Polycythemia Vera

Online Mendelian Inheritance in Man (OMIM)

Polycythemia Vera | Johns Hopkins Medicine

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    , Vainchenker, W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434: 1144-1148, 2005. [PubMed: 15793561] [Full Text: https://doi.org/10.


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    , Pahl, H. L. MPN patients harbor recurrent truncating mutations in transcription factor NF-E2. J. Exp. Med. 210: 1003-1019, 2013. [PubMed: 23589569] [Full Text: https://rupress.org/jem/article-lookup/doi/10.1084/jem.


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  22. Sozer, S., Fiel, M. I., Schiano, T., Xu, M., Mascarenhas, J., Hoffman, R. The presence of JAK2V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome. Blood 113: 5246-5249, 2009. [PubMed: 19293426] [Full Text: https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2008-11-191544]

  23. Spivak, J. L., Considine, M., Williams, D. M., Talbot, C. C., Jr., Rogers, O., Moliterno, A. R., Jie, C., Ochs, M. F. Two clinical phenotypes in polycythemia vera. New Eng. J. Med. 371: 808-817, 2014. [PubMed: 25162887] [Full Text: http://www.nejm.org/doi/full/10.1056/NEJMoa1403141?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed]

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    Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes (Letter) Leukemia 28: 935-938, 2014.

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Source: https://www.omim.org/entry/263300

Molecular Defect Could Be Mysterious Cause Of Blood Disorder

Polycythemia Vera | Johns Hopkins Medicine

A unique molecular defect in an unusual blood disorder first identified and described at Johns Hopkins by the late Sir William Osler almost a century ago has now been discovered by a team of his professional descendants.

The molecular defect that may be responsible for polycythemia vera was reported by the Hopkins team recently in The New England Journal of Medicine. The finding could eventually serve as a definitive test for the disorder, which can be frustratingly difficult to diagnose. It also could be used as a model for identifying the origins of malignant disease.

“Polycythemia vera mimics other cancerous and non-cancerous blood diseases,” says Jerry L. Spivak, M.D., professor of medicine and oncology at Hopkins and senior author of the research report. “We now have a diagnostic tool that we hope will identify patients earlier, perhaps increasing their lifespan.”

The Hopkins research, supported by the National Institutes of Health, found that patients with polycythemia vera express a defective form of the receptor for thrombopoietin, an essential growth factor that regulates the growth of bone marrow stem cells. It also regulates the production of platelets, disc-shaped structures in the blood that promote clotting.

This receptor, when located on platelets, normally triggers the chemical reactions that sustain platelet function. But in polycythemia vera platelets, the correct signals are not sent.

This reduced activity was observed in all patients with polycythemia vera, helping distinguish it from all other blood diseases with which it can be confused.

A similar reduction was noticed in patients with idiopathic myelofibrosis, a condition closely related to polycythemia vera in which blood production occurs outside of the bone marrow in the spleen and liver.

Polycythemia vera is marked by a great increase in the number of red cells in the blood, resulting in headaches and potentially fatal blood clots. It is usually treated by a modern form of bloodletting, although more severe cases may require chemotherapy.

In 1903, Sir William Osler, Hopkins' first physician-in-chief and chair of the Department of Medicine, was the first to recognize polycythemia vera as a unique entity and relate its symptoms to the increase in the number of red blood cells. The disorder, which can be malignant, affects five to 10 of every 100,000 people and is now being recognized more frequently in young women of reproductive age.

Hopkins researchers compared platelets and bone marrow samples from 34 people with polycythemia vera to a control group of 44 people who either were normal or had disorders similar to polycythemia vera. Platelets were exposed to either thrombopoietin or thrombin, another platelet activating factor, and then analyzed for the expected responses and protein expression.

Platelets from normal subjects, when exposed to thrombopoietin, produced the correct signals and expressed a normal thrombopoietin receptor.

By contrast, platelets from polycythemia vera patients were much less active or showed no signaling at all to thrombopoietin in contrast to thrombin.

