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
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
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
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
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 genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Heterozygous DPYD c.1905+1G>A.
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
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 50% dose reduction or alternate therapy. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Heterozygous c.2846A>T p.(Asp949Val)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
The patient is heterozygous for the variant DPYD c.2846A>T p.(Asp949Val). A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles. If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% may be possible, but caution is advised.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Heterozygous c.1679T>G p.(Ile560Ser).
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is heterozygous for the variant DPYD c.1679T>G p.(Ile560Ser). A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction or alternative therapy. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Heterozygous c.1236G>A/HapB3
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
The patient is heterozygous for the variant DPYD c.1236G>A/HapB3. A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles. If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% may be possible, but caution is advised.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Homozygous and compound heterozygous genotypes
c.1236G>A/HapB3 / c.1905+1G>A
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
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 (raltitexed or trifluridine/tipiracil). Centres with expertise and therapeutic drug monitoring may consider a starting dose of 10% of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of 25% of the target dose.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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c.2846A>T / c.1905+1G>A
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1905+1G>A and c.2846A>T p.(Asp949Val).
Consider alternate therapy (raltitexed or trifluridine/tipiracil). Centres with expertise and therapeutic drug monitoring may consider a starting dose of 10% of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of 25% of the target dose.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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c.1236G>A/HapB3 and c.2846A>T
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1236G>A/HapB3 and c.2846A>T p.(Asp949Val).
Consider alternate therapy (raltitexed or trifluridine/tipiracil). Centres with expertise and therapeutic drug monitoring may consider 10% of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of 50% of the target dose.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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c.2846A>T p.(Asp949Val) HOMOZYGOUS
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is homozygous for the variant DPYD c.2846A>T p.Asp949Val).
Consider alternate therapy (raltitexed or trifluridine/tipiracil). Centres with expertise and therapeutic drug monitoring may consider 10% of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of 50% of the target dose.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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c.1236G>A/HapB3 HOMOZYGOUS
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is homozygous for the variant DPYD c.1236G>A/HapB3.
Consider alternate therapy (raltitexed or trifluridine/tipiracil). Centres with expertise and therapeutic drug monitoring may consider 10% of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of 50% of the target dose.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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c.1905+1G>A HOMOZYGOUS
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is homozygous for the variant DPYD c.1905+1G>A. A homozygous genotype is associated with complete DPD deficiency and extremely severe, usually fatal toxicity to fluoropyrimidine therapy.
Do not use fluoropyrimidine therapy. Consider raltitrexed or trifluridine/tipiracil.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Example report comments for heterozygous variant DPYD genotypes:
Wildtype
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
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 genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Heterozygous DPYD c.1905+1G>A.
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
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 50% dose reduction or alternate therapy. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Heterozygous c.2846A>T p.(Asp949Val)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
The patient is heterozygous for the variant DPYD c.2846A>T p.(Asp949Val). A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles. If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% may be possible, but caution is advised.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Heterozygous c.1679T>G p.(Ile560Ser).
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is heterozygous for the variant DPYD c.1679T>G p.(Ile560Ser). A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction or alternative therapy. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Heterozygous c.1236G>A/HapB3
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
The patient is heterozygous for the variant DPYD c.1236G>A/HapB3. A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles. If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% may be possible, but caution is advised.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Homozygous and compound heterozygous genotypes
c.1236G>A/HapB3 / c.1905+1G>A
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
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 (raltitexed or trifluridine/tipiracil). Centres with expertise and therapeutic drug monitoring may consider a starting dose of 10% of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of 25% of the target dose.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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c.2846A>T / c.1905+1G>A
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1905+1G>A and c.2846A>T p.(Asp949Val).
Consider alternate therapy (raltitexed or trifluridine/tipiracil). Centres with expertise and therapeutic drug monitoring may consider a starting dose of 10% of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of 25% of the target dose.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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c.1236G>A/HapB3 and c.2846A>T
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1236G>A/HapB3 and c.2846A>T p.(Asp949Val).
Consider alternate therapy (raltitexed or trifluridine/tipiracil). Centres with expertise and therapeutic drug monitoring may consider 10% of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of 50% of the target dose.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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c.2846A>T p.(Asp949Val) HOMOZYGOUS
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is homozygous for the variant DPYD c.2846A>T p.Asp949Val).
Consider alternate therapy (raltitexed or trifluridine/tipiracil). Centres with expertise and therapeutic drug monitoring may consider 10% of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of 50% of the target dose.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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c.1236G>A/HapB3 HOMOZYGOUS
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is homozygous for the variant DPYD c.1236G>A/HapB3.
Consider alternate therapy (raltitexed or trifluridine/tipiracil). Centres with expertise and therapeutic drug monitoring may consider 10% of the target dose. If tolerant after the first cycle, titrate dose increases against toxicity over subsequent cycles to a maximum of 50% of the target dose.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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c.1905+1G>A HOMOZYGOUS
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is homozygous for the variant DPYD c.1905+1G>A. A homozygous genotype is associated with complete DPD deficiency and extremely severe, usually fatal toxicity to fluoropyrimidine therapy.
Do not use fluoropyrimidine therapy. Consider raltitrexed or trifluridine/tipiracil.
The patient was genotyped for the DPYD variants c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) and c.1236G>A/HapB3 p.(Glu412=) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies, July 2020.
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Department:
Location:
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
North Wing - 4th Floor
Westminster Bridge Road
London SE1 7EH
Laboratory:
Last updated: 04/10/2022
