Residency · Residency · Medical Genetics Genomics
Pharmacogenomics in Oncology: Germline Variants Affecting Chemotherapy
Introduction
Germline pharmacogenomic variants significantly influence the safety and efficacy of chemotherapy agents. Unlike somatic tumor profiling that guides targeted therapy selection, germline pharmacogenomics identifies inherited variants in drug-metabolizing enzymes, transporters, and drug targets that affect toxicity risk and optimal dosing of cytotoxic agents. These variants are present in every cell and testable from a blood sample before treatment begins.
DPYD and Fluoropyrimidines
Clinical Significance
Fluoropyrimidines (5-fluorouracil, capecitabine, tegafur) are among the most widely prescribed chemotherapy agents, used in colorectal, breast, gastric, head and neck, and pancreatic cancers. Dihydropyrimidine dehydrogenase (DPD), encoded by DPYD, is the rate-limiting enzyme in fluoropyrimidine catabolism, responsible for degrading more than 80% of administered 5-FU. DPD deficiency leads to severe, potentially fatal toxicity including neutropenia, mucositis, diarrhea, and neurotoxicity. The incidence of severe toxicity is approximately 10-30% of patients receiving standard-dose fluoropyrimidines, with fatal toxicity in approximately 0.1-0.5%.
Key Variants
DPYD2A (c.1905+1G>A, rs3918290) is a splice site variant causing exon skipping with complete loss of function and approximately 1-2% carrier frequency in Europeans. DPYD c.1679T>G (rs55886062, 13) is a missense variant with significantly reduced enzyme activity. DPYD c.2846A>T (rs67376798) is a missense variant with reduced activity. DPYD c.1236G>A/HapB3 (rs56038477) is an intronic variant affecting splicing with reduced activity. An activity score system assigns each allele a value of 0 (no function), 0.5 (decreased function), or 1 (normal function).
Clinical Guidelines
The CPIC guideline recommends 50% dose reduction for activity score 1.0-1.5 (intermediate metabolizers) and avoidance of fluoropyrimidines or markedly reduced dose with therapeutic drug monitoring for activity score 0-0.5 (poor metabolizers). The EMA mandated DPYD testing before fluoropyrimidine administration in the EU in 2020. The FDA warns about DPD deficiency in drug labeling but has not mandated preemptive testing. DPD phenotyping via uracil levels or dihydrouracil/uracil ratio can complement genotyping.
TPMT, NUDT15, and Thiopurines
Thiopurine Metabolism
Thiopurines (6-mercaptopurine, azathioprine, thioguanine) are used in ALL, IBD, autoimmune diseases, and transplant immunosuppression. TPMT (thiopurine S-methyltransferase) and NUDT15 are key enzymes in thiopurine metabolism. Deficiency leads to accumulation of active thioguanine nucleotides (TGN), causing life-threatening myelosuppression.
TPMT Variants
TPMT3A (the most common variant in Europeans with approximately 5% carrier frequency) involves two missense variants causing protein degradation. TPMT3C (the most common variant in East Asian and African populations) is a single missense variant. Homozygous or compound heterozygous loss-of-function affects approximately 0.3% of the population and requires 10% of standard dose or an alternative agent. Heterozygous carriers comprise approximately 10% of the population and typically require 30-70% dose reduction.
NUDT15 Variants
NUDT15*3 (c.415C>T, p.Arg139Cys) is the most important variant, with a frequency of approximately 10% in East Asians, approximately 2% in Hispanics, and rare in Europeans. NUDT15 poor metabolizers are at extremely high risk of thiopurine-induced leukopenia. The CPIC guideline now incorporates both TPMT and NUDT15 for thiopurine dosing, with combined genotyping capturing risk across diverse populations.
UGT1A1 and Irinotecan
Irinotecan (a topoisomerase I inhibitor) is used in colorectal, pancreatic, and other cancers. Its active metabolite SN-38 is glucuronidated by UGT1A1 for elimination. UGT1A128 (a TA repeat polymorphism in the promoter with 7 repeats versus the normal 6) results in reduced UGT1A1 expression. Homozygous 28/28 (the Gilbert syndrome genotype) increases risk of severe neutropenia and diarrhea, with a frequency of approximately 10-15% in Europeans. UGT1A16 is a reduced-function coding variant important in East Asian populations (15-25% allele frequency). FDA labeling recommends considering reduced starting dose for UGT1A1*28 homozygotes.
