Influence of Genetic Variation in COMT on Cisplatin-Induced Nephrotoxicity in Cancer Patients
Abstract
:1. Introduction
2. Methods
2.1. Study Design
2.2. Classification of Endpoints and Adverse Events
2.3. DNA Isolation and TaqMan® Genotyping
2.4. Statistical Analysis
3. Results
3.1. Patients
3.2. Effect of COMT SNPs on Nephrotoxicity
4. Discussion
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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CTCAE | KDIGO | |||
---|---|---|---|---|
Grade | Serum creatinine | Stage | Serum creatinine | Urine output |
1 | 1.5–2.0 × baseline; OR ≥0.3 mg/dL (26.5 µmol/L) increase | 1 | 1.5–1.9 × baseline; OR ≥0.3 mg/dL (26.5 µmol/L | <0.5 mL/kg/h for 6–12 h |
2 | 2.0–3.0 × baseline | 2 | 2.0–2.9 × baseline | <0.5 mL/kg/h for ≥12 h |
3 | >3.0 × baseline; OR > 4.0 mg/dL (353.6 µmol/L) increase; OR Hospitalization indicated | 3 | 3.0 x baseline; OR ≥ 4.0 mg/dL (353.6 µmol/L) increase; OR Initiation of renal replacement therapy | <0.3 mL/kg/h for ≥24 h; OR anuria for ≥12 h |
4 | Life-threatening consequences; OR Dialysis indicated | |||
5 | Death |
Gene | rs number | Variant | Assay ID | WT | HT | HM | MAF | HW |
---|---|---|---|---|---|---|---|---|
COMT | rs4646316 | c.615 + 310C>T | C__29193982_10 | 316 | 204 | 31 | 24% | 0.80 |
rs9332377 | c.616-367C>T | C__29614343_10 | 400 | 140 | 11 | 15% | 0.76 | |
rs4680 | c.472G>A (Val158Met) | C__25746809_50 | 117 | 282 | 152 | 53% | 0.51 |
Characteristics | Controls, n = 524 | AKI grade 3 (n = 27) |
---|---|---|
Gender (n) | ||
- Male | 310 (59%) | 20 (74%) |
- Female | 214 (39%) | 7 (26%) |
Age (years) | ||
- Median (IQR) | 57 (45–65) | 62 (57–66) |
Primary tumour (n) | ||
- Pulmonary | 139 (27%) | 4 (15%) |
- Gastrointestinal | 121 (23%) | 2 (7%) |
- Testicular | 71 (14%) | 1 (4%) |
- Gynaecological | 66 (13%) | 3 (11%) |
- Head / neck | 56 (11%) | 14 (52%) |
- Other | 71 (14%) | 3 (11%) |
Baseline plasma creatinine concentrations | ||
- Median (IQR) (μmol/L) | 69 (59–81) | 70 (64-77) |
- Median (IQR) (mg/dL) | 0.78 (0.67–0.92) | 0.79 (0.72–0.87) |
eGFR | ||
- Median CKD-EPI (IQR) (mL/min) | 98 (85–106) | 95 (81–99) |
Peak creatinine concentrations | ||
- Median (IQR) (μmol/L) | 81 (69–96) | 131 (117–166) |
- Median (IQR) (mg/dL) | 0.92 (0.78–1.09) | 1.48 (1.32–1.88) |
eGFR | ||
- Median CKD-EPI (IQR) (mL/min) | 87 (70–99) | 44 (35–51) |
Dehydration as potential cause of AKI (n) | N/A | 25 (93%) |
Irreversible creatinine augmentation (n) | N/A | 4 (15%) |
Cisplatin dosage (n) | ||
- <50 mg/m2 | 119 (23%) | 10 (37%) |
- 50–79 mg/m2 | 298 (57%) | 12 (44%) |
- ≥ 80 mg/m2 | 107 (20%) | 5 (19%) |
Endpoint | Factor | Groups (AKI grade 3/patients) | Univariable | |
---|---|---|---|---|
OR ɣ (95% CI) | p-value | |||
AKI grade 3 | COMT (615+310C>T) | TT (4/31) vs CC + CT (23/520) | 3.201 (1.034-9.912) | 0.058 * |
COMT (616-367C>T) | CT + TT (2/151) vs CC (25/400) | 0.201 (0.047-0.861) | 0.014 * | |
COMT (1947G>A) | GA + AA (21/434) vs GG (6/117) | 1.063 (0.419-2.697) | 0.814 * | |
Age ≥ 65 | ≥65 (10/111) vs <65 (17/440) | 2.464 (1.095-5.542) | 0.025 | |
Dosage ≥ 80mg/m2 | ≥80 (7/112) vs <80 (20/439) | 1.397 (0.575-3.391) | 0.464 * | |
Gender | Male (20/310) vs Female (7/221) | 1.972 (0.820-4.746) | 0.159 * |
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Agema, B.C.; Koolen, S.L.W.; de With, M.; van Doorn, N.; Heersche, N.; Oomen-de Hoop, E.; Visser, S.; Aerts, J.G.J.V.; Bins, S.; van Schaik, R.H.N.; et al. Influence of Genetic Variation in COMT on Cisplatin-Induced Nephrotoxicity in Cancer Patients. Genes 2020, 11, 358. https://doi.org/10.3390/genes11040358
Agema BC, Koolen SLW, de With M, van Doorn N, Heersche N, Oomen-de Hoop E, Visser S, Aerts JGJV, Bins S, van Schaik RHN, et al. Influence of Genetic Variation in COMT on Cisplatin-Induced Nephrotoxicity in Cancer Patients. Genes. 2020; 11(4):358. https://doi.org/10.3390/genes11040358
Chicago/Turabian StyleAgema, Bram C., Stijn L.W. Koolen, Mirjam de With, Nadia van Doorn, Niels Heersche, Esther Oomen-de Hoop, Sabine Visser, Joachim G.J.V. Aerts, Sander Bins, Ron H.N. van Schaik, and et al. 2020. "Influence of Genetic Variation in COMT on Cisplatin-Induced Nephrotoxicity in Cancer Patients" Genes 11, no. 4: 358. https://doi.org/10.3390/genes11040358