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Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer

Cancer treatment with a fluoropyrimidine (FP) is often accompanied by severe toxicity that may be dependent on the activity of catalytic enzymes encoded by the DPYD, DPYS, and UPB1 genes. Genotype‐guided dose individualization of FP therapy has been proposed in western countries, but our knowledge o...

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Autores principales: Yokoi, Katsuyuki, Nakajima, Yoko, Matsuoka, Hiroshi, Shinkai, Yasuko, Ishihara, Takuma, Maeda, Yasuhiro, Kato, Takema, Katsuno, Hidetoshi, Masumori, Koji, Kawada, Kenji, Yoshikawa, Tetsushi, Ito, Tetsuya, Kurahashi, Hiroki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469832/
https://www.ncbi.nlm.nih.gov/pubmed/32619063
http://dx.doi.org/10.1111/cas.14553
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author Yokoi, Katsuyuki
Nakajima, Yoko
Matsuoka, Hiroshi
Shinkai, Yasuko
Ishihara, Takuma
Maeda, Yasuhiro
Kato, Takema
Katsuno, Hidetoshi
Masumori, Koji
Kawada, Kenji
Yoshikawa, Tetsushi
Ito, Tetsuya
Kurahashi, Hiroki
author_facet Yokoi, Katsuyuki
Nakajima, Yoko
Matsuoka, Hiroshi
Shinkai, Yasuko
Ishihara, Takuma
Maeda, Yasuhiro
Kato, Takema
Katsuno, Hidetoshi
Masumori, Koji
Kawada, Kenji
Yoshikawa, Tetsushi
Ito, Tetsuya
Kurahashi, Hiroki
author_sort Yokoi, Katsuyuki
collection PubMed
description Cancer treatment with a fluoropyrimidine (FP) is often accompanied by severe toxicity that may be dependent on the activity of catalytic enzymes encoded by the DPYD, DPYS, and UPB1 genes. Genotype‐guided dose individualization of FP therapy has been proposed in western countries, but our knowledge of the relevant genetic variants in East Asian populations is presently limited. To investigate the association between these genetic variations and FP‐related high toxicity in a Japanese population, we obtained blood samples from 301 patients who received this chemotherapy and sequenced the coding exons and flanking intron regions of their DPYD, DPYS, and UPB1 genes. In total, 24 single nucleotide variants (15 in DPYD, 7 in DPYS and 2 in UPB1) were identified including 3 novel variants in DPYD and 1 novel variant in DPYS. We did not find a significant association between FP‐related high toxicity and each of these individual variants, although a certain trend toward significance was observed for p.Arg181Trp and p.Gln334Arg in DPYS (P = .0813 and .087). When we focused on 7 DPYD rare variants (p.Ser199Asn, p.IIe245Phe, p.Thr305Lys, p.Glu386Ter, p.Ser556Arg, p.Ala571Asp, p.Trp621Cys) which have an allele frequency of less than 0.01% in the Japanese population and are predicted to be loss‐of‐function mutations by in silico analysis, the group of patients who were heterozygous carriers of at least one these rare variants showed a strong association with FP‐related high toxicity (P = .003). Although the availability of screening of these rare loss‐of‐function variants is still unknown, our data provide useful information that may help to alleviate FP‐related toxicity in Japanese patients with cancer.
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spelling pubmed-74698322020-09-09 Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer Yokoi, Katsuyuki Nakajima, Yoko Matsuoka, Hiroshi Shinkai, Yasuko Ishihara, Takuma Maeda, Yasuhiro Kato, Takema Katsuno, Hidetoshi Masumori, Koji Kawada, Kenji Yoshikawa, Tetsushi Ito, Tetsuya Kurahashi, Hiroki Cancer Sci Original Articles Cancer treatment with a fluoropyrimidine (FP) is often accompanied by severe toxicity that may be dependent on the activity of catalytic enzymes encoded by the DPYD, DPYS, and UPB1 genes. Genotype‐guided dose individualization of FP therapy has been proposed in western countries, but our knowledge of the relevant genetic variants in East Asian populations is presently limited. To investigate the association between these genetic variations and FP‐related high toxicity in a Japanese population, we obtained blood samples from 301 patients who received this chemotherapy and sequenced the coding exons and flanking intron regions of their DPYD, DPYS, and UPB1 genes. In total, 24 single nucleotide variants (15 in DPYD, 7 in DPYS and 2 in UPB1) were identified including 3 novel variants in DPYD and 1 novel variant in DPYS. We did not find a significant association between FP‐related high toxicity and each of these individual variants, although a certain trend toward significance was observed for p.Arg181Trp and p.Gln334Arg in DPYS (P = .0813 and .087). When we focused on 7 DPYD rare variants (p.Ser199Asn, p.IIe245Phe, p.Thr305Lys, p.Glu386Ter, p.Ser556Arg, p.Ala571Asp, p.Trp621Cys) which have an allele frequency of less than 0.01% in the Japanese population and are predicted to be loss‐of‐function mutations by in silico analysis, the group of patients who were heterozygous carriers of at least one these rare variants showed a strong association with FP‐related high toxicity (P = .003). Although the availability of screening of these rare loss‐of‐function variants is still unknown, our data provide useful information that may help to alleviate FP‐related toxicity in Japanese patients with cancer. John Wiley and Sons Inc. 2020-07-20 2020-09 /pmc/articles/PMC7469832/ /pubmed/32619063 http://dx.doi.org/10.1111/cas.14553 Text en © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Yokoi, Katsuyuki
Nakajima, Yoko
Matsuoka, Hiroshi
Shinkai, Yasuko
Ishihara, Takuma
Maeda, Yasuhiro
Kato, Takema
Katsuno, Hidetoshi
Masumori, Koji
Kawada, Kenji
Yoshikawa, Tetsushi
Ito, Tetsuya
Kurahashi, Hiroki
Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer
title Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer
title_full Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer
title_fullStr Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer
title_full_unstemmed Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer
title_short Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer
title_sort impact of dpyd, dpys, and upb1 gene variations on severe drug‐related toxicity in patients with cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469832/
https://www.ncbi.nlm.nih.gov/pubmed/32619063
http://dx.doi.org/10.1111/cas.14553
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