Resources for doctors and health consumers about genetic tests, clinical trials

Collecting buccal or cheek swab for genetic test

The following video will review proper techniques for collecting a buccal or cheek swab sample for processing in our laboratory in three easy steps. This will reduce the need for resample and is critical to yield good test results.

For general information about pharmacogenomics or drug-specific resources and clinical trials, visit the following websites:

Genetic tests description from Wiki

https://en.wikipedia.org/wiki/Genetic_testing

Clinical trials registries by country

https://en.wikipedia.org/wiki/Clinical_trials_registry

The Value of DNA Sequencing

DNA sequencing: what it tells us about DNA changes in cancer, how looking across many tumors will help to identify meaningful changes and potential drug targets, and how genomics is changing the way we think about cancer.

The Link Between TCGA and Personalized Cancer Therapies

How cancers from the same anatomical site, such as breast cancer, are often genomically different. Knowing the genomic defect in an individual’s cancer can help doctors tailor treatment.

Cancer Genome ATLAS

https://cancergenome.nih.gov/

Talking Glossary of Genetic Terms

https://www.genome.gov/glossary/index.cfm?id=70

FDA Guidance on Pharmacogenetic Tests and Genetic Tests for Heritable Markers

Click to access ucm071075.pdf

A comprehensive list of FDA-approved drugs that have pharmacogenetic information in their labeling. This list includes the drugs relevant to PGxOne™ reporting.

http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

https://clinicaltrials.gov/

ClinicalTrials.gov is a registry and results database for clinical studies involving human participants. The database contains studies conducted around the world, funded by both public and private sources. This is a good source of information for clinical trials investigating the pharmacogenetic effects for drugs in development and as well as for drugs already commercially available.

FDA-approved drugs with biomarker/pharmacogenetics

A comprehensive list of FDA-approved drugs that have pharmacogenetic information in their labeling. This list includes the drugs relevant to PGxOne™ reporting.

http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

National Institute of Health (NIH): Personalized Medicine

ClinicalTrials.gov is a registry and results database for clinical studies involving human participants. The database contains studies conducted around the world, funded by both public and private sources. This is a good source of information for clinical trials investigating the pharmacogenetic effects for drugs in development and as well as for drugs already commercially available.

http://www.nih.gov/about/discovery/technology/personalmed.htm

National Institute of General Medical Sciences (NIGMS)

NIGMS is one of the NIH institute and part of the US Department of Health and Human Services. The NIGMS supports basic research and training nationwide, leading to advances in disease diagnosis, treatment and prevention. Along with other NIH institutes, the NIGMS contributes support to the NIH Pharmacogenomics Research Network (PGRN).

http://www.nigms.nih.gov/Research/SpecificAreas/PGRN/Background/Pages/pgrn_faq.aspx

FDA Orange Book

The publication Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known as the Orange Book).

A US Food and Drug Administration (FDA) database that provides timely consumer information on generic drugs

http://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm

http://www.accessdata.fda.gov/scripts/Cder/ob/default.cfm

American Society of Genes and Cell Therapy

http://www.asgct.org/general-public

Clinical Trials by Therapeutic Area

https://www.centerwatch.com/clinical-trials/listings/therapeutic-description.aspx

Cancer Related Genes

Cancer Related Genes

Gene Therapeutic Area
ABL1 Chronic Myeloid Leukemia
AKT1 Breast Cancer
Colorectal Cancer
Non-Small Cell Lung Cancer
ALK Anaplastic Large Cell Lymphoma
Inflammatory Myofibroblastic Tumor
Neuroblastoma
Non-Small Cell Lung Cancer
Rhabdomyosarcoma
ATM Diffuse Large B-Cell Lymphoma
Mantle Cell Lymphoma
Chronic Lymphocytic Leukemia
AURKA Colorectal Cancer
BCL2 Lymphoma
BCL6 Lymphoma
BCR Chronic Myeloid Leukemia
BRAF Colorectal Cancer
Gastrointestinal Stromal Tumor
Glioma
Melanoma
Non-Small Cell Lung Cancer
Ovarian Cancer
Thyroid Cancer
BRCA1 Breast Cancer
Ovarian Cancer
BRCA2 Breast Cancer
 Ovarian Cancer
CCND1 Breast Cancer
Gene Therapeutic Area
CCNE1 Ovarian Cancer
CDK4 Breast Cancer
Liposarcoma
CEBPA Acute Myeloid Leukemia
CRLF2 Acute Lymphoblastic Leukemia
CTNNB1 Melanoma
DDR2 Non-Small Cell Lung Cancer
DNMT3A Acute Myeloid Leukemia
Myelodysplastic Syndromes
EGFR Colorectal Cancer
Glioblastoma
Head and Neck Squamous Cell Carcinoma
Non-Small Cell Lung Cancer
ERBB2 Breast Cancer
Gastric Cancer
Non-Small Cell Lung Cancer
ESR1 Breast Cancer
ETV6 Myelodysplastic Syndromes
Prostate Cancer
FGFR1 Breast Cancer
Non-Small Cell Lung Cancer
FGFR2 Breast Cancer
FGFR3 Bladder Cancer
Glioblastoma
FLT3 Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
GNA11 Melanoma
GNAQ Melanoma
Gene Therapeutic Area
HRAS Thyroid Cancer
IDH1 Acute Myeloid Leukemia
Glioma
IDH2 Acute Myeloid Leukemia
Glioma
JAK1 Acute Lymphoblastic Leukemia
Myeloproliferative Neoplasms
JAK2 Acute Lymphoblastic Leukemia
Myeloproliferative Neoplasms
KIT Acute Myeloid Leukemia
Gastrointestinal Stromal Tumor
Melanoma
Non-Small Cell Lung Cancer
Thymic Carcinoma
KMT2A Acute Myeloid Leukemia
KRAS Colorectal Cancer
Non-Small Cell Lung Cancer
Ovarian Cancer
Thyroid Cancer
MAP2K1 Melanoma
Non-Small Cell Lung Cancer
MET Non-Small Cell Lung Cancer
MPL Haematopoietic Neoplasms
MYC Small Cell Lung Cancer
NF1 Melanoma
Myelodysplastic Syndromes
NPM1 Anaplastic Large Cell Lymphoma
Acute Myeloid Leukemia
Gene Therapeutic Area
NRAS Colorectal Cancer
Melanoma
Non-Small Cell Lung Cancer
Thyroid Cancer
PDGFRA Gastrointestinal Stromal Tumor
PDGFRB Myeloid Neoplasms
PIK3CA Breast Cancer
Colorectal Cancer
Non-Small Cell Lung Cancer
Ovarian Cancer
Squamous Cell Cervical Cancer
PTCH1 Gastric Cancer
Medulloblastoma
PTEN Breast Cancer
Colorectal Cancer
Non-Small Cell Lung Cancer
Ovarian Cancer
RARA Acute Myeloid Leukemia
RET Non-Small Cell Lung Cancer
Thyroid Cancer
ROS1 Non-Small Cell Lung Cancer
RUNX1 Acute Myeloid Leukemia
Myelodysplastic Syndromes
SMO Basal Cell Carcinoma
Medulloblastoma
TP53 Cancer
Myelodysplastic Syndromes
TSC1 Bladder Cancer

