutations in each specimen was 13.3. Of these, the average of the ratios of nonsynonymous substitutions in each specimen was 74.8%. The most frequent mutations in 27 specimens were in PIM1, MYD88, CD79B, DST, IRF4, ERBB3, MYH11, DCC, and KMT2D. Furthermore, somatic mutations of MYH11 were related to poor prognoses in PCNSL patients. Copy number variations were also duplicated and/or deleted from deep-sequencing in segmental genomic islands. In addition to these prognostic marker candidates, analysis of RTK-RAS-MAPK signaling and the PTEN-PI3K-AKT proapoptotic pathway showed that somatic activations and aberrations, respectively, may be involved in a promising central oncopathway harboring mTOR, c-Myc, FOXO1, and p53. This study provides a foundation for molecular targeted therapies based on genome diagnostics and prognosis in PCNSL.


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