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Genetic Testing: Ready, Set … Actionable?

December 30, 2021

In June 2000, President Bill Clinton announced that the international Human Genome Project and Celera Genomics had completed the initial sequencing of the human genome. This landmark accomplishment cost an estimated $2.7 billion.1 Nearly 20 years later, what once took years and cost billions can now be accomplished for a little less than $1,000 – and falling.2,3

This genetic revolution has made it possible to record and analyze the genetic code of thousands of people and has led to greater insights into how differences in genetic material, such as mutations or translocations, cause diseases.

"We do not know how many hematopoietic or bone marrow (BM)–derived malignancies have a genetic component, but we suspect the number is much higher than anything people have thought of in the past," explained Lucy Godley, MD, PhD, professor in the Departments of Medicine and Human Genetics at the University of Chicago. Dr. Godley also is a member of the American Society of Hematology (ASH) Task Force on Precision Medicine.

ASH Clinical News spoke with experts about the growing and evolving role of genetic testing within hematology, the acquired mutations that may – or may not – lead to disease, and what questions need to be answered to prepare for the future.

The Tip of the Iceberg

"Most hematologic malignancies will have one or more genetic changes that could be important in diagnosis or management decisions," said Charles G. Mullighan, MBBS (Hons), MSc, MD, co-leader of the Hematological Malignancies Program at St. Jude Children's Research Hospital in Memphis, chair of the ASH Committee on Scientific Affairs, and a co-chair of the ASH Task Force on Precision Medicine.

One of the greatest success stories within hematology was the discovery that chronic myeloid leukemia (CML) is caused by one translocation that results in a single mutation, the BCR-ABL fusion gene. "The investigators found that the BCR-ABL fusion gene is a gas pedal for the cell and drives proliferation," Dr. Mullighan said.

After this breakthrough, researchers set out to develop a drug that could target and kill CML cells. Imatinib was one of the first oral, targeted treatments approved for any cancer type, and it altered the prognosis of patients with CML from a likely death sentence to the possibility of a long, productive life.4

Imatinib was developed and tested prior to the completion of human genome sequencing, but experiences with the drug set a precedent for how researchers could harness genetic information to benefit patients, Dr. Mullighan explained.

Opening Pandora's Box

Since imatinib's introduction, growing research into genes has unearthed a multitude of abnormalities – including amplifications, insertions, or deletions – that may guide treatment decisions associated with hematologic malignancies. For example, the presence of TP53 and del17p mutations confer a poor prognosis in patients with chronic lymphocytic leukemia (CLL) and other hematologic malignancies. Patients with TP53-mutated CLL have an estimated overall survival of three to five years, but the presence of the mutated gene also indicates that a patient's disease is likely resistant to immunochemotherapy and can help determine whether a patient is a candidate for targeted agents (like ibrutinib or idelalisib plus rituximab).5

However, regular testing for TP53 is not recommended, because, for patients for whom no clear treatment is indicated, knowledge of the TP53 mutation might turn a situation of "watch-and-wait" into one of "watch-and-worry." In these cases, genetic information increases patients' anxieties with no immediate therapeutic consequences.

Unlike with CML and BCR-ABL, many malignancies are not caused by a single mutation. A patient diagnosed with diffuse large B-cell lymphoma could have an average of 30 to more than 100 genetic aberrations.6 Individual patients may respond better to certain chemotherapy regimens than others depending on the genetic make-up of their disease.

The use of genetic information to guide treatment is not limited to malignancies. Newborns are routinely screened for inherited mutations in the α- and β-globin genes to test for hemoglobinopathies; an abnormal result could prompt genetic testing to confirm or rule out a diagnosis of sickle cell anemia.

Testing the Limits

Now that its value has been demonstrated, many hematologists are grappling with the issue of how to best perform genetic testing, according to Dr. Mullighan.

"Many genetic tests are done with a gene panel or by looking for single changes in a panel of genes," Dr. Mullighan said. "Increasingly though, we have begun to appreciate that many malignancies have more complex genetic changes, such as breaks in chromosomes or gene rearrangements. As the complexity of these changes increases, the tests are going to need to become more comprehensive."

Dr. Mullighan admitted that the field faces issues with accuracy and standardization. The Centers for Medicare & Medicaid Services (CMS) regulates clinical laboratories, including those that conduct genetic testing, through its Clinical Laboratory Improvement Amendments (CLIA) program. To legally conduct clinical testing, laboratories must pass the CLIA certification process.

Despite these quality measures, there are gene panels being used in clinical testing that are out of date, said Jorge DiPaola, MD, director of basic and translational research in pediatric hemostasis and thrombosis at the University of Colorado School of Medicine.

Dr. DiPaola noted that there is a big variability in genetics in the different types of panels available. Over the last 20 years, many new genes relevant to platelet disorders have been discovered and added to panels, he explained, "but some panels still do not have all the genes that have been described." Others may look for genes that have been disproven to cause platelet disorders.