Pharmacogenomics Related Genes

CYP2C8 CYP2D6 DPDYD MTHFR TPMT TYMS UGT1A1 XRCC1

Pharmacogenetics

Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects.[1] The term pharmacogenetics is often used interchangeably with the term pharmacogenomics which also investigates the role of acquired and inherited genetic differences in relation to drug response and drug behavior through a systematic examination of genes, gene products, and inter- and intra-individual variation in gene expression and function.[2]

In oncology, pharmacogenetics historically is the study of germline mutations (e.g., single-nucleotide polymorphisms affecting genes coding for liver enzymes responsible for drug deposition and pharmacokinetics), whereas pharmacogenomics refers to somatic mutations in tumoral DNA leading to alteration in drug response (e.g., KRAS mutations in patients treated with anti-Her1 biologics).[3]

Predicting drug-drug interactions

Much of current clinical interest is at the level of pharmacogenetics, involving variation in genes involved in drug metabolism with a particular emphasis on improving drug safety. The wider use of pharmacogenetic testing is viewed by many as an outstanding opportunity to improve prescribing safety and efficacy. Driving this trend are the 106,000 deaths and 2.2 Million serious events caused by adverse drug reactions in the US each year.[4][unreliable medical source?] As such ADRs are responsible for 5-7% of hospital admissions in the US and Europe, lead to the withdrawal of 4% of new medicines, and cost society an amount equal to the costs of drug treatment.[5]

Comparisons of the list of drugs most commonly implicated in adverse drug reactions with the list of metabolizing enzymes with known polymorphisms found that drugs commonly involved in adverse drug reactions were also those that were metabolized by enzymes with known polymorphisms (see Phillips, 2001).

Scientists and doctors are using this new technology for a variety of things, one being improving the efficacy of drugs. In psychology, we can predict quite accurately which anti-depressant a patient will best respond to by simply looking into their genetic code.[citation needed][dubious ] This is a huge step from the previous practice of adjusting and experimenting with different medications to get the best response. Antidepressants also have a large percentage of unresponsive patients and poor prediction rate of ADRs (adverse drug reactions). In depressed patients, 30% are not helped by antidepressants. In psychopharmacological therapy, a patient must be on a drug for 2 weeks before the effects can be fully examined and evaluated. For a patient in that 30%, this could mean months of trying medications to find an antidote to their pain. Any assistance in predicting a patient’s drug reaction to psychopharmacological therapy should be taken advantage of. Pharmacogenetics is a very useful and important tool in predicting which drugs will be effective in various patients.[6] The drug Plavix blocks platelet reception and is the second best selling prescription drug in the world, however, it is known to warrant different responses among patients.[7] GWAS studies have linked the gene CYP2C19 to those who cannot normally metabolize Plavix. Plavix is given to patients after receiving a stent in the coronary artery to prevent clotting.

Stent clots almost always result in heart attack or sudden death, fortunately it only occurs in 1 or 2% of the population. That 1 or 2% are those with the CYP2C19 SNP.[8] This finding has been applied in at least two hospitals, Scripps and Vanderbilt University, where patients who are candidates for heart stents are screened for the CYP2C19 variants.[9]

Another newfound use of pharmacogenetics involves the use of Vitamin E. The Technion Israel Institute of Technology observed that vitamin E can be used to in certain genotypes to lower the risk of cardiovascular disease in patients with diabetes, but in the same patients with another genotype, vitamin E can raise the risk of cardiovascular disease. A study was carried out, showing vitamin E is able to increase the function of HDL in those with the genotype haptoglobin 2-2 who suffer from diabetes. HDL is a lipoprotein that removes cholesterol from the blood and is associated with a reduced risk of atherosclerosis and heart disease. However, if you have the misfortune to possess the genotype haptoglobin 2-1, the study shows that this same treatment can drastically decrease your HDL function and cause cardiovascular disease.[10]

Pharmacogenetics is a rising concern in clinical oncology, because the therapeutic window of most anticancer drugs is narrow and patients with impaired ability to detoxify drugs will undergo life-threatening toxicities. In particular, genetic deregulations affecting genes coding for DPD, UGT1A1, TPMT, CDA and CYP2D6 are now considered as critical issues for patients treated with 5-FU/capecitabine, irinotecan, mercaptopurine/azathioprine, gemcitabine/capecitabine/AraC and tamoxifen, respectively. The decision to use pharmacogenetic techniques is influenced by the relative costs of genotyping technologies and the cost of providing a treatment to a patient with an incompatible genotype. When available, phenotype-based approaches proved their usefulness while being cost-effective.[11]

In the search for informative correlates of psychotropic drug response, pharmacogenetics has several advantages:[12]

  • The genotype of an individual is essentially invariable and remains unaffected by the treatment itself.[clarification needed]
  • Molecular biology techniques provide an accurate assessment of the genotype of an individual.[weasel words]
  • There has been a dramatic increase in the amount of genomic information that is available. This information provides the necessary data for comprehensive studies of individual genes and broad investigation of genome-wide variation.
  • The ease of accessibility to genotype information through peripheral blood or saliva sampling and advances in molecular techniques has increased the feasibility of DNA collection and genotyping in large-scale clinical trials.

History

The first observations of genetic variation in drug response date from the 1950s, involving the muscle relaxant suxamethonium chloride, and drugs metabolized by N-acetyltransferase. One in 3500 Caucasians has less efficient variant of the enzyme (butyrylcholinesterase) that metabolizes suxamethonium chloride.[13] As a consequence, the drug’s effect is prolonged, with slower recovery from surgical paralysis. Variation in the N-acetyltransferase gene divides people into “slow acetylators” and “fast acetylators”, with very different half-lives and blood concentrations of such important drugs as isoniazid (antituberculosis) and procainamide(antiarrhythmic). As part of the inborn system for clearing the body of xenobiotics, the cytochrome P450 oxidases (CYPs) are heavily involved in drug metabolism, and genetic variations in CYPs affect large populations. One member of the CYP superfamily, CYP2D6, now has over 75 known allelic variations, some of which lead to no activity, and some to enhanced activity. An estimated 29% of people in parts of East Africa may have multiple copies of the gene, and will therefore not be adequately treated with standard doses of drugs such as the painkiller codeine (which is activated by the enzyme). The first study using Genome-wide association studies (GWAS) linked age-related macular degeneration (AMD) with a SNP located on chromosome 1 that increased one’s risk of AMD. AMD is the most common cause of blindness, affecting more than seven million Americans. Until this study in 2005, we only knew about the inflammation of the retinal tissue causing AMD, not the genes responsible.[9]

Thiopurines and TPMT (thiopurine methyl transferase)

One of the earliest tests for a genetic variation resulting in a clinically important consequence was on the enzyme thiopurine methyltransferase (TPMT). TPMT metabolizes 6-mercaptopurine and azathioprine, two thiopurine drugs used in a range of indications, from childhood leukemia to autoimmune diseases. In people with a deficiency in TPMT activity, thiopurine metabolism must proceed by other pathways, one of which leads to the active thiopurine metabolite that is toxic to the bone marrow at high concentrations. Deficiency of TPMT affects a small proportion of people, though seriously. One in 300 people have two variant alleles and lack TPMT activity; these people need only 6-10% of the standard dose of the drug, and, if treated with the full dose, are at risk of severe bone marrow suppression. For them, genotype predicts clinical outcome, a prerequisite for an effective pharmacogenetic test. In 85-90% of affected people, this deficiency results from one of three common variant alleles.[14] Around 10% of people are heterozygous – they carry one variant allele – and produce a reduced quantity of functional enzyme. Overall, they are at greater risk of adverse effects, although as individuals their genotype is not necessarily predictive of their clinical outcome, which makes the interpretation of a clinical test difficult. Recent research suggests that patients who are heterozygous may have a better response to treatment, which raises whether people who have two wild-type alleles could tolerate a higher therapeutic dose.[15] The US Food and Drug Administration (FDA) have recently deliberated the inclusion of a recommendation for testing for TPMT deficiency to the prescribing information for 6-mercaptopurine and azathioprine. The information previously carried the warning that inherited deficiency of the enzyme could increase the risk of severe bone marrow suppression. It now carries the recommendation that people who develop bone marrow suppression while receiving 6-mercaptopurine or azathioprine be tested for TPMT deficiency.[citation needed]

Hepatitis C

A polymorphism near a human interferon gene is predictive of the effectiveness of an artificial interferon treatment for Hepatitis C. For genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment.[16] Genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more probable to achieve sustained virological response after the treatment than others, and demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.

Tumor genes

Gene expression profiling is a technique used in molecular biology to query the expression of thousands of genes simultaneously. While almost all cells in an organism contain the entire genome of the organism, only a small subset of those genes is expressed as messenger RNA (mRNA) at any given time, and their relative expression can be evaluated. Techniques include DNA microarray technology or sequenced-based techniques such as serial analysis of gene expression(SAGE).

Current cancer research makes use primarily of DNA microarrays in which an arrayed series of microscopic spots of pre-defined DNA oligonucleotides known as probes are covalently attached to a solid surface such as glass, forming what is known as a gene chip. DNA labeled with fluorophores (target) is prepared from a sample such as a tumor biopsy and is hybridized to the complementary DNA (cDNA) sequences on the gene chip. The chip is then scanned for the presence and strength of the fluorescent labels at each spot representing probe-target hybrids. The level of fluorescence at a particular spot provides quantitative information about the expression of the particular gene corresponding to the spotted cDNA sequence. DNA microarrays evolved from Southern blotting which allows for detection of a specific DNA sequence in a sample of DNA.

Due to lowering costs, RNA-Sequencing is becoming more common as a method for cancer gene expression profiling. It is superior to microarray techniques due to not having the bias inherent in probe selection.

Cancer classification

Background

Histopathology of invasive ductal carcinoma of the breast representing a scirrhous growth.

Microscopic view of a histopathologic specimen of an invasive ductal carcinoma of the breast representing a scirrhous growth stained with haematoxylin and eosin.

Classification of cancers has been dominated by the fields of histology and histopathology which aim to leverage morphological markers for accurate identification of a tumor type. Histological methods rely on chemical staining of tissues with pigments such as haematoxylin and eosin and microscopy-based visualization by a pathologist. The identification of tumor subtypes is based on established classification schemes such as the International Classification of Diseases published by the World Health Organization which provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or diseases. For some types of cancer, these methods are unable to distinguish between subclasses; for example, defining subgroups of diffuse large B-cell lymphoma(DLBCL) have largely failed due to discrepancies between inter- and intra-observer reproducibility.[1] Furthermore, the clinical outcomes of tumors classified as DLBCLs is highly variable[1] suggesting that there are multiple subtypes of DLBCL that cannot be distinguished based on these histological markers. Breast tumor classification too has largely failed based on these predictors.[2] Development of effective therapies depends on accurate diagnosis; additionally, poor diagnosis can lead to patient suffering due to needless side-effects from non-targeted treatments and to increased health care expenditure. Most telling perhaps is that 70-80% of breast cancer patients receiving chemotherapy based on traditional predictors would have survived without it.[3][4]

Of note, similar gene expression patterns associated with metastatic behaviour of breast cancer tumor cells have also been found in breast cancer of dog, the most common tumor of the female dog.[5] [6]

Presented below are ways that gene expression profiling has been used to more precisely classify tumors into subgroups, often with clinical effect.

Molecular Signature

In a particular type of cell or tissue, only a small subset of an organism’s genomic DNA will be expressed as mRNAs at any given time. The unique pattern of gene expression for a given cell or tissue is referred to as its molecular signature. For example, the expression of genes in skin cells would be very different compared to those expressed in blood cells. Microarray analysis can provide quantitative gene expression information allowing for the generation of a molecular signature, each unique to a particular class of tumor. This idea was first shown experimentally[7] in 2000 by researchers at Stanford University published in Nature Genetics. The authors measured the relative expression of 9,703 human cDNAs in sixty cancer cell lines previously studied and characterized by the National Cancer Institute’s Developmental Therapeutics Program. A hierarchical clustering algorithm was used to group cell lines based on the similarity by which the pattern of gene expression varied. In this study by Ross et al., the majority of cell lines with common organs of origin (based on information from the National Institutes of Health) clustered together at terminal branches, suggesting that cancer cells arising from the same tissue share many molecular characteristics. This allows for reliable identification of tumor type based on gene expression.

Tumor subclass

A more powerful result of gene expression profiling is the ability to further classify tumors into subtypes having distinct biological properties and affect prognoses. For example, some diffuse large B-cell lymphomas (DLBCLs) are indistinguishable based on histological methods yet are clinically heterogeneous: 40% of patients respond well and exhibit prolonged survival while the remaining 60% do not.[8]

In 2000, Stanford researchers published results[8] in Nature, utilizing expression profiling techniques to stratify DLBCL to two subtypes: germinal center B-like DLBCL and activated B-like DLBCL. The authors developed custom microarrays termed “lymphochips” that were used to query expression of 17,856 genes preferentially expressed in lymphoid cells and those with roles in cancer or immunology for 96 lymphocyte samples. The hierarchical clustering algorithm identified a subset of tumors that would have been labeled DLBCLs by traditional histological methods; however, the expression profiles of these tumors were heterogeneous. When the tumors were re-clustered based on expression of germinal center B-cell genes, a second group of genes characteristic of activated B-cells emerged and were oppositely regulated compared to the first set of genes. Based on these expression patterns, the heterogeneous DLBCL cluster was subclassified to the germinal center B-like DLBCL and activated B-like DLBCL. The distinction of these groups is significant in terms of patient overall survival: the probability of survival for patients with germinal center B-like DLBCLs over 10 years was about 80% while those with activated B-like DLBCLs was lowered to about 40% over a shorter eight-year period.

Breast cancers are also difficult to distinguish based on histological markers. In a 2000 study published in Nature, Stanford researchers led by Perou, C.M. characterized gene expression patterns across 8,102 genes for 65 biopsies obtained from breast cancers.[9] The goal of the study was to identify patterns of gene expression that could be used to describe the phenotypic diversity of breast tumors by comparing the profiles of the biopsies to those of cultured cell lines and relating this information to clinical data. The tumors were clustered into two major groups that largely reflected the ER-positive and ER-negative clinical descriptions. The ER-positive tumors were characterized by high expression of genes normally expressed in breast luminal cells. The authors suggest that this higher-order distinction may encompass at least two biologically distinct types of cancer that may each require a unique course of treatment. Within the ER-negative group, additional clusters were identified based on expression of Erb-B2 and keratin 5- and 17-enriched basal epithelial-like genes. These groups reflect distinct molecular features as related to mammary epithelial biology, based on the outcome of disease.

Clinical application

Kaplan-Meier survival plot

A representative Kaplan-Meier survival plot. Patients with a Gene A signature have better percent survival than patients with a Gene B signature.

In a 2001 study published in the Proceedings of the National Academy of Sciences, Sørlie et al.[10] further stratified the classifications described by Perou et al.[9] and explored the clinical value of these breast cancer subtypes. The authors separated the ER-positive tumors into two distinct groups and found that tumor classification based on gene expression was related to patient survival. The expression of 427 genes was measured for 78 cancers and seven non-malignant breast samples. Following hierarchical clustering, the samples formed two groups at the highest level of organization reflecting the ER-positive and ER-negative phenotypes; the ER-negative cluster further stratified to groups identical to those described by Perou et al.[9] In contrast to previous results, Sørlie et al.[10] found that the ER-positive group could also be separated into three distinct subgroups termed luminal subtypes A, B, and, C based on patterns of luminal-specific gene expression with different outcomes. The authors further found once they performed survival analyses that tumors belonging to the various groups showed significantly different outcomes when treated uniformly. Survival analyses are often shown as Kaplan-Meier survival plots, an example of which is shown to the right.

In addition to identifying genes that correlate to survival, microarray analyses have been utilized to establish gene expression profiles associated with prognosis. It is agreed upon that patients with tumors exhibiting poor prognostic features would benefit the most from adjuvant therapy as these treatments substantially improve overall survival for women with breast cancer. Traditional prognostic factors, however, are inexact as mentioned above. Researchers at the Netherlands Cancer Institute were able to identify “good-prognosis” and “bad-prognosis” signatures based on the expression of 70 genes that was better able to predict the likelihood of metastasis development within five years for breast cancer patients[11][12] Metastasis involves the spread of cancer from one organ to others throughout the body and is the principal cause of death in cancer patients. While the study at the Netherlands Cancer Institute applied to breast cancer patients only, researchers at Massachusetts Institute of Technologyidentified a molecular signature of metastasis that applied to adenocarcinomas in general.[13]


Motherhealth will soon partner with a lab that accepts insurance billing (with collaboration with your doctor and genetic counselor) for most of the genetic tests such as one for cancer genetic panel (64 genes). Email motherhealth@gmail.com for more info. A personalized diet ebook comes with each genetic test ordered from Motherhealth site ( http://www.avatarcare.net – site coming soon).

Genetic Testing

Genetic Testing

The CDC Office of Public Health Genomics ranks the following list for levels of evidence of genomic tests and family health history in practice . This approach was based on a paper by KhouryExternal Web Site Icon and updated in accordance with criteria presented by a 2014 paper in Clinical Pharmacology and TherapeuticsExternal Web Site Icon. The criteria are  shown in the following figure to provide additional information to our readers.This list is updated on an ongoing basis andprovided only for informational purposes to researchers, healthcare providers, public health programs and others.

Green

  • FDA label requires use of test to inform choice or dose of a drug
  • CMS covers testing
  • Clinical practice guidelines based on systematic review supports testing

Yellow

  • FDA label mentions biomarkers*
  • CMS coverage with evidence development
  • Clinical practice guideline, not based on systematic review, supports use of test
  • Clinical practice guideline finds insufficient evidence but does not discourage use of test
  • Systematic review, without clinical practice guideline, supports use of test
  • Systematic review finds insufficient evidence but does not discourage use of test
  • Clinical practice guideline recommends dosage adjustment, but does not address testing

Red

  • FDA label cautions against use
  • CMS decision against coverage
  • Clinical practice guideline recommends against use of test
  • Clinical practice guideline finds insufficient evidence and discourages use of test
  • Systematic review recommends against use
  • Systematic review finds insufficient evidence and discourages use
  • Evidence available only from published studies without systematic reviews, clinical practice guidelines, FDA label or CMS labels coverage decision

*Can be reassigned to Green of Red of one or more conditions in these categories apply

Tier 1/Green category: represents genomic and family health history applications which have a base of synthesized evidence supporting implementation into practice.
Gene, Gene/Drug, Test, or Family History Disorder/Indication Use* Synthesized Evidence Sources
Cancer—Breast/Ovarian
family history of breast/ovarian or other types of BRCA-related cancer hereditary breast and ovarian cancer in women risk prediction for referral for BRCA genetic counseling USPSTFExternal Web Site Icon (2013)

NCCN Guideline Adobe PDF file [PDF 836.97 KB]External Web Site Icon(2013)

NCCN Task ForceExternal Web Site Icon (2011)

first-degree family history of breast cancer chemoprevention of breast cancer risk prediction USPSTFExternal Web Site Icon (2013)
family history of known breast/ovarian cancer with deleterious BRCA mutation hereditary breast and ovarian cancer in women risk prediction; referral to counseling for BRCA genetic testing USPSTFExternal Web Site Icon (2013)
HER2/trastuzumab invasive breast cancer PGx NICE Adobe PDF file [PDF 2.00 MB]External Web Site Icon (2009)

ASCOExternal Web Site Icon (2007)

FDA-DeviceExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon (2013)

HER2/pertuzumab invasive breast cancer PGx FDA-DeviceExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon (2013)

HER2/ado-trastuzumab emtansine metastatic breast cancer PGx FDA-PGx Drug InformationExternal Web Site Icon (2013)
HER2/everolimus advanced HR+ HER2- breast cancer PGx FDA-PGx Drug InformationExternal Web Site Icon (2013)
HER2/lapatinib (in combination with capecitabine or letrozole) advanced or metastatic breast cancer PGx FDA-PGx Drug InformationExternal Web Site Icon (2013)
HER2 invasive breast cancer PGx ASCO/CAPExternal Web Site Icon (2007)

NICE Adobe PDF file [PDF 178.88 KB]External Web Site Icon (2009)

ER /fulvestrant metastatic breast cancer PGx FDA-PGx Drug InformationExternal Web Site Icon (2012)
ER/exemestane ER+ early breast cancer PGx FDA-PGx Drug InformationExternal Web Site Icon (2013)

NICE Adobe PDF file [PDF 178.88 KB]External Web Site Icon (2009)

ER/anastrozole or letrozole ER+ early invasive breast cancer PGx NICE Adobe PDF file [PDF 178.88 KB]External Web Site Icon (2009)

FDA-PGx Drug Information [anastrozole]External Web Site Icon (2013)

FDA-PGx Drug Information [letrozole]External Web Site Icon (2011)

ER and PgR invasive breast cancer, breast cancer recurrences PGx ASCO/CAPExternal Web Site Icon (2010)

NCCN Task ForceExternal Web Site Icon (2011)

Oncotype DX® adjuvant chemotherapy ER+/LN-/HER2- breast cancer, intermediate risk of recurrence prognostic; guiding decision-making: adjuvant chemotherapy NICEExternal Web Site Icon (2013)

NCCN Task ForceExternal Web Site Icon (2011)

Cancer—Colorectal
Testing for Lynch syndrome newly diagnosed colorectal cancer screening, cascade testing of relatives EGAPP (2009)
Testing for Lynch syndrome known Lynch syndrome in family diagnostic, screening EGAPP (2009)

NCCNExternal Web Site Icon: Genetic/Familial High-Risk Assessment – Colorectal  (2014)

KRAS/cetuximab, panitumumab metastatic colorectal cancer PGx EGAPP Adobe PDF file [PDF 456.16 KB]External Web Site Icon (2013)

NCCNExternal Web Site Icon (2011)

ASCOExternal Web Site Icon (2009)

FDA-DeviceExternal Web Site Icon

FDA-PGx Drug InformationExternal Web Site Icon (2013)

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5 or CEA) invasive colorectal cancer prognostic ASCO/CAPExternal Web Site Icon (2006)

NCCN Adobe PDF file [PDF 1.27 MB]External Web Site Icon (2013)

NCCN Task ForceExternal Web Site Icon (2011)

Cancer—Gastric
HER2/trastuzumab gastric or gastroesophageal junction adenocarcinoma PGx FDA-DeviceExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon (2013)

c-Kit protein (CD 117)/imatinib gastrointestinal stromal tumors PGx FDA-DeviceExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon (2013)

Cancer—Leukemia/lymphoma
Philadelphia chromosome, T315I mutation/dasatinib chronic myeloid leukemia, acute lymphoblastic leukemia PGx; diagnostic FDA-PGx Drug InformationExternal Web Site Icon (2013)
Philadelphia chromosome/imatinib chronic myeloid leukemia, acute lymphoblastic leukemia PGx; diagnostic FDA-PGx Drug InformationExternal Web Site Icon (2013)
Philadelphia chromosome/bosutinib chronic myelogenous leukemia PGx; diagnostic FDA-PGx Drug InformationExternal Web Site Icon (2013)
Philadelphia chromosome/nilotinib chronic myeloid leukemia PGx; diagnostic FDA-PGx Drug InformationExternal Web Site Icon (2013)
PML/RARα/tretinoin acute promyelocytic leukemia PGx FDA-PGx Drug InformationExternal Web Site Icon (2004)
PML/RARα/arsenic trioxide acute promyelocytic leukemia PGx FDA-PGx Drug InformationExternal Web Site Icon (2010)
PDGFRB/imatinib myelodysplastic/ myeloproliferative diseases PGx FDA-PGx Drug InformationExternal Web Site Icon (2013)
CD25/denileukin diftitox persistent or recurrent cutaneous T-cell  lymphoma PGx FDA-PGx Drug InformationExternal Web Site Icon (2011)
CD20/tositumomab Non-Hodgkin’s lymphoma PGx FDA-PGx Drug InformationExternal Web Site Icon (2012)

Alberta Health Services Adobe PDF file [PDF 792.34 KB]External Web Site Icon (2013)

G6PD/rasburicase leukemia, lymphoma, solid tumor malignancies PGx, pretreatment screening in patients at higher risk for G6PD deficiency (e.g., African or Mediterranean ancestry) FDA-PGx Drug InformationExternal Web Site Icon (2009)

CPICExternal Web Site Icon (2014)

Chromosome 5q deletion/lenalidomide transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q PGx FDA-PGx Drug InformationExternal Web Site Icon (2013)
Cancer—Lung
EGFR (exon 19 deletions and exon 21 (L858R) substitution mutations)/afatinib metastatic non-small-cell lung cancer PGx FDA-DeviceExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon (2013)

EGFR (exon 19 deletions and exon 21 (L858R) substitution mutations)/erlotinib locally advanced or metastatic non-small-cell lung cancer PGx NICE Adobe PDF file [PDF 189.11 KB]External Web Site Icon (2012)

NCCN Task ForceExternal Web Site Icon (2011)

FDA-DeviceExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon (2013)

ALK gene rearrangement/crizotinib non-small cell lung cancer PGx FDA-DeviceExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon (2013)

NCCN Task ForceExternal Web Site Icon (2011)

NCCN Guideline Adobe PDF file [PDF 1.61 MB]External Web Site Icon(2013)

Cancer—Melanoma
BRAF V600E/K /trametinib unresectable or metastatic melanoma PGx FDA-PGx Drug InformationExternal Web Site Icon (2013)

FDA-DeviceExternal Web Site Icon (2013)

BRAF V600E/dabrafenib unresectable or metastatic melanoma PGx FDA-PGx Drug InformationExternal Web Site Icon (2013)

FDA-DeviceExternal Web Site Icon (2013)

BRAFV600E/vemurafenib unresectable or metastatic melanoma PGx NICEExternal Web Site Icon (2012)

FDA-PGx Drug InformationExternal Web Site Icon (2013)

FDA-DeviceExternal Web Site Icon (2013)

Cardiovascular disease
DNA testing and LDL-C concentration measurement familial hypercholesterolemia cascade testing of relatives of people diagnosed with FH NICEExternal Web Site Icon (2008)
family history of cardiovascular disease before age 50 years in male relatives and age 60 years in female relatives cholesterol screening risk prediction USPSTFExternal Web Site Icon  (2008)
Infectious disease
HLA-B*5701/abacavir HIV PGx DHHS Advisory Committee Adobe PDF file [PDF 1.46 MB]External Web Site Icon (2013)

CPICExternal Web Site Icon (2014)

FDA-PGx Drug InformationExternal Web Site Icon (2013)

CCR5-tropic HIV-1 /maraviroc HIV PGx FDA-PGx Drug InformationExternal Web Site Icon (2013)

HHS Panel Adobe PDF file [PDF 1.46 MB]External Web Site Icon(2013)

Other
CFTR (G551D)/ivacaftor cystic fibrosis PGx FDA-PGx Drug InformationExternal Web Site Icon (2012)
HLA-B*1502/carbamazepine epilepsy, trigeminal neuralgia; pretreatment screening for those with ancestry in populations  genetically at-risk for certain serious dermatologic reactions PGx, pretreatment screening for those with ancestry in populations  genetically at-risk for certain serious dermatologic reactions FDA-PGx Drug InformationExternal Web Site Icon (2013)
CYP2D6/pimozide Tourette’s disorder PGx-dose FDA-PGx Drug InformationExternal Web Site Icon (2011)
CYP2D6/tetrabenazine chorea associated with Huntington’s disease PGx-dose FDA-PGx Drug InformationExternal Web Site Icon (2011)
G6PD/pegloticase chronic gout in adults refractory to conventional therapy PGx, pretreatment screening in patients at higher risk for G6PD deficiency (e.g., African or Mediterranean ancestry) FDA-PGx Drug InformationExternal Web Site Icon (2012)
Parental history of hip fracture

osteoporosis screening in women risk prediction USPSTFExternal Web Site Icon (2011)
family history, especially siblings, with hereditary hemochromatosis hereditary hemochromatosis risk prediction; counseling for genetic testing among asymptomatic people USPSTFExternal Web Site Icon (2006)
newborn screening panel 31 core conditions screening SACHDNCExternal Web Site Icon (2013)

*Pharmacogenomic applications have been classified in the Use column as either PGx (which may relate to drug choice, prevention of adverse events, or other uses of the information gained through testing), or PGx-dose (when specific dosing-related guidance is provided, or mention of a potential effect on dose is noted in the evidence sources cited). Additional Use categories include: screening, cascade testing, risk prediction, diagnostic, and prognostic.