The response to thrombopoietin was found to be due to the presence of an abnormality in the thrombopoietin receptor. A similar abnormality was observed in the megakaryocytes, the bone marrow cells that produce platelets.

The study's other authors were Alison R. Moliterno, M.D., and W. David Hankins, Ph.D.


Johns Hopkins Medical Institutions' news releases are available on a PRE-EMBARGOED basis on EurekAlert at http://www.eurekalert.org, Newswise at http://www.newswise.com and from the Office of Communications and Public Affairs' direct e-mail news release service. To enroll, call 410-955-4288 or send e-mail to bsimpkin@welchlink.welch.jhu.edu or 76520.560@compuserve.com.

On a POST-EMBARGOED basis find them at http://hopkins.med.jhu.edu, Quadnet at http://www.quad-net.com, ScienceDaily at http://www.sciencedaily.com or on CompuServe in the SciNews-MedNews library of the Journalism Forum under file extension “.JHM”.

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Source: https://www.sciencedaily.com/releases/1998/03/980331155840.htm

Polycythemia Vera

Polycythemia Vera | Johns Hopkins Medicine

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Polycythemia vera is a rare blood disorder in which there is an increase in all blood cells, particularly red blood cells. The increase in blood cells makes your blood thicker. This can lead to strokes or tissue and organ damage.

What causes polycythemia vera?

Polycythemia vera is caused by a genetic change (mutation) that develops during your lifetime. It is not an inherited genetic disorder. In most cases it is not known why this happens.

What are the symptoms of polycythemia vera?

When you have more blood and it is thicker than normal, problems can occur. Each person’s symptoms may vary. Symptoms may include:

  • Lack of energy (fatigue) or weakness
  • Headache
  • Dizziness
  • Shortness of breath and trouble breathing while lying down
  • Vision problems, such as double vision, blurred vision, and blind spots
  • Inability to concentrate
  • Night sweats
  • Face and becomes red and warm (flushed)
  • Nosebleeds
  • Bleeding gums
  • Too much menstrual bleeding
  • Coughing up blood
  • Bruising
  • Itchy skin (often after a hot bath)
  • Gout
  • Numbness
  • High blood pressure

These symptoms may look other blood disorders or health problems. Always see your healthcare provider for a diagnosis.

How is polycythemia vera diagnosed?

Your healthcare provider will take your medical history and give you a physical exam. Your provider may also do blood tests. These tests will check the increased number of red blood cells in your body. They will also check if there are other conditions that could cause your higher red blood cell count.

How is polycythemia vera treated?

Your healthcare provider will figure out the best treatment :

  • Your age, overall health, and medical history
  • How sick you are
  • How well you handle certain medicines, treatments, or therapies
  • If your condition is expected to get worse
  • What you would to do

Treatment may include:

  • Phlebotomy. This procedure removes blood from your body. At first this must be done often, such as every week. Once enough blood has been removed to reduce your body's iron stores (needed to make blood quickly), you will not need this done as often.
  • Certain medicines, including chemotherapy. The medicines help to stop your bone marrow from making too many blood cells. They also keep your blood flow and blood thickness closer to normal.

What are the complications of polycythemia vera?

Polycythemia vera can be fatal if not diagnosed and treated. It can cause blood clots resulting in a heart attack, stroke, or pulmonary embolism. Liver and spleen enlargement are other possible complications.

Living with polycythemia vera

There is no cure for polycythemia vera, but proper treatment can help to reduce or delay any problems. Work with your healthcare provider to create a treatment plan that fits your needs. You should also be physically active in order to increase your heart rate and improve your blood flow.

Other ways to improve your blood flow include:

  • Stretching your legs and ankles
  • Wearing warm gloves and socks during cold weather
  • Avoiding extreme heat
  • Drinking plenty of water

You should also avoid situations in which you could be hurt, and check your feet for any sores.

