Whole exome sequencing detects variants of genes that mediate response to anticancer drugs

Ohnami, Sumiko; Nagashima, Takeshi; Urakami, Kenichi; Shimoda, Yuji; Kamada, Fukumi; Saito, Junko; Naruoka, Akane; Serizawa, Masakuni; Masuda, Yoko; Ohnami, Shumpei; Kusuhara, Masatoshi; Yamaguchi, Ken

doi:10.2131/jts.42.137

Cited by 4 publications

(5 citation statements)

References 35 publications

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“…In this study, we systematically detected selected SNPs using whole-exome sequencing, theses variants were visually confirmed by Integrative Genomics Viewer. [17] Variants at the following 8 sites were investigated: the opioid m receptor 1 variant rs1799971, [18] the opioid d receptor 1 variant rs2234918, [19] the opioid k receptor 1 variant rs1051660, [20] the catechol-Omethyltransferase (COMT) variant rs4680, [21] the dopamine receptor D2 variant rs6275, [22] the P-glycoprotein adenosine triphosphate binding cassette B1 variant rs1045642, [23] the Gprotein regulated inward rectifier potassium channel 2 variant rs2070995, [24] and the fatty acid amide hydrolase variant rs324420. [25] Incidence of each adverse effect was compared between variants.…”

Section: Genetic Variantsmentioning

confidence: 99%

Influence of genetic variants of opioid-related genes on opioid-induced adverse effects in patients with lung cancer

et al. 2021

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Despite the dramatic advancement of cancer chemotherapy and immunotherapy, the insufficient progress has been made in basic or translational research on personalization of opioid therapy. Predicting the effectiveness of opioid analgesic therapy and the risk of adverse effects prior to therapy are expected to enable safer and more appropriate opioid therapy for cancer patients. In this study, we compared the incidence of opioid-induced adverse effects between patients with different variants of the genes related to responsiveness to opioid analgesics.Participants were 88 patients with lung cancer who provided general consent for exome sequencing and were treated with morphine or oxycodone at Shizuoka Cancer Center Hospital between April 2014 and August 2018. Incidence rates for 6 adverse effects of opioid therapy (somnolence, nausea, constipation, delirium, urinary retention, and pruritus) were determined and the influence of single nucleotide polymorphisms in coding regions of the opioid m receptor 1 (OPRM1) (rs1799971), opioid d receptor 1 (rs2234918), opioid k receptor 1 (rs1051660), catechol-O-methyltransferase (COMT) (rs4680), dopamine receptor D2 (rs6275), adenosine triphosphate binding cassette B1 (rs1045642), G-protein regulated inward rectifier potassium channel 2 (rs2070995), and fatty acid amide hydrolase (rs324420) genes on those adverse effects were analyzed.Analysis of OPRM1 gene variant status (Asn133Asp A > G) showed that G/G homozygotes were at significantly lower risk of somnolence compared with A allele carriers (0% vs 28.4%; Fisher exact test, P = .005; OR, 0; 95% CI, 0-0.6), and analysis of COMT gene variant status (Val158Met, G > A) showed that G/G homozygotes were at significantly higher risk of somnolence compared with A allele carriers (35.0% vs 10.4%; Fisher exact test, P = .008; OR, 4.5; 95% CI, 1.4-18.1). No relationship between variant status and adverse effects was found for the other genes.These findings demonstrate that OPRM1 and COMT gene variants influence the risk of somnolence as an adverse effect of opioid analgesic therapy.

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Section: Genetic Variantsmentioning

confidence: 99%

Influence of genetic variants of opioid-related genes on opioid-induced adverse effects in patients with lung cancer

et al. 2021

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“…We analyzed the genes encoding CYP isoforms ( CYP1A2 , CYP2A6 , CYP2B6 , CYP2C9 , CYP2C19 , CYP2D6, CYP2E1 , CYP3A4 , and CYP3A5 ), thiopurine methyltransferase ( TPMT ), dihydropyrimidine dehydrogenase ( DPYD ), N-acetyltransferase 2 ( NAT2 ), UDP glucuronosyltransferase family member A1 ( UGT1A1 ), catechol-O-methyltransferase ( COMT ), ATP binding cassette subfamily G member 2 ( ABCG2 ), cytidine deaminase ( CDA ), alcohol dehydrogenase 1B ( ADH1B ), aldehyde dehydrogenase 2 ( ALDH2 ), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase ( MTRR ), and methylenetetrahydrofolate reductase ( MTHFR ) in this study because the variants of these genes have been reported to affect drug response in Japanese populations 11 , 24 .…”

Section: Methodsmentioning

confidence: 99%

“…Widespread use of next-generation sequencing has enabled comprehensive investigation of genetic variants, such as drug-metabolizing enzymes, using whole-genome sequencing (WGS) and whole-exome sequencing (WES). However, genes with high homologies, such as CYP genes, still have unanalyzable genetic variants 11 , 12 . Therefore, we constructed a unique genetic variant panel that mainly covers the exon regions of 20 genes, including both lifestyle- and cancer-related genes, focusing on drug-metabolizing enzyme-coding genes that influence the therapeutic and adverse effects of anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