Source Abbreviations: Agency for Healthcare Research and Quality (AHRQ), American College of Medical Genetics and Genomics (ACMG), American Society of Clinical Oncology (ASCO), Centers for Medicare and Medicaid Services (CMS), Clinical Pharmacogenetics Implementation Consortium (CPIC), Evaluation of Genomic Applications in Practice and Prevention (EGAPP), National Comprehensive Cancer Network (NCCN), National Institute for Health and Care Excellence (NICE), National Institutes of Health (NIH), Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC), US Department of Health and Human Services (DHHS), US Food and Drug Administration (FDA), United States Preventive Services Task Force (USPSTF)

Tier 2/Yellow category: represents genomic and family health history applications have synthesized evidence that is insufficient to support routine implementation in practice; however, existing evidence may provide information for informed decision making by providers and patients.
Gene, Gene/Drug, Test, or Family History Disorder/Indication Use* Synthesized Evidence Sources
Cancer—Breast
gene expression profiles breast cancer Recurrence:  risk prediction; prognostic EGAPPExternal Web Site Icon (2009)
ER-alpha and PgR status/ER-alpha (ESR1)-modulating agents invasive breast cancer and breast cancer PGx – recurrence risk prediction; prognostic NCCN Task ForceExternal Web Site Icon (2011)

NCCN Task ForceExternal Web Site Icon (2009)

ASCO/CAPExternal Web Site Icon (2010)

CYP2D6/tamoxifen risk for primary breast cancer or breast cancer recurrence PGx – informing therapeutic choice BCBSA TECExternal Web Site Icon (2014)
Cancer—Colorectal
first-degree family history of colorectal cancer at a younger age or multiple affected first-degree relatives colorectal cancer screening risk prediction USPSTFExternal Web Site Icon (2008)
BRAF c.1799T>A (p.V600E) colon cancer prognostic NCCN Task ForceExternal Web Site Icon (2011)

NCCN Guideline Adobe PDF file [PDF 1.30 MB]External Web Site Icon (2013)

BRAF V600E/cetuximab, panitumumab metastatic colorectal cancer PGx EGAPP Adobe PDF file [PDF 456.16 KB]External Web Site Icon(2013)

NCCN Task ForceExternal Web Site Icon (2011)

UGT1A1/irinotecan Metastatic carcinoma of the colon or rectum PGx FDA-PGx Drug InformationExternal Web Site Icon(2012)

EGAPPExternal Web Site Icon (2009)

testing for Lynch syndrome patients meeting revised Bethesda guidelines or Amsterdam criteria diagnostic, screening NCCNExternal Web Site Icon: Genetic/Familial High-Risk Assessment – Colorectal  (2014)
testing for Lynch syndrome endometrial cancer in women under 50 years of age diagnostic, screening NCCNExternal Web Site Icon: Genetic/Familial High-Risk Assessment – Colorectal  (2014)
consideration of testing for Lynch syndrome people with 5% or higher risk of Lynch syndrome based on any prediction model diagnostic, screening NCCNExternal Web Site Icon: Genetic/Familial High-Risk Assessment – Colorectal  (2014)
testing for Lynch syndrome colorectal cancer diagnosed under 70 years of age, and those 70 and older who meet Bethesda guidelines diagnostic, screening NCCNExternal Web Site Icon: Genetic/Familial High-Risk Assessment – Colorectal  (2014)
testing for Lynch syndrome colorectal cancer in patients younger than 50 years diagnostic, screening NCCNExternal Web Site Icon: Genetic/Familial High-Risk Assessment – Colorectal  (2014)
testing for Lynch syndrome synchronous or metachronous colorectal or other Lynch syndrome-related tumors, at any age diagnostic, screening NCCNExternal Web Site Icon: Genetic/Familial High-Risk Assessment – Colorectal  (2014)
testing for Lynch syndrome MSI-H histology in colorectal cancer patients younger than 60 years diagnostic, screening NCCNExternal Web Site Icon: Genetic/Familial High-Risk Assessment – Colorectal  (2014)
testing for Lynch syndrome colorectal cancer in patient with relative (one or more first-degree) with Lynch syndrome related cancer that was diagnosed under age 50 years diagnostic, screening NCCNExternal Web Site Icon: Genetic/Familial High-Risk Assessment – Colorectal  (2014)
testing for Lynch syndrome colorectal cancer in patient with relatives (two or more first- or second-degree) with Lynch syndrome related cancer at any age diagnostic, screening NCCNExternal Web Site Icon: Genetic/Familial High-Risk Assessment – Colorectal  (2014)
Cancer—Leukemia
FLT3-ITD acute myeloid leukemia predictive; prognostic NCCN Task ForceExternal Web Site Icon (2011)

NCCN Guideline Adobe PDF file [PDF 852.75 KB]External Web Site Icon (2013)

CEBPA mutation acute myeloid leukemia predictive; prognostic NCCN Task ForceExternal Web Site Icon (2011)

NCCN Guideline Adobe PDF file [PDF 852.78 KB]External Web Site Icon (2013)

NPM1 mutation acute myeloid leukemia predictive; prognostic NCCN Task ForceExternal Web Site Icon (2011)

NCCN Guideline Adobe PDF file [PDF 852.80 KB]External Web Site Icon (2013)

KIT mutation acute myeloid leukemia predictive; prognostic NCCN Task ForceExternal Web Site Icon (2011)

NCCN Guideline Adobe PDF file [PDF 852.70 KB]External Web Site Icon (2013)

Philadelphia chromosome/busulfan chronic myelogenous leukemia PGx FDA-PGx Drug InformationExternal Web Site Icon(2003)
UGT1A1*28homozygotes/nilotinib Philadelphia chromosome positive chronic myeloid leukemia PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
FIP1L1-PDGFRα kinase/imatinib hypereosinophilic syndrome and/or chronic eosinophilic leukemia PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2013)
TPMT/thiopurines (mercaptopurine) acute lymphatic leukemia PGx-dose CPICExternal Web Site Icon (2011)

FDA-PGx Drug InformationExternal Web Site Icon(2011)

TPMT/thiopurines (thioguanine) acute, non-lymphocytic leukemias PGx-dose CPICExternal Web Site Icon (2011)

FDA-PGx Drug InformationExternal Web Site Icon(2004)

Cancer—Lung
KRAS mutations [except c38G>A]/anti-EGFR therapy non–small cell lung cancer predictive; prognostic NCCN Task ForceExternal Web Site Icon (2011)
Cancer—Melanoma
G6PD/dabrafenib unresectable or metastatic melanoma PGx FDA-PGx Drug InformationExternal Web Site Icon(2014)
family history of skin cancer skin cancer screening in adults risk prediction USPSTFExternal Web Site Icon (2009)
Cancer—Other
DPD testing/5-FU (capecitabine) Dukes’ C colon cancer, metastatic colorectal cancer, metastatic breast cancer PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
family history of bladder cancer bladder cancer screening risk prediction USPSTFExternal Web Site Icon (2011)
c-Kit D816V/imatinib aggressive systemic mastocytosis PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
TPMT/cisplatin metastatic testicular tumors, metastatic ovarian tumors, advanced bladder cancer PGx FDA-PGx Drug InformationExternal Web Site Icon(2011)
Cardiovascular
family history relevant to dyslipidemia (otherwise undefined) lipid screening in  infants, children, adolescents, or young adults (up to age 20) risk prediction USPSTFExternal Web Site Icon (2007)
first-degree family history of abdominal aortic aneurysm requiring surgical repair abdominal aortic aneurysm screening risk prediction USPSTFExternal Web Site Icon (2005)
SLCO1B1/simvastatin dyslipidemia PGx-dose CPICExternal Web Site Icon (2012)
CYP2C9, VKORC1/warfarin venous thrombosis, pulmonary embolism, thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement, myocardial infarction PGx-dose CMS CEDExternal Web Site Icon (2009)