There are also several limitations associated with genetic testing of germline or inherited mutations, Dr. Godley added. For example, the tissues that are easiest to use in testing for germline mutations – blood and BM – are the tissues affected in hematologic conditions.

"There is an accumulation of mutations during the development of diseases, so if we test the blood and BM we can't tell if the mutation was acquired with the development of the disease or if it was inherited," Dr. Godley explained. "In hematologic patients, we have to go to extra lengths to test DNA that represents inherited genetic material."

That additional testing introduces another limitation: time. Skin fibroblasts are effective for detecting germline mutations in patients with hematologic malignancies, she explained, but "we have to take a skin biopsy and it takes weeks for skin to grow out."

“In hematologic patients, we have to go to extra lengths to test DNA that represents inherited genetic material."

—Lucy Godley, MD, PhD

"These patients often need to be transplanted quickly," she said. Finding an appropriate donor, which is often a limitation even when germline mutations are not present, becomes a greater obstacle when germline mutations are found.

A CHIP off the Old Block

In a 2015 Blood article, authors coined the term "clonal hematopoiesis of indeterminate potential," or CHIP, to describe patients who have detectable somatic (or acquired) clonal mutations in genes recurrently mutated in hematologic malignancies, but without overt signs of a hematologic malignancy or other clonal disorder.7

In 2014, researchers found that CHIP was associated with increased risks of hematologic malignancies, all-cause mortality, and cardiovascular disease – suggesting that clonal hematopoiesis was a precursor to cancer.8-10 For other patients, though, it was just an innocuous aspect of aging.

The discovery of CHIP sparked interest in this premalignant state and even prompted some cancer centers to open clinics specifically for this condition. There are still many unanswered questions about the implications of a CHIP diagnosis, including why it progresses to cancer in certain patients and not others and whether there is a way to intervene to prevent malignant transformation.

CHIP has the potential to aid in early detection, change the standard of care for hematologic malignancies, and improve outcomes for patients with myelodysplastic syndromes or acute myeloid leukemia. For now, though, clinicians lack formal guidelines for how to treat a patient when CHIP is identified.

"As we begin to do deeper sequencing, we can find mutations in everybody at low levels," said Ross Levine, MD, director of the Center for Hematologic Malignancies at Memorial Sloan Kettering Cancer Center, which recently launched a specialty CHIP clinic. Dr. Levine also is the vice chair of the ASH Committee on Scientific Affairs and a member of the ASH Task Force on Precision Medicine. "It's not just whether a patient has these mutations, but also whether he or she has mutations at enough of a burden to be clinically relevant. That's one of the questions the field needs to figure out."

Whether CHIP should affect treatment, and how, depends on the clinical context of the discovery.

For example, a study of patients with solid-tumor malignancies undergoing chemotherapy who had CHIP at the time of primary diagnosis were almost six times more likely to later develop a therapy-related malignancy than those without CHIP (odds ratio = 5.75; 95% CI 1.52-25.09; p=0.013).11 This finding could have important clinical implications for treatment of patients who present with CHIP at the time of primary cancer diagnosis, the study's lead author Nancy K. Gillis, PharmD, postdoctoral fellow at the Moffitt Cancer Center in Florida, told ASH Clinical News.

"Our eventual goal is to incorporate this into decision algorithms to help guide a treatment plan," she explained, offering the following example: "If you are trying to determine whether a patient should receive adjuvant therapy for her breast cancer, and you know that she has CHIP, maybe you would decide against giving additional chemotherapy because the risk [of developing a second malignancy] outweighs the benefit." It would also need to be determined whether it makes sense from a health policy perspective to screen a large population of patients with solid tumors to detect the relatively small number of patients destined to develop a therapy-related myeloid neoplasm.

Dr. Levine recommends patients be evaluated for a myeloid malignancy if they exhibit CHIP with high-risk features (like high variant allele frequency or multiple distinct mutations). In the absence of these risk factors, clinicians should consider a "watch-and-wait" approach with regular bloodwork. (For an in-depth look at CHIP, see "Determining CHIP's Potential" in our special edition, "Focus on Myeloid Malignancies.")

Banking on Genomics

While the significance of certain genetic mutations is still being defined, CMS has answered a critical question regarding the clinical use of genetic testing: "Who's paying for it?"

On March 16, CMS finalized its National Coverage Determination (NCD) for diagnostic, next-generation sequencing (NGS) tests for Medicare beneficiaries with advanced cancers. The decision was issued shortly after the U.S. Food and Drug Administration (FDA) approved the first genetic cancer test, the FoundationOne CDx test, a 324-gene panel test and companion diagnostic for 15 targeted therapies.12

"CMS believes [that] these tests can assist patients and their oncologists in making more informed treatment decisions," the agency stated in a press release announcing the decision. "Additionally, when a known cancer mutation cannot be matched to a treatment, then results from the diagnostic lab test using NGS can help determine a patient's candidacy for cancer clinical trials."12

The decision means CMS will fully cover FDA-approved or cleared companