Mutation analysis: DPD for 5-fluorouracil toxicity

Description: 
Polymorphic variants in the DPYD gene are associated with severe, sometimes fatal, toxicity to fluoropyrimidine therapy. The Purine Research Laboratory in Biochemical Sciences offers a DPYD panel of five variants as a diagnostic test to predict fluoropyrimidine toxicity.

The DPYD panel:
• rs3918290 c.1905+1G>A (DPYD*2A)
• rs67376798 c.2846A>T p.D949V
• rs55886062 c.1679T>G p.I560S
• rs56038477 c.1236G>A/HapB3
• rs1801158 c.1601G>A p.S534N
Clinical details: 
The fluoropyrimidine drugs capecitabine and 5-fluorouracil are widely used for the treatment of solid tumours, including colorectal and metastatic breast cancers. Pharmacogenetic variation in the DPYD gene is associated with early, severe toxicity to fluoropyrimidine therapy. Testing should be done prior to the start of therapy and the starting dose adjusted according to DPYD genotype.

Example report comments for heterozygous variant DPYD genotypes:

Wildtype
MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated comment.

No DPYD mutations were found. DPD deficiency is unlikely to be a cause of severe toxicity to fluoropyrimidine therapy. However, the presence of a rare variant which could cause toxicity cannot be excluded.

The patient was tested for the five DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).
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Heterozygous c.1905+1G>A.

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated comment.

CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is heterozygous for the variant DPYD c.1905+1G>A. A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses. Consider a starting dose of one half of the target dose or alternate therapy.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).

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Heterozygous c.1679T>G

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated comment.

CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is heterozygous for the variant DPYD c.1679T>G (p.I560S). A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses. Consider a starting dose of one half of the target dose or alternate therapy.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).

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Heterozygous c.2846A>T

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated dosing advice.

The patient is heterozygous for the variant DPYD c.2846A>T (p.D949V) and at risk of severe toxicity to fluoropyrimidine therapy at standard doses.

Consider a starting dose of one half of the target dose. If tolerant after the first cycle, dose increment to a maximum of three quarters of the target dose over subsequent cycles.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).
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Heterozygous c.1236G>A/HapB3

SUGGESTED UPDATES TO c.1236G>A/HapB3
MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated dosing advice.

The patient is heterozygous for the variant DPYD c.1236G>A/HapB3 and at risk of severe toxicity to fluoropyrimidine therapy at standard doses.

Consider a starting dose of one half of the target dose. If tolerant after the first cycle, dose increment to a maximum of three quarters of the target dose over subsequent cycles.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).


Heterozygous c.1601G>A

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated comment.

The patient is heterozygous for the variant DPYD c.1601G>A (p.S534N). Note that the evidence for the association of this variant with severe toxicity to fluoropyrimidine therapy is contradictory. Consider a starting dose of four fifths of the target dose. If tolerant after the first cycle, dose increment to the target dose.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).

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Homozygous and compound heterozygous genotypes


c.1236G>A/HapB3 / c.1905+1G>A

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated dosing advice.

CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1905+1G>A and c.1236G>A/HapB3.

Consider alternate therapy or if this is not possible, consider a starting dose of one tenth of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of one quarter of the target dose.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).
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c.2846A>T / c.1905+1G>A suggested update

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated dosing advice.

CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1905+1G>A and c.2846A>T (p.D949V).

Consider alternate therapy or if this is not possible, consider a starting dose of one tenth of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of one quarter of the target dose.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).

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c.1236G>A/HapB3 and c.2846A>T

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated dosing advice.

CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1236G>A/HapB3 and c.2846A>T (p.D949V).

Consider alternate therapy or if this is not possible, the patient may tolerate a very low fluoropyrimidine dose. Consider a starting dose of one tenth of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of one half of the target dose.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).

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c.1601G>A/ c.1905+1G>A

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated dosing advice.

CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1905+1G>A and c.1601G>A (p.S534N. Consider a starting dose of one third of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of one half of the target dose.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).

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c.2846A>T (p.D949V) HOMOZYGOUS

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated dosing advice.

CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is homozygous for the variant DPYD c.2846A>T (p.D949V). Consider alternate therapy or if this is not possible, the patient may tolerate a very low fluoropyrimidine dose. Consider a starting dose of one tenth of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of one half of the target dose.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).

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c.1601G>A/ c.1236G>A HapB3

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated dosing advice.

The patient is compound heterozygous for the variants DPYD c.1601G>A (p.S534N) and c.1236G>A/HapB3. This genotype is associated with partial DPD deficiency and early, severe toxicity to fluoropyrimidine therapy.

Consider reducing the starting dose to two fifths of the target dose. If tolerant after the first cycle, increase the dose in subsequent cycles to a maximum of three quarters of the target dose. Also consider an alternate therapy.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).

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c.2846A>T (p.D949V) and c.1601G>A

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY
Please note updated dosing advice.

The patient is compound heterozygous for the variants DPYD c.1601G>A (p.S534N) and c.2846A>T (p.D949V). This genotype is associated with partial DPD deficiency and early, severe toxicity to fluoropyrimidine therapy.

Consider reducing the starting dose to two fifths of the target dose. If tolerant after the first cycle, increase the dose in subsequent cycles to a maximum of three quarters of the target dose. Also consider an alternate therapy.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).


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HOMOZYGOUS c.1601G>A

MUTATION ANALYSIS – 5FLUOROURACIL TOXICITY

The patient is homozygous for the variant DPYD c.1601G>A (p.S534N). Consider a starting dose of one half of the target dose and if tolerant after the first cycle, titrate dose increases over subsequent cycles to three quarters of the target dose. Also consider an alternate therapy.

The patient was genotyped for the DPYD variants c.1905+1G>A, c.2846A>T (p.D949V), c.1679T>G (p.I560S), c.1236G>A/HapB3 and c.1601G>A (p.S534N).

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Reference range: 
XLS (460Kb)
Sample type and Volume required: 
3 mL blood EDTA (purple top)
Turnaround time: 
3 days
Storage and transport: 
Store in fridge, (don’t freeze) to lab within 5 days/1st class post
Contacts:
Purine Research Laboratory at St Thomas'
020 7188 1266
St Thomas’ Hospital
North Wing - 4th Floor
Westminster Bridge Road
London SE1 7EH
For clinical advice or interpretation of results, please contact the laboratory in the first instance.

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Last updated: 06/03/2020