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Targeted sequencing reveals genetic variants associated with sensitivity of 79 human cancer xenografts to anticancer drugs.

Abstract：

:Although there has been progress moving from a 'one-size-fits-all' cytotoxic approach to personalized molecular medicine, the majority of patients with cancer receive chemotherapy using cytotoxic anticancer drugs. The sequencing analysis of 409 genes associated with cancer was conducted in the present study using 59 DNA sequences extracted from human cancer xenografts implanted into nude mice, of which sensitivity to 9 cytotoxic anticancer drugs [5-fluorouracil, nimustine, adriamycin, cyclophosphamide, cisplatin, mitomycin C (MMC), methotrexate, vincristine (VCR), and vinblastine] was examined. The present study investigated the association between the sensitivities of the xenografts to the 9 anticancer drugs and the frequency of single nucleotide variants (SNV). The correlation between the expression level of the genes and sensitivities to the 9 drugs in the above xenografts was also estimated. In the screening study using 59 xenografts, 3 SNVs (rs1805321, rs62456182 in PMS1 Homolog 2, Mismatch Repair System Component and rs13382825 in LDL Receptor Related Protein 1B), were associated with sensitivity to VCR and MMC, respectively (P<0.001). A replication study of 596 SNVs was subsequently performed, which indicated P<0.05 in the screening study using independent samples of 20 xenografts. A combined result of the screening and replication studies indicated that 35 SNVs were potentially associated with sensitivities to one or more of the nine anticancer drugs (Pcombined=0.0011-0.035). Of the 35 SNVs, rs16903989 and rs201432181 in Leukemia Inhibitory Factor Receptor α and Adhesion G Protein-Coupled Receptor A2 were commonly associated with sensitivity to 2 or 4 anticancer drugs, respectively. These findings provide novel insights which may benefit the development of personalized anticancer therapy for patients with cancer in the future.

journal_name

Exp Ther Med

journal_title

Experimental and therapeutic medicine

authors

Udagawa C,Sasaki Y,Suemizu H,Ohnishi Y,Ohnishi H,Tokino T,Zembutsu H

doi

10.3892/etm.2017.5533

subject

Has Abstract

pub_date

2018-02-01 00:00:00

pages

1339-1359

issue

eissn

1792-0981

issn

1792-1015

pii

ETM-0-0-5533

journal_volume

pub_type

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Targeted sequencing reveals genetic variants associated with sensitivity of 79 human cancer xenografts to anticancer drugs.