Key points about polycythemia vera

  • Polycythemia vera is a rare blood disorder in which there is an increase in all blood cells, particularly red blood cells.
  • The increase in blood cells makes the blood thicker.
  • Thick blood can lead to strokes or tissue and organ damage.
  • Symptoms include lack of energy (fatigue) or weakness, headaches, dizziness, shortness of breath, visual disturbances, nose bleeds, bleeding gums, heavy menstrual periods, and bruising.
  • Treatment may include medicines and phlebotomy, a procedure that removes extra blood from your body.

Next steps

Tips to help you get the most from a visit to your healthcare provider:

  • Know the reason for your visit and what you want to happen.
  • Before your visit, write down questions you want answered.
  • Bring someone with you to help you ask questions and remember what your provider tells you.
  • At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.
  • Know why a new medicine or treatment is prescribed, and how it will help you. Also know what the side effects are.
  • Ask if your condition can be treated in other ways.
  • Know why a test or procedure is recommended and what the results could mean.
  • Know what to expect if you do not take the medicine or have the test or procedure.
  • If you have a follow-up appointment, write down the date, time, and purpose for that visit.
  • Know how you can contact your provider if you have questions.

Source: https://www.hopkinsmedicine.org/health/conditions-and-diseases/polycythemia-vera

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What Are the Symptoms of Polycythemia Vera?

Polycythemia Vera | Johns Hopkins Medicine

Polycythemia vera (PV) is a rare blood cancer that causes your body to make too many red blood cells. Extra cells may not sound a problem, but they are. They thicken your blood, which means it doesn’t flow as quickly, so it’s more maple syrup than water.

When your blood slows down, none of your body parts — from your eyes to your toes — get enough oxygen. This brings about the early symptoms of PV, including dizziness, itchiness, and headaches.

Thicker blood is also more ly to form a clot — a clump of blood that stops up a vein or artery. Blood clots can lead to life-threatening problems such as a heart attack or stroke.

PV is a slow-growing cancer. You can go years without seeing symptoms. Your doctor can check for PV with a basic blood test, but most people with PV find out because they had the test for some other reason.

There’s no cure for PV, but there are treatments. Most people with PV live a normal life when they get the care they need.

Doctors don’t know what causes polycythemia vera. It’s not linked to anything you do, the way smoking makes you more ly to get lung cancer. Anyone can get PV, but it’s usually seen in people over 60. Men are a little more ly than women to get it.

While the cause isn’t clear, most people with PV have a problem in a gene called JAK2. Your bone marrow — the spongy center part of your bone — creates your blood cells. Normally, it makes just the right amount. But if your JAK2 gene doesn’t work right, your bone marrow makes too many red blood cells.

Even though the problem is in a gene, you don’t get PV from your parents. The gene changes at some point after you're born, but doctors don’t know why.

Because PV grows slowly, you might have it for years without knowing it. When you do see symptoms, they may not seem all that unusual. In fact, they’re the same as with many other illnesses:

  • Dizziness
  • Headache
  • Itchiness, often after a warm bath or shower
  • More sweating than normal, sometimes at night
  • Shortness of breath or trouble breathing when you lie down
  • Tiredness
  • Weakness
  • Brief vision problems, seeing flashes

You may also have:

  • Bloating or a feeling of fullness on the upper left side of your belly
  • Nosebleeds, bleeding gums, or more menstrual bleeding than normal
  • Numbness, tingling, or burning in your hands and feet
  • Problems with your vision, seeing double or things seeming blurry
  • Reddened face
  • Swelling and pain in one joint, usually your big toe

PV can lead to other issues. But your doctor will work to avoid those problems.

Blood clots are the most serious concern because they can cause a stroke, heart attack, or other life-threatening problems, such as a DVT (a blood clot in your legs) or a pulmonary embolism (a blood clot that travels to your lungs). Clots can also make your spleen and liver larger than normal, giving you sharp pains in your belly.

It’s rare, but some people with PV get leukemia or another bone marrow illness called myelofibrosis.

No, but many people with PV live a normal life span. With the right care, you can limit your symptoms and, in some cases, make them go away completely.

