Wednesday, August 14, 2019

Pilot study from Genomics England to report on DPYD variants

A pilot study from Genomics England is now reporting back DPYD variants in cancer patients as part of the 100,000 Genomes Project.

The DPYD protein is responsible for degrading fluoropyrimidine drugs, which include 5-fluorouracil and capecitabine. These drugs are commonly used in the treatment of cancer. Decreased activity of the DPYD protein is associated with an increased risk for severe or fatal toxicity from standard doses of fluoropyrimidine drugs. Guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommend reducing the starting dose of fluorouracil and capecitabine in patients with decreased DPYD activity, and avoiding use of the drugs in patients with absent DPYD activity.

For cancer patients recruited into the 100,000 Genomes Project, Genomics England is prospectively analyzing germline whole genome sequence (WGS) data for the presence of the rs3918290 (1905+1G>A; DPYD*2A), rs55886062 (1679T>G; DPYD*13), rs67376798 (2846A>T) and rs56038477/rs75017182 (1236G>A/1129-5923C>G; haplotype B3) variants. rs3918290 and rs55886062 are associated with absent DPYD activity, while rs67376798 and rs56038477/rs75017182 confer decreased DPYD activity. If any of these DPYD variants are discovered in the analysis, the genome analysis report for those variants includes a link out to the PharmGKB website for more information.

The WGS results are made available to Genomic Medicine Centres, allowing clinicians to assess whether adjusting treatment regimens may help reduce toxicity risk. Feedback on any actions taken by clinicians will be recorded and analyzed to determine the clinical effectiveness of reporting these variants within the National Health Service (NHS). The program aims to demonstrate how WGS results can help cancer patients receive effective treatment with a lower risk for severe toxicity.

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Read the Genomics England blogpost
Read the CPIC guideline for fluoropyrimidines and DPYD

Monday, July 29, 2019

PharmCAT article published in Clinical Pharmacology & Therapeutics

The article describing the Pharmacogenomics Clinical Annotation Tool (PharmCATand a pilot validation using GeT-RM samples was recently published in Clinical Pharmacology & Therapeutics
PharmCAT (1) extracts variants specified in guidelines from a genetic dataset derived from sequencing or genotyping technologies; (2) infers haplotypes and diplotypes; and (3) generates a report containing genotype/diplotype-based annotations and guideline recommendations. 
In this initial version, the tool only considers variants contained in the allele definition files, which are based on CPIC guidelines and provides CPIC recommendations in the output. PharmCAT assumes the sample VCF file has already undergone extensive quality control. Requirements for the VCF files are accessible in GitHub.
PharmCAT was highly concordant with the GeT-RM data and discordant results are discussed in detail in the article and supplemental material [add link to journal or to PharmCAT.org, if we post it there].

Seeking community input and testing. With this initial beta release of PharmCAT, the pharmacogenomics community is asked to support the continuing evaluation of this freely available tool by running VCF samples, documenting issues and successfully identifying variants. GitHub can be used to communicate feedback. 

PharmCAT is available under the Mozilla Public License (MPL 2.0) for the scientific and clinical community to review, test, and improve. 

Wednesday, July 10, 2019

CYP2C9, CYP2C19, and CYP2D6 core alleles

We recently blogged about the use of PharmVar core alleles as the basis for the PharmGKB/CPIC CYP2D6CYP2C19, and CYP2C9 allele definition tables, which are available as part of the gene-specific information tables. In addition to the core variant(s), the definition includes ambiguous nucleotides to reflect variation present in some suballeles of an allele which are also core variants of other alleles. The allele definitions are now used by the PharmGKB database for all annotations for these 3 genes.

CYP2D6 example:
CYP2D6 100C>T (P34S) is part of some but not all CYP2D6*4 suballeles. Therefore, it is not present in the CYP2D6*4 core allele. However, 100 C>T is part of core allele definitions of a number of CYP2D6 star alleles such as CYP2D6*10.
To reflect the possible presence of 100C>T in the *4 allele, the variant is represented as a “R” using IUPAC nucleotide code. "R" reflects that either a “G” or “A” (positive strand) can be present at the 100C>T position in *4. This is shown on the PharmGKB CYP2D6*4 overview page, which lists 100C>T positions and others next to the *4 key splicing variant 1847G>A (rs3892097).

CYP2C19 example:
For CYP2C19*1, the genomic reference sequence at position GRCh38 NC_000010.11:g.94842866 (rs3758581) is "A", which is present in CYP2C19*1.001(*1A), however all other *1 suballeles have a "G" (I331V) at this position. All suballeles of a star (*) are assumed to have similar functional status. The I331V is prominent in CYP2C19 and part of many alleles.  To reflect the possibility of either base at this position, the NC_000010.11:g.94842866 position is included as "R" for the CYP2C19*1 allele at PharmGKB.

For more information about cytochrome P450 star alleles and suballeles, see PharmVar .

PharmGKB has been updated to contain annotations on main star alleles such as *2, *3, etc. and not individual suballeles. If a publication specifically mentions a suballele, this association will be annotated on the main star allele and the suballele will be mentioned in the annotation notes.


Tuesday, July 2, 2019

CPIC to issue guidance on non-actionable pharmacogenes


The Clinical Pharmacogenetics Implementation Consortium (CPIC) hopes to provide more guidance in the future about gene-drug pairs which have a weak evidence base and are not clinically actionable, despite being heavily marketed to healthcare providers and the public. Many of these gene-drug pairs have already been curated by CPIC staff and assigned a CPIC level of C or D, indicating low or highly conflicting evidence.

The plan was announced at CPIC’s 2019 open meeting in Memphis by Dr. Mary Relling, co-leader of CPIC. It is hoped that this new initiative will improve standardization of pharmacogenomic (PGx) testing, particularly in the face of increased scrutiny from the FDA.

Other CPIC projects announced at the meeting include the development of a CPIC database and API, incorporation of the CPIC guidelines into external resources such as ClinVar and ClinGen and a second phase of the PGx term standardization project which will focus on receptors and other pharmacodynamic genes.

You can find out more about CPIC’s future plans in this GenomeWeb article.

Wednesday, May 22, 2019

PharmGKB ondansetron and tropisetron pathways published in Pharmacogenetics and Genomics


The PharmGKB pathways for ondansetron and tropisetron have been published in the June 2019 issue of Pharmacogenetics and Genomics. Ondansetron and tropisetron are serotonin receptor antagonists which are prescribed for their antiemetic activity. After an overview of the pharmacokinetics and pharmacodynamics of each drug, the publication discusses the current pharmacogenetic evidence available, some of which has informed the CPIC guidelines for ondansetron and tropisetron.

You can access interactive versions of the Ondansetron Pathway, Pharmacokinetics/Pharmacodynamics and the Tropisetron Pathway,Pharmacokinetics/Pharmacodynamics at the PharmGKB website.

Monday, May 20, 2019

PharmVar core alleles to be used by PharmGKB and CPIC

PharmVar has released core alleles - single, rule-based definitions per star allele distilled from the respective suballeles - for the cytochrome P450 genes CYP2C9CYP2C19, and CYP2D6. Only sequence variations that change an amino acid or impact function by changing expression levels or interfere with splicing and are present in ALL suballeles within a star allele, are part of the core allele definition. Read more about the core alleles in the PharmVar STANDARDS document and in each gene's "READ ME" document. 

Furthermore, part of the latest PharmVar release was the reassignment of CYP2C19*27 to CYP2C19*1.006.

The PharmGKB/CPIC allele definition tables are updated to reflect the core alleles for CYP2C9, CYP2C19, and CYP2D6 and the CYP2C19*27 change.

The PharmGKB/CPIC allele definition files include a “core alleles + overlap” view which reflects the existence of variants in some, but not all, suballeles of a star allele (therefore not part of the core allele) which are also part of core alleles of other star alleles. 

See the following examples.

CYP2D6 100C>T (P34S) is part of some but not all CYP2D6*4 suballeles. Therefore, it is not present in the CYP2D6*4 core allele. However, 100 C>T is part of core allele definitions of a number of CYP2D6 star alleles such as CYP2D6*10.
To reflect the ambiguous presence of 100C>T in the *4 core allele, the variant is represented as a “R” using IUPAC nucleotide code. "R" reflects that either a “G” or “A” (positive strand) can be present at the 100C>T position in *4.

A similar example is 12802G>A (R150H) in CYP2C19. The variant is present in the CYP2C19*11 core allele but also in one of the CYP2C19*2 suballeles. Therefore, 12802G>A is represented as a “R” in the CYP2C19*2 core allele.

This overlap of variants between alleles is visualized in gray (G) in PharmVar’s Comparative Allele ViewEr (CAVE) tool (accessible through the ‘Compare View’ on the gene page), which was released on PharmVar together with the core alleles (see gene "READ ME" documents for more information).

Friday, May 17, 2019

Pharmacogenomics for dermatologists


An introduction to pharmacogenomics in dermatology has been published in Seminars in Cutaneous Medicine and Surgery by Stanford Medicine dermatology resident Dr. Roxana Daneshjou, PharmGKB curator Dr. Rachel Huddart and PharmGKB co-PIs Dr. Teri Klein and Dr. Russ Altman.

After introducing the field of pharmacogenomics, the paper highlights some of the features of PharmGKB, including our search functionality, curated pathways and drug label annotations. The work of CPIC is also introduced with examples of dermatology-relevant guidelines such as carbamazepine and HLA-A/HLA-B. The article concludes with a discussion of the current state of pharmacogenomics implementation in the clinic.

Although the article has a focus on dermatology, it is relevant to anyone who wants to learn more about pharmacogenomic resources and implementation, regardless of their clinical field. The paper can be accessed here.