ACMGExternal Web Site Icon (2008)

FDA-PGx Drug InformationExternal Web Site Icon

CPICExternal Web Site Icon (2011)

CYP2D6/metoprolol hypertension, angina pectoris, heart failure PGx FDA-PGx Drug InformationExternal Web Site Icon(2012)
CYP2D6/carvedilol chronic heart failure, left ventricular dysfunction following myocardial infarction, hypertension PGx FDA-PGx Drug InformationExternal Web Site Icon(2012)
CYP2D6/carvedilol chronic heart failure, left ventricular dysfunction following myocardial infarction, hypertension PGx FDA-PGx Drug InformationExternal Web Site Icon(2011)
CYP2D6/propafenone atrial fibrillation PGx FDA-PGx Drug InformationExternal Web Site Icon(2011)
CYP2C19/clopidogrel non-ST-segment elevation acute coronary syndrome, ST-elevation myocardial infarction, myocardial
infarction, stroke, peripheral arterial disease
PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)

CPICExternal Web Site Icon (2013)

AHRQExternal Web Site Icon (2013)

CYP2C19/prasugrel acute coronary syndrome managed with percutaneous coronary intervention PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2C19/tricagrelor acute coronary syndrome PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
LDLR/pravastatin hypercholesterolemia PGx FDA-PGx Drug InformationExternal Web Site Icon(2012)
F5, SERPINC1/eltrombopag thrombocytopenia PGx FDA-PGx Drug InformationExternal Web Site Icon(2012)
Endocrine disorders
G6PD/chlorpropamide glycemic control, type 2 diabetes in adults PGx FDA-PGx Drug InformationExternal Web Site Icon(2011)
G6PD/glimepiride glycemic control, type 2 diabetes in adults PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
G6PD/glipizide glycemic control, type 2 diabetes in adults PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
G6PD/glyburide glycemic control, type 2 diabetes in adults PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
Gastroenterology
CYP2C19/pantoprazole gastroesophageal reflux disease, pathological hypersecretory conditions PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2C19/omeprazole duodenal ulcer, gastric ulcer, gastroesophageal reflux disease PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2C19/esomeprazole gastroesophageal reflux disease, NSAID-associated gastric ulcer, duodenal ulcer recurrence, pathological hypersecretory
conditions
PGx FDA-PGx Drug InformationExternal Web Site Icon(2012)
CYP2C19/rabeprazole gastroesophageal reflux disease, duodenal ulcers, pathological hypersecretory conditions PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2C19, CYP1A2/dexlansoprazole erosive esophagitis, heartburn PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
Infectious Disease
G6PD/chloroquine phosphate malaria, extraintestinal amebiasis PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
G6PD/dapsone (tablet) leprosy PGx FDA-PGx Drug InformationExternal Web Site Icon

DailyMedExternal Web Site Icon (2011)

G6PD/mafenide acetate (for 5% topical solution) bacterial infections PGx FDA-PGx Drug InformationExternal Web Site Icon(1998)
G6PD/nitrofurantoin antibacterial, specific urinary tract infections PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
G6PD/primaquine vivax malaria, radical cure (prevention of relapse) PGx FDA-PGx Drug InformationExternal Web Site Icon(2008)
G6PD/quinine sulfate uncomplicatedPlasmodium falciparum malaria PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
G6PD/sulfamethoxazole & trimethoprim bacterial infections PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
IL28B/boceprevir chronic hepatitis C genotype 1 PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
IL28B/telaprevir chronic hepatitis C genotype 1 PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
IL28B/peginterferon alfa-2b chronic hepatitis C PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2C19/voriconazole invasive aspergillosis, candidemia and disseminated candidiasis, esophageal candidiasis,Scedosporium apiospermum andFusarium spp. infection PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2011)
Neurology
CYP2C19/clobazam seizures associated with Lennox-Gastaut syndrome PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2013)
HLA-B*1502/phenytoin generalized tonic-clonic status epilepticus and for seizures that occur during neurosurgery; testing pertains to risk for certain serious dermatologic reactions, which may be higher in patients of Chinese or Asian ancestry PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
HLAB*1502/ carbamazepine epilepsy, other seizure disorders, trigeminal neuralgia, bipolar disorder PGx-dose CPICExternal Web Site Icon (2013)
CYP2D6, CYP2C19/diazepam epilepsy PGx FDA-PGx Drug InformationExternal Web Site Icon(2005)
CYP2D6/dextromethorphan and quinidine pseudobulbar affect PGx, PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2010)
Psychiatry
parental history of depression major depressive disorder screening in adolescents risk prediction USPSTFExternal Web Site Icon (2009)
family history of depression depression screening in adults risk prediction USPSTFExternal Web Site Icon (2009)
CYP2D6/amitriptyline depression PGx-dose CPICExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon

CYP2D6/desipramine depression PGx-dose CPICExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon(2012)

CYP2D6/fluoxetine major depressive disorder, obsessive compulsive disorder, bulimia nervosa, panic disorder PGx FDA-PGx Drug InformationExternal Web Site Icon(2009)
CYP2D6/imipramine depression PGx-dose CPICExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon(2012)

CYP2D6/nortriptyline depression PGx-dose CPICExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon(2012)

CYP2D6/trimipramine depression PGx-dose CPICExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon(2012)

CYP2D6/venlafaxine major depressive disorder, social anxiety disorder PGx, PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2012)
CYP2C19, CYP2D6/citalopram depression PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2012)
CYP2D6/aripiprazole schizophrenia, bipolar I disorder, major depressive disorder, autistic disorder PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2D6/clozapine schizophrenia, schizoaffective disorder PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2D6/iloperidone schizophrenia PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2D6/risperidone schizophrenia, bipolar I disorder, autistic disorder PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2012)
CYP2D6/atomoxetine attention-deficit/hyperactivity disorder PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2D6/clomipramine obsessive-compulsive disorder PGx-dose CPICExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon(2012)

CYP2D6, CYP2C19/fluvoxamine obsessive compulsive disorder PGx FDA-PGx Drug InformationExternal Web Site Icon(2012)
CYP2D6, CYP2C19/doxepin insomnia PGx-dose CPICExternal Web Site Icon (2013)

FDA-PGx Drug InformationExternal Web Site Icon(2010)

CYP2D6/modafinil narcolepsy, obstructive sleep apnea, and shift work disorder PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2010)
Rheumatology
CYP2C19/carisoprodol musculoskeletal conditions PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2C9/celecoxib osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain, primary dysmenorrhea PGx-dose FDA-PGx Drug InformationExternal Web Site Icon(2011)
CYP2C9/flurbiprofen rheumatoid arthritis, osteoarthritis PGx FDA-PGx Drug InformationExternal Web Site Icon(2010)
TPMT/thiopurines (azathioprine) renal homotransplantation, rheumatoid arthritis PGx-dose CPICExternal Web Site Icon (2011)

FDA-PGx Drug InformationExternal Web Site Icon(2011)

Other
family history of developmental dysplasia of the hip developmental dysplasia of the hip screening in infants risk prediction USPSTFExternal Web Site Icon (2006)
family history of diabetes gestational diabetes screening risk prediction USPSTFExternal Web Site Icon (2008)
family history of neonatal jaundice Hyberbilirubinemia screening in infants; prevention of chronic bilirubin encephalopathy risk prediction USPSTFExternal Web Site Icon (2009)
family history of age-related macular degeneration visual acuity screening in older adults risk prediction USPSTFExternal Web Site Icon (2009)
family history of chronic kidney disease chronic kidney disease screening risk prediction USPSTFExternal Web Site Icon (2012)
family history for common diseases common diseases risk prediction NIH State of the ScienceExternal Web Site Icon (2009)
CYP2D6/tolterodine overactive bladder PGx FDA-PGx Drug InformationExternal Web Site Icon(2012)
HPRT1/mycophenolic acid organ rejection PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2C19/drospirenone and ethinyl estradiol pregnancy prevention, premenstrual dysphoric disorder, moderate acne PGx FDA-PGx Drug InformationExternal Web Site Icon(2012)
UGT1A1/indacaterol chronic obstructive pulmonary disease, including chronic bronchitis and/or emphysema PGx FDA-PGx Drug InformationExternal Web Site Icon(2012)
CYP2D6/codeine pain PGx-dose CPICExternal Web Site Icon (2012)

FDA-PGx Drug InformationExternal Web Site Icon(2013)

CYP2D6/tramadol and acetaminophen acute pain PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
CYP2D6/cevimeline dry mouth in patients with Sjögren’s Syndrome PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
DPD/fluorouracil cream multiple
actinic or solar keratoses
PGx FDA-PGx Drug InformationExternal Web Site Icon(2003)
G6PD/dapsone (gel) acne vulgaris PGx FDA-PGx Drug InformationExternal Web Site Icon(2009)
G6PD/dapsone (tablet) dermatitis herpetiformis PGx FDA-PGx Drug InformationExternal Web Site Icon

DailyMedExternal Web Site Icon (2011)

G6PD/(polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, & ascorbice acid for oral solution) laxative, preparation for colonoscopy in adults PGx FDA-PGx Drug InformationExternal Web Site Icon(2013)
G6PD/sodium nitrite life-threatening, acute cyanide poisoning PGx FDA-PGx Drug InformationExternal Web Site Icon(2012)
G6PD/succimer lead poisoning, pediatric PGx FDA-PGx Drug InformationExternal Web Site Icon(2007)
next generation sequencing/whole genome sequence various rare familial diseases diagnostic BCBS TEC Adobe PDF file [PDF 210.52 KB]External Web Site Icon(2013)
various molecular, cytogenetic biochemical and other tests** single gene disorders and chromosomal abnormalities where diagnosis and management may require use of genetic tests even without formal evidence synthesis and reviews by evidence panels diagnosis, management, carrier testing NIH GTRExternal Web Site Icon (2013)

*Pharmacogenomic applications have been classified in the Use column as either PGx (which may relate to drug choice, prevention of adverse events, or other uses of the information gained through testing), or PGx-dose (when specific dosing-related guidance is provided, or mention of a potential effect on dose is noted in the evidence sources cited). Additional Use categories include: screening, cascade testing, risk prediction, diagnostic, and prognostic.

**This entry includes many genetic disorders for which there are no evidence-based recommendations, clinical guidelines or systematic reviews. However, a systematic search for evidence-based recommendations and reviews has not been conducted to date by our office. We expect further refinements in this classification in the near future.

Source Abbreviations: Agency for Healthcare Research and Quality (AHRQ), American College of Medical Genetics and Genomics (ACMG), American Society of Clinical Oncology (ASCO), Centers for Medicare and Medicaid Services (CMS), Clinical Pharmacogenetics Implementation Consortium (CPIC), Evaluation of Genomic Applications in Practice and Prevention (EGAPP), National Comprehensive Cancer Network (NCCN), National Institute for Health and Care Excellence (NICE), National Institutes of Health (NIH), Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC), US Department of Health and Human Services (DHHS), US Food and Drug Administration (FDA), United States Preventive Services Task Force (USPSTF)

Tier 3/Red category: represents genomic and family health history applications either have synthesized evidence culminating in recommendations against use (or discouraging use), OR no relevant synthesized evidence was identified. Such applications are not ready for routine practice, but may be considered in clinical and population research.
Gene, Gene/Drug, Test, or Family History Disorder/Indication Use* Synthesized Evidence Sources
HFE hereditary hemochromatosis population screening USPSTFExternal Web Site Icon (2006)
routine BRCA genetic counseling, routine BRCA testing Hereditary breast/ovarian cancer, in women whose family history is not associated with an increased risk of BRCA mutations population screening USPSTFExternal Web Site Icon (2013)
panels for various genetic risk factors common diseases risk assessment, disease prevention Multiple sources, for example:EGAPPExternal Web Site Icon (2010)
next generation sequencing/whole genome sequence various common diseases risk prediction Rapidly evolving landscape; gaps in knowledge exist for analytic validity, clinical validity and clinical utility
SNP panels type 2 diabetes risk prediction EGAPP Adobe PDF file [PDF 242.05 KB]External Web Site Icon (2013)
TCF7L2 genotyping type 2 diabetes risk prediction EGAPP Adobe PDF file [PDF 242.05 KB]External Web Site Icon (2013)
NRAS or PIK3CA mutation analysis and/or testing for loss of PTEN or AKT protein expression/anti-EGFR therapy metastatic colorectal cancer PGx EGAPP Adobe PDF file [PDF 456.16 KB]External Web Site Icon (2013)

Systematic reviewExternal Web Site Icon (2011)

CYP450 testing/SSRIs non-psychotic depression PGx, PGx-dose EGAPPExternal Web Site Icon (2007)
tumor gene expression analysis (Prolaris®, Oncotype Dx® Prostate prostate cancer prognostic, management BCBS TECExternal Web Site Icon (2014)
emerging genomic tests in the CDC’sGAPP FinderExternal Web Site Icon of theGAPP Knowledge BaseExternal Web Site Icon various disorders various uses Almost all of these applications (except when listed above) have insufficient information on analytic or clinical validity, or clinical utility

*Pharmacogenomic applications have been classified in the Use column as either PGx (which may relate to drug choice, prevention of adverse events, or other uses of the information gained through testing), or PGx-dose (when specific dosing-related guidance is provided, or mention of a potential effect on dose is noted in the evidence sources cited). Additional Use categories include: screening, cascade testing, risk prediction, diagnostic, and prognostic.

Source Abbreviations: Agency for Healthcare Research and Quality (AHRQ), American College of Medical Genetics and Genomics (ACMG), American Society of Clinical Oncology (ASCO), Centers for Medicare and Medicaid Services (CMS), Clinical Pharmacogenetics Implementation Consortium (CPIC), Evaluation of Genomic Applications in Practice and Prevention (EGAPP), National Comprehensive Cancer Network (NCCN), National Institute for Health and Care Excellence (NICE), National Institutes of Health (NIH), Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC), US Department of Health and Human Services (DHHS), US Food and Drug Administration (FDA), United States Preventive Services Task Force (USPSTF)

Other Abbreviations: estrogen receptor (ER), progesterone receptor (PgR), pharmacogenomics (PGx), single-nucleotide polymorphism (SNP)

Connie Dello Buono

Prevent vascular disease, manage inflammation, get GYV health caps to boost ATP cells performance and speedy repair of your body, email connie to get the caps and join in spreading the benefits with extra income for you at motherhealth@gmail.com and text 408-854-1883