Influence of DPYD*9A, DPYD*6 and GSTP1 ile105val Genetic Polymorphisms on Capecitabine and Oxaliplatin (CAPOX) Associated Toxicities in Colorectal Cancer (CRC) Patients

K, Ashok Varma; Mathaiyan, Jayanthi; Dubashi, Biswajit; Shewade, Deepak Gopal

doi:10.31557/apjcp.2019.20.10.3093

Cited by 10 publications

(17 citation statements)

References 24 publications

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“…Significance: P < 0.05 are classified to not affect the DPD function in a clinically relevant manner in the context of 5-fluorouracil related toxicity [30]. Interestingly, in accordance with our results, recent reports have shown an association with severe toxicity and high levels of 5-FU post-treatment for DPYD-rs1801265 [92][93][94].…”

Section: Discussionsupporting

confidence: 90%

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer

et al. 2021

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Background Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity. Methods Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

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Section: Discussionsupporting

confidence: 90%

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer

et al. 2021

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“…As shown in Table 6, the pooling of Indian data of 5‐FU/capecitabine toxicity 11–16 with the present study showed a lack of association of rs1801265, rs1801159 and rs2297595 variants with FU‐mediated toxicity. The rs1801160, rs1801158 and rs3918290 variants showed a 1.88‐, 4.40‐ and 158.14‐fold increased risk for FU‐mediated toxicity in Indians.…”

Section: Resultssupporting

confidence: 44%

“…A few Indian studies have explored the association of DPYD variants with 5‐FU/capecitabine‐mediated toxicity 11–16,24 . Low DPYD expression was linked to unfavourable overall survival in colorectal cancer patients 24 .…”

Section: Discussionmentioning

confidence: 99%

“…Low DPYD expression was linked to unfavourable overall survival in colorectal cancer patients 24 . DPYD*9A (rs1801265) variant was found to increase the risk for the hand‐foot syndrome, diarrhea and thrombocytopenia following treatment with capecitabine and oxaliplatin in colorectal cancer 11 . Carriers of rs1801265, rs1801159 and rs1801160 variants exhibited severe mucositis and severe diarrhea following 5‐FU therapy in head and neck cancer 12 .…”

Section: Discussionmentioning

confidence: 99%

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Pharmacogenetic profiling of dihydropyrimidine dehydrogenase (DPYD) variants in the Indian population

Naushad¹,

Hussain

Alrokayan

et al. 2020

The Journal of Gene Medicine

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BackgroundThe present study aimed to delineate the pharmacologically relevant dihydropyrimidine dehydrogenase (DPYD) variants in the Indian population.MethodsWe screened 2000 Indian subjects for DPYD variants using the Infinium Global Screening Array (GSA) (Illumina Inc., San Diego, CA, USA).ResultsThe GSA analysis identified seven coding, two intronic and three synonymous DPYD variants. Level 1A alleles (rs75017182, rs3918290, P633Qfs*5 and D949V) were found to be rare (minor allele frequency: 1.889%), whereas Level 3 alleles were observed to be predominant (C29R: 24.91%, I543V: 9.047%, M166V: 8.993% and V732I: 8.44%). In silico predictions revealed that all Level 1A alleles were deleterious, whereas three (M166V, S534N and V732I) of seven Level 3 alleles were damaging. CUPSAT analysis revealed that two Level 1A (P633Qfs*, D949V) and three Level 3 (I543V, V732I and S534N) variants were thermolabile. The pooled Indian data showed that V732I, S534N and rs3918290 variants were associated with 5‐FU/capecitabine toxicity, whereas C29R, I543V and M166V variants exhibited the null association. A comparison of our data with other population data from the ‘Allele Frequency Aggregator’ (https://www.ncbi.nlm.nih.gov/snp/docs/gsr/alfa/) database showed similarities with the South Asian data.ConclusionsWe have identified four Level 1A (non‐functional/dysfunctional) and seven Level 3 variants in the DPYD gene. The pooled Indian data revealed the association of V732I, S534N and rs3918290 variants with 5‐FU/capecitabine toxicity. Clustering analysis revealed the similarities in the DPYD profiles of the Indian and South Asian populations.

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“…Despite this association, one of the suggested limitations for the lack of association in clinical studies may be due to the linkage disequilibrium observed with c.496A>G (rs2297595) and c.1129-5923C>G (rs75017182) (two candidate markers known as risk allele for 5- FU toxicity) [ 63 ], so further evaluation of these variants in the context of clinical outcomes is suggested. In light of the fact that 19.4% of the Ecuadorian population is a carrier of the polymorphic allele, it is important to carry out future studies to evaluate the side effects in carriers of this variant, especially considering the recent reports on toxicity in oncology patients [ 64 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Variations of the DPYD Gene and Its Relationship with Ancestry Proportions in Different Ecuadorian Trihybrid Populations

Farinango

Gallardo-Cóndor

Freire‐Paspuel

et al. 2022

JPM

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Dihydropyrimidine dehydrogenase is one of the main pharmacological metabolizers of fluoropyrimidines, a group of drugs widely used in clinical oncology. Around 20 to 30% of patients treated with fluoropyrimidines experience severe toxicity caused by a partial or total decrease in enzymatic activity. This decrease is due to molecular variants in the DPYD gene. Their prevalence and allelic frequencies vary considerably worldwide, so their description in heterogeneous groups such as the Ecuadorian population will allow for the description of pharmacogenetic variants and proper characterization of this population. Thus, we genotyped all the molecular variants with a predictive value for DPYD in a total of 410 Ecuadorian individuals belonging to Mestizo, Afro-Ecuadorian, and Indigenous ethnic groups. Moreover, we developed a genetic ancestry analysis using 46 autosomal ancestry informative markers. We determined 20 genetic variations in 5 amplified regions, including 3 novel single nucleotide variants. The allele frequencies for DPYD variants c.1627G>A (*5, rs1801159), c.1129-15T>C (rs56293913), c.1218G>A (rs61622928), rs1337752, rs141050810, rs2786783, rs2811178, and g.97450142G>A (chr1, GRCh38.p13) are significantly related to Native American and African ancestry proportions. In addition, the FST calculated from these variants demonstrates the closeness between Indigenous and Mestizo populations, and evidences genetic divergence between Afro-Ecuadorian groups when compared with Mestizo and Indigenous ethnic groups. In conclusion, the genetic variability in the DPYD gene is related to the genetic component of ancestral populations in different Ecuadorian ethnic groups. The absence and low frequency of variants with predictive value for fluoropyrimidine toxicity such as DPYD *2A, HapB3, and c.2846A>T (prevalent in populations with European ancestry) is consistent with the genetic background found.

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Influence of DPYD9A, DPYD6 and GSTP1 ile105val Genetic Polymorphisms on Capecitabine and Oxaliplatin (CAPOX) Associated Toxicities in Colorectal Cancer (CRC) Patients

Cited by 10 publications

References 24 publications

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer

Pharmacogenetic profiling of dihydropyrimidine dehydrogenase (DPYD) variants in the Indian population

Genetic Variations of the DPYD Gene and Its Relationship with Ancestry Proportions in Different Ecuadorian Trihybrid Populations

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