TYMS 3′-UTR Polymorphism: A Novel Association with FOLFIRINOX-Induced Neurotoxicity in Pancreatic Cancer Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Assessment and Management of Chemotherapy Toxicity
2.3. Clinical Specimens and DNA Isolation
2.4. Control Samples
2.5. Sequencing
2.6. Oligonucleotide Probes, Primers, and Microarray Fabrication
2.7. Genotyping of DNA Samples by Hybridization on Microarrays
2.8. Image Acquisition and Processing
2.9. Validation of the Microarray
2.10. Statistical Analysis
3. Results
3.1. Design of Multiplex PCR
3.2. Microarray for Genotyping Analysis
3.3. Genotyping of Clinical Samples
3.3.1. Neurological Toxicity
3.3.2. Hematological Toxicity
3.3.3. Allele Frequencies
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Patient Characteristics | |
---|---|
Sex, n (%) | |
Male | 37 (47.4%) |
Female | 41 (52.6%) |
Median age, years (Range) | 59 (28–77) |
T stage, n (%) | |
T1–T2 | 7 (9.0%) |
T3 | 31 (39.7%) |
T4 | 40 (51.3%) |
Primary tumor diameter, mm | |
Median (Range) | 40 (0–115) |
Primary tumor site, n (%) | |
Pancreatic head | 41 (52.6%) |
Pancreatic body-tail | 37 (47.4%) |
CA 19-9, (IU/mL) | |
Median (Range) | 317 (1–51,878) |
Performance status (ECOG) | |
0–1 | 77 (98.7%) |
2 | 1 (1.3%) |
Extent of disease, n (%) | |
Resectable or borderline resectable | 9 (11.5%) |
Advanced and metastatic | 69 (88.5%) |
Indication for chemotherapy, n (%) | |
Induction with or w/o adjuvant | 40 (51.3%) |
Adjuvant | 1 (1.3%) |
First-line in metastatic setting | 37 (47.4%) |
Number of therapy cycles | |
Median (Range) | 6 (1–12) |
Cancellation reason, n (%) | |
Progressive disease | 14 (17.9%) |
Toxicity | 6 (7.7%) |
Completion of the scheduled number of cycles | 51 (65.4%) |
Patient refusal | 3 (14.1%) |
Other | 4 (5.1 %) |
Gene, rs ID Number | Type of Variation | Nucleotide (Amino Acid) Change | Consequence | Genotype Counts (Frequency) * | Allele Frequency * | |||
---|---|---|---|---|---|---|---|---|
AA | Aa | aa | A | a | ||||
DPYD, rs2297595 | SNV | T > C (Met166Val) | Initiator Codon Variant | 56 (0.72) | 22 (0.28) | 0 (0) | 0.86 | 0.14 |
DPYD, rs3918290 | SNV | G > A | Splice Donor Variant | 76 (0.97) | 2 (0.03) | 0 (0) | 0.99 | 0.01 |
DPYD, rs55886062 | SNV | A > C (Ile560Ser) | Missense Variant | 78 (1) | 0 (0) | 0 (0) | 1.00 | 0 |
DPYD, rs67376798 | SNV | T > A (Asp949Val) | Missense Variant | 78 (1) | 0 (0) | 0 (0) | 1.00 | 0 |
DPYD, rs75017182 | SNV | G > C | Intron Variant | 77 (0.99) | 1 (0.01) | 0 (0) | 0.99 | 0.01 |
ERCC1, rs3212986 | SNV | G > T (Gln506Lys) | 3 Prime UTR Variant | 39 (0.5) | 34 (0.44) | 5 (0.06) | 0.72 | 0.28 |
ERCC1, rs11615 | SNV | T > C (Asn118Asn) | Synonymous Variant | 27 (0.35) | 39 (0.5) | 12 (0.15) | 0.58 | 0.42 |
GSTP1, rs1695 | SNV | A > G (Ile105Val) | Missense Variant | 32 (0.41) | 31 (0.4) | 15 (0.19) | 0.61 | 0.39 |
MTHFR, rs1801133 | SNV | C > T (Ala222Val) | Missense Variant | 42 (0.54) | 27 (0.35) | 9 (0.12) | 0.71 | 0.29 |
TYMS, rs11280056 | 6 bp deletion | Insertion/ Deletion | 3 Prime UTR Variant | 37 (0.47) | 34 (0.44) | 7 (0.09) | 0.69 | 0.31 |
UGT1A1, rs3064744 | 2 bp insertion | Insertion/ Deletion | Insertion/Del Variation | 33 (0.42) | 35 (0.45) | 10 (0.13) | 0.65 | 0.35 |
XPC, rs2228001 | SNV | A > C (Lys939Gln) | Missense Variant | 27 (0.35) | 40 (0.51) | 11 (0.14) | 0.60 | 0.40 |
Toxicity | Genotype Counts (Frequency) | p-Value | ||
---|---|---|---|---|
TYMS rs11280056 | ||||
Neurological toxicity | ||||
nonDel/ nonDel | nonDel/Del | Del/Del | ||
Grade 1–2 Peripheral neuropathy (n = 25) | 9 (36%) | 10 (40%) | 6 (24%) | 0.0072 (co-dominant model) 0.0019 (recessive model) |
No AEs a (n = 53) | 28 (53%) | 24 (45%) | 1 (2%) | |
GSTP1 rs1695 | ||||
Hematological toxicity | ||||
AA | AG | GG | ||
Grade 3–4 leukopenia, neutropenia or thrombocytopenia b (n = 31) | 13 (42%) | 16 (52%) | 2 (6%) | 0.032 (co-dominant model), 0.014 (recessive model) |
No AEs (n = 47) | 19 (40%) | 15 (32%) | 13 (28%) |
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Emelyanova, M.; Pokataev, I.; Shashkov, I.; Kopantseva, E.; Lyadov, V.; Heydarov, R.; Mikhailovich, V. TYMS 3′-UTR Polymorphism: A Novel Association with FOLFIRINOX-Induced Neurotoxicity in Pancreatic Cancer Patients. Pharmaceutics 2022, 14, 77. https://doi.org/10.3390/pharmaceutics14010077
Emelyanova M, Pokataev I, Shashkov I, Kopantseva E, Lyadov V, Heydarov R, Mikhailovich V. TYMS 3′-UTR Polymorphism: A Novel Association with FOLFIRINOX-Induced Neurotoxicity in Pancreatic Cancer Patients. Pharmaceutics. 2022; 14(1):77. https://doi.org/10.3390/pharmaceutics14010077
Chicago/Turabian StyleEmelyanova, Marina, Ilya Pokataev, Igor Shashkov, Elena Kopantseva, Vladimir Lyadov, Rustam Heydarov, and Vladimir Mikhailovich. 2022. "TYMS 3′-UTR Polymorphism: A Novel Association with FOLFIRINOX-Induced Neurotoxicity in Pancreatic Cancer Patients" Pharmaceutics 14, no. 1: 77. https://doi.org/10.3390/pharmaceutics14010077
APA StyleEmelyanova, M., Pokataev, I., Shashkov, I., Kopantseva, E., Lyadov, V., Heydarov, R., & Mikhailovich, V. (2022). TYMS 3′-UTR Polymorphism: A Novel Association with FOLFIRINOX-Induced Neurotoxicity in Pancreatic Cancer Patients. Pharmaceutics, 14(1), 77. https://doi.org/10.3390/pharmaceutics14010077