| Gene | Drug(s) | Toxicity in Deficient Patients | Key Variants | Guideline Recommendation |
|---|---|---|---|---|
| DPYD | 5-FU, capecitabine | Severe neutropenia, mucositis, diarrhea; potentially fatal | *2A, c.1679T>G, c.2846A>T, HapB3 | 50% dose reduction (IM); avoid or very low dose (PM); EMA mandates testing |
| TPMT | 6-MP, azathioprine, thioguanine | Life-threatening myelosuppression | 3A, 3C, *2 | Dose reduce 30–70% (heterozygous); 10% dose or alternative (homozygous) |
| NUDT15 | 6-MP, azathioprine | Severe leukopenia | *3 (p.Arg139Cys) | Combined with TPMT for dosing; especially important in East Asians |
| UGT1A1 | Irinotecan | Severe neutropenia, diarrhea | 28 (TA repeat), 6 | Reduce dose for 28/28; consider *6 in East Asians |
| CYP2D6 | Tamoxifen | Reduced efficacy (low endoxifen) | Multiple (4, 5, *10, etc.) | Alternative endocrine therapy for PM; avoid CYP2D6 inhibitors |
CYP2D6 and Tamoxifen
Tamoxifen is a selective estrogen receptor modulator used in hormone receptor-positive breast cancer. CYP2D6 converts tamoxifen to its most potent active metabolite, endoxifen. CYP2D6 poor metabolizers have significantly lower endoxifen levels. Several studies link CYP2D6 PM status to higher recurrence rates, though results have been debated. The CPIC guideline recommends alternative endocrine therapy (aromatase inhibitor, or higher-dose tamoxifen with endoxifen monitoring) for CYP2D6 poor metabolizers. Importantly, CYP2D6 inhibitor drugs (paroxetine, fluoxetine, bupropion) should be avoided with tamoxifen as they can phenocopy a poor metabolizer state.
Additional Oncology Pharmacogenes
SLCO1B1 and Methotrexate
SLCO1B1 encodes the hepatic uptake transporter OATP1B1. Variants (particularly rs4149056 and rs11045879) are associated with delayed methotrexate clearance and increased toxicity risk in pediatric ALL. CPIC guidelines provide dosing adjustments based on SLCO1B1 genotype.
CYP2B6 and Cyclophosphamide
CYP2B6 is involved in cyclophosphamide activation. Polymorphisms may affect drug activation and toxicity, though clinical guidelines are less established than for other gene-drug pairs.
G6PD Deficiency and Rasburicase
Rasburicase (recombinant urate oxidase), used for tumor lysis syndrome, generates hydrogen peroxide. It is contraindicated in G6PD deficiency due to risk of severe hemolytic anemia and methemoglobinemia. G6PD testing should be performed before rasburicase administration, especially in populations with high G6PD deficiency prevalence.
Implementation in Oncology Practice
Pretreatment PGx panels covering DPYD, TPMT, NUDT15, UGT1A1, and CYP2D6 can be run from a single blood sample, with results available before the first cycle of chemotherapy. Therapeutic drug monitoring (TDM) complements genotyping for drugs with measurable active metabolites. Pharmacogenomics should be distinguished from somatic tumor profiling, which identifies targetable mutations in the tumor. Integration into multidisciplinary tumor boards optimizes treatment planning.
Clinical Pearls
DPYD testing before fluoropyrimidine chemotherapy can prevent fatal toxicity and is mandated in the EU; advocacy for preemptive testing continues in the US. NUDT15 genotyping is essential for safe thiopurine dosing in East Asian and Hispanic populations, complementing TPMT testing which was developed primarily in European cohorts. CYP2D6 inhibitor drugs (particularly SSRIs) co-prescribed with tamoxifen can phenocopy a poor metabolizer genotype, making drug interaction review critical. Germline pharmacogenomics and somatic tumor profiling serve distinct purposes: the former guides toxicity avoidance and dosing, while the latter guides targeted therapy selection.
References
- Amstutz U, Henricks LM, Offer SM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clinical Pharmacology & Therapeutics. 2018;103(2):210-216.
- Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clinical Pharmacology & Therapeutics. 2019;105(5):1095-1105.
- Goetz MP, Sangkuhl K, Guchelaar HJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and tamoxifen therapy. Clinical Pharmacology & Therapeutics. 2018;103(5):770-777.
- Henricks LM, Lunenburg CATC, de Man FM, et al. DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncology. 2018;19(11):1459-1467.