Comparison of genetic susceptibility to lung adenocarcinoma and squamous cell carcinoma in Japanese patients using a novel panel for cancer-related drug-metabolizing enzyme genes

Ohnami

Naruoka²,

Isaka³

et al. 2022

Sci Rep

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The differences in genetic susceptibility to lung adenocarcinoma and squamous cell carcinoma remain unclear. We developed a customized, targeted gene sequencing panel for efficient and sensitive identification of germline variants, including whole-gene deletion types for cancer-related drug-metabolizing enzyme genes in lung adenocarcinoma and squamous cell carcinoma. The minor allele frequencies of the variants, confirmed as clinically significant in the Japanese population, did not differ significantly from those of normal participants listed in the public database. Genotype analysis comparing lung adenocarcinoma (n = 559) and squamous cell carcinoma (n = 151) indicated that the variants of DPYD (rs190771411, Fisher’s exact test, P = 0.045; rs200562975, P = 0.045) and ALDH2 (rs568781254, P = 0.032) were associated with an increased risk of squamous cell carcinoma compared to adenocarcinoma. Conversely, whole-gene deletion of CYP2A6 was associated with adenocarcinoma but not squamous cell carcinoma. Notably, whole-gene deletion of CYP2A6 was confirmed in 22 patients with lung adenocarcinoma but not in any patients with squamous cell carcinoma. Most patients with whole-gene deletion of CYP2A6 were female non-smokers. The discovery of a whole-gene deletion of CYP2A6 in patients with lung adenocarcinoma may have an important role in clinical practice and advance our understanding of CYP2A6 germline variants and their association with carcinogenesis or their susceptibility to lung adenocarcinoma.

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“…We analyzed the genes encoding CYP isoforms ( CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5), thiopurine methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPYD), N-acetyltransferase 2 (NAT2), UDP glucuronosyltransferase family member A1 (UGT1A1), catechol-O-methyltransferase (COMT), ATP binding cassette subfamily G member 2 (ABCG2), cytidine deaminase (CDA), alcohol dehydrogenase 1B (ADH1B), aldehyde dehydrogenase 2 (ALDH2), 5methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), and methylenetetrahydrofolate reductase (MTHFR) in this study because the variants of these genes have been reported to affect drug response in Japanese populations 11,22 .…”

Section: Construction Of An In-house Custom Dme Panelmentioning

confidence: 99%

“…Widespread use of next-generation sequencing has enabled to comprehensively investigate genetic variants, such as drug-metabolizing enzymes, using whole-genome sequencing (WGS) and whole-exome sequencing (WES). However, genes with high homologies, such as CYP genes, still have unanalyzable genetic variants 11,12 . Therefore, we constructed a unique genetic variant panel that mainly covers the exon regions of 20 genes, including both lifestyle-and cancer-related genes, focusing on drugmetabolizing enzyme-coding genes that in uence the therapeutic and adverse effects of anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

Comparison of genetic susceptibility to lung adenocarcinoma and squamous cell carcinoma in Japanese patients using a novel panel for cancer-related drug- metabolizing enzyme genes

Ohnami

Naruoka

Mizuguchi

et al. 2022

Preprint

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The differences in genetic susceptibility to lung adenocarcinoma and squamous cell carcinoma are unclear. Hence, we developed a customized, targeted gene sequencing panel for efficient and sensitive identification of germline variants, including whole-gene deletion types for cancer-related drug-metabolizing enzyme genes in lung adenocarcinoma and squamous cell carcinoma. The minor allele frequencies of the variants, confirmed as clinically significant in the Japanese population, did not differ significantly from those of normal participants listed in the public database. Genotype analysis comparing lung adenocarcinoma (n = 559) and squamous cell carcinoma (n = 151) indicated that the variants of DPYD (rs190771411, Fisher’s exact test, P = 0.045; rs200562975, P = 0.045) and ALDH2 (rs568781254, P = 0.032) were associated with an increased risk of squamous cell carcinoma compared to adenocarcinoma. Conversely, whole-gene deletion of CYP2A6 was associated with adenocarcinoma but not squamous cell carcinoma. Notably, whole-gene deletion of CYP2A6 was confirmed in 22 patients with lung adenocarcinoma but in no patients with squamous cell carcinoma. The majority of patients with whole-gene deletion of CYP2A6 were female non-smokers. The discovery of a whole-gene deletion of CYP2A6 in patients with lung adenocarcinoma may have an important role in clinical practice and advance our understanding of CYP2A6 germline variants and their association with carcinogenesis or their susceptibility to lung adenocarcinoma.

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Whole exome sequencing detects variants of genes that mediate response to anticancer drugs

Cited by 4 publications

References 35 publications

Influence of genetic variants of opioid-related genes on opioid-induced adverse effects in patients with lung cancer

Influence of genetic variants of opioid-related genes on opioid-induced adverse effects in patients with lung cancer

Comparison of genetic susceptibility to lung adenocarcinoma and squamous cell carcinoma in Japanese patients using a novel panel for cancer-related drug-metabolizing enzyme genes

Comparison of genetic susceptibility to lung adenocarcinoma and squamous cell carcinoma in Japanese patients using a novel panel for cancer-related drug- metabolizing enzyme genes

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