The best treatment for you depends on your age, history, and how far along the PV is. Your doctor can help you make the best choices for your health now and in the years to come with follow-up care to make sure you don’t have complications.


Mayo Clinic: “Polycythemia Vera.”

National Heart, Lung, and Blood Institute: “Explore Polycythemia Vera.”

Johns Hopkins Medicine, The Sidney Kimmel Comprehensive Cancer Center: “Polycythemia Vera.”

Johns Hopkins Medicine, Health Library: “Polycythemia Vera.”

How It's Diagnosed

Source: https://www.webmd.com/cancer/polycythemia-vera-causes-symptoms

Polycythemia Vera: Johns Hopkins Kimmel Cancer Center

Polycythemia Vera | Johns Hopkins Medicine

Polycythemia vera (PV) is a rare blood disorder in which there is an increase in all blood cells, particularly red blood cells.

The increase in blood cells makes the blood thicker, leading to strokes or tissue and organ damage. PV patients have an excellent chance of living out a normal life span if properly monitored and treated.

A small number of patients may develop acute leukemia or a bone marrow disorder called myelofibrosis.

Risk Factors

The causes of PV are still unknown. In 2005, it was discovered that 95 percent of patients with PV have a mutation in the JAK2 gene.

This gene plays a significant role in the production of red blood cells (in addition to white blood cells and platelets).

When the gene is mutated, there is a loss of normal regulation, and an overproduction of red blood cells, and at times, white blood cells and platelets.

PV is complex and may have many contributing factors. Epidemiologic factors associated with PV include:

  • Gender — Men may be slightly more ly than women to develop the condition.
  • Age — People older than 60 are most ly to develop the condition, though it may occur at any age.
  • Environment – Exposure to intense radiation may increase the risk for the condition.


Symptoms of PV may include:

  • Fatigue and/or weakness
  • Headache
  • Dizziness
  • Shortness of breath and difficulty breathing while lying down
  • Visual disturbance, such as double vision, blurred vision, and blind spots
  • Inability to concentrate
  • Night sweats
  • Flushed complexion
  • Nosebleeds
  • Bleeding gums
  • Excessive menstrual bleeding
  • Hemoptysis (coughing up blood)
  • Bruising
  • Itchy skin, particularly after a hot bath
  • Gout
  • Numbness
  • High blood pressure

Blood clots also can occur, resulting in a heart attack, stroke, or pulmonary embolism. Liver and spleen enlargement are other potential complications.


PV may be detected on blood tests done for other reasons, before there are any symptoms. Or, doctors may recognize signs of PV during an examination. Additional tests may include:

  • Complete blood count – to measure an increase in hemoglobin ( class=”st”a protein in red blood cells that carries oxygen), white blood cells and/or platelets in the blood
  • Erythropoietin test – a blood test to measure the amount of a hormone called erythropoietin, which tells stem cells in the bone marrow to make more red blood cells
  • Genetic testing – to look for mutations to the JAK2 gene
  • Bone marrow tests – Your doctor may take a sample of bone marrow tissue to study the increase of precursor cells to platelets, red blood cells, and white blood cells


Treatments for PV can vary depending on a patient's symptoms. Some patients may not need active treatment but should still be monitored by a physician expert. Treatments include:

  • Phlebotomy — a procedure that involves removing blood from the body, can thin the blood to let it flow more easily.
  • Low-dose aspirin – may be given to reduce the risk of blood clotting
  • Medications – There are no drugs approved by the Food and Drug Administration specifically to treat PV. However, some medicines approved for other diseases are used to treat the signs and symptoms of this condition. They include platelet-lowering medications hydroxyurea, anagrelide, and interferon, which may be prescribed to reduce the risk of bleeding or clotting complications.
  • Radiation – to help suppress overactive bone marrow cells. This therapy helps lower the red blood cell count and keeps blood flow and blood thickness closer to normal.

At Johns Hopkins:

The Johns Hopkins Center for the Chronic Myeloproliferative Disorders coordinates the care of patients with PV and other related disorders and conducts research in these areas.


For more information, see the website for the MPN Research Foundation

Source: https://www.hopkinsmedicine.org/kimmel_cancer_center/centers/bone_marrow_failure_disorders/polycythemia_vera.html

A Polycythemia Vera JAK2 Mutation Masquerading as a Duodenal Cancer Mutation

Polycythemia Vera | Johns Hopkins Medicine

A 66-year-old woman experienced 2 weeks of abdominal pain and then noted dark urine, prompting evaluation. Blood work revealed an elevated lipase level, and CT scan results showed an “apple core” lesion in her duodenum.

Upper endoscopy demonstrated a stricture at the duodenum, and bloodwork was notable for elevated levels of total bilirubin (4.5 mg/dL), alkaline phosphatase (443 U/L), aspartate transaminase (388 U/L), and alanine transaminase (675 U/L). Her blood counts were within normal limits.

A pancreatic CT showed a circumferential mass around the duodenum. She underwent a pancreaticoduodenectomy (Whipple) procedure, with pathology showing a 3.0-cm moderately to poorly differentiated duodenal adenocarcinoma. Of 28 lymph nodes, 6 were positive for disease.

The patient initiated adjuvant chemotherapy with folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX); however, recurrence in her liver was discovered during her adjuvant treatment. Due to side effects, her therapy was changed to capecitabine.

Her disease progressed and she was placed on folinic acid, 5-fluorouracil and irinotecan (FOLFIRI). She continued to have progressive disease and was then started on cetuximab; however, her disease worsened. Her primary duodenal cancer was subjected to NGS using a cancer gene panel (FoundationOne; Foundation Medicine, Inc.

, Cambridge, MA) (see supplemental eAppendix 1, available with this article at JNCCN.org). The Genetic Alterations in Tumors With Actionable Yields (GAITWAY) tumor board at Johns Hopkins received the results and discussed potential mutations that could be targeted for therapy.

The patient's NGS results contained CCND3, CDK4, ERBB3, VEGFA, GLI1, and MDM2 amplifications and SMAD4 E538* and JAK2 V617F mutations.

Of these alterations, the JAK2 mutation was noted to be potentially actionable given that this mutation is found in the vast majority of patients with polycythemia vera (PV) and is predictive of response to the targeted kinase inhibitor ruxolitinib.

2 After conferring with the referring physician, it was discovered that the patient had a history of JAK2-positive PV treated for many years exclusively with phlebotomy. At this point, we reasoned that the JAK2 mutation was ly blood contamination of the duodenal tissue.

However, there was still the remote possibility that this was instead a heritable, germline mutation, which cannot be differentiated from somatic mutations when only tumor tissue is sequenced.

Although the JAK2 V617F mutation has never been reported in the germline of patients with sporadic or hereditary PV, there have been reports of other JAK2 mutations, including V617I, in the germline of patients with the related myeloproliferative disorder essential thrombocytosis.

3–5 Therefore, we wanted to definitively rule this out, because it would have implications for treatment and genetic counseling. Because blood could not be used in this instance as a source of germline DNA, we performed Sanger sequencing using DNA extracted from a buccal swab.

Surprisingly, this analysis showed an approximately 50% allelic fraction, suggesting the mutation was potentially germline (Figure 1). Although saliva and buccal swab samples can contain contaminating hematopoietic cells,6 we had reasoned that DNA from blood cells would contribute only a minor allelic fraction that would be below the limit of detection on standard Sanger sequencing.7 To address this further, we obtained the primary tumor and adjacent normal tissues and repeated NGS testing. The JAK2 V617F mutation was present in both tumor and normal samples, but at low allelic frequencies of 13% and 4%, respectively (Figure 2A). This strongly suggested that the mutation arose from the blood cells and was not germline, because germline mutations would be expected to have an allelic frequency close to 50%.

Figure 1.

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Genomic DNA isolated from buccal swab demonstrates heterozygosity for the JAK2 V617F mutation. DNA was isolated and subjected to polymerase chain reaction amplification and Sanger sequencing.

Shown are results from capillary electrophoretic sequencing in (A) forward and (B) reverse directions.

The V617 corresponding DNA locus is shown with 2 peaks highlighted in blue, representing the bases G (wild-type) and T (mutant) in the forward direction and C (wild-type) and A (mutant) in the reverse direction.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 12; 10.6004/jnccn.2016.0161

Figure 2.

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False-positive sequencing results due to blood contamination. (A) Schematic showing results from next-generation sequencing (NGS) of (1) the duodenal tumor and (2) normal adjacent tissue, and Sanger sequencing from (3) a buccal swab sample and (4) finger nail clippings.

(B) Duodenal adenocarcinoma with blood vessels and hemorrhage (hematoxylin and eosin, original magnification x40). Normal duodenal mucosa (top) with underlying invasive adenocarcinoma (bottom). Note the intraglandular hemorrhage (arrow) and rich vasculature (arrowheads).

Neutrophils are noted in the vessels (inset; original magnification x400).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 12; 10.6004/jnccn.2016.0161

To definitively prove the mutation was not germline, we obtained fingernail clippings as an alternative source of normal tissue. Sanger sequencing analysis demonstrated only wild-type sequence at the JAK2 V617 locus (Figure 3). Unfortunately, the patient's disease continued to progress, and she ultimately was referred to hospice care.

This case report highlights several considerations when evaluating tumor sequencing results. First, if germline

Figure 3.

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Genomic DNA isolated from fingernails show wild-type sequence for the JAK2 V617 locus. DNA was isolated and subjected to polymerase chain reaction amplification and Sanger sequencing.

Shown are results from capillary electrophoretic sequencing in (A) forward and (B) reverse directions.

The V617 corresponding DNA locus is highlighted in blue with only wild-type bases present in the forward and reverse direction.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 12; 10.6004/jnccn.2016.0161

DNA is being tested for comparative purposes, the source of germline DNA needs to be considered in the context of a patient's clinical history and disease state. Peripheral blood lymphocytes, buccal swabs, and saliva are often used as sources of DNA for germline noncancer controls, but clearly cancer DNA can be overrepresented in these fluid/tissue sources when a patient has a hematologic cancer or myeloproliferative disorder. In this case report, it is ly that there was an extremely high level of blood cells present in the patient's saliva leading to a 50% allelic fraction.

Second, this case illustrates the need for interpreting NGS results within the context of clinical history, as well as the knowledge of mutations that are strongly associated with a given cancer.

Genes frequently mutated in hematologic disorders, including JAK2, IDH1, IDH2, SF3B1, KRAS, NRAS, and others, have also been found to be somatically mutated in a variety of solid tumors.8 Several of these genes are viewed as potential therapeutic targets or predictors of drug response or resistance.

In this case, the referring physician knew of the patient's PV diagnosis.

However, it is possible that for some solid tumors with reported mutations that are typically found in hematologic diseases, the mutation may originate from undiagnosed blood disorders that have contaminated tumor specimens used for NGS, as was the case for our patient (Figure 2B). Oncologists and molecular tumor boards reviewing NGS reports should be vigilant for this possibility.

Third, although tumor cellularity is often assessed when evaluating tissue specimens for NGS, there may be utility in reporting hematopoietic cellularity within the tissue specimens used for such analyses, especially when mutations in genes typically associated with hematopoietic disorders are identified. Along these lines, we advocate reporting of mutational allelic frequencies in NGS results, which can aid in interpretation of subclonal populations and contamination by blood cells.

Finally, we propose that fingernail clippings are a viable source of germline DNA and offer significant advantages over currently used tissue sources, including painless procurement, lack of blood contamination, minimal cost, and ease of obtainment. Although nail clippings are used routinely in forensic medicine, newer extraction techniques have allowed for higher-quality DNA that is now suitable for NGS analysis.9


The authors would to thank the entire GAITWAY tumor board for their input and assistance on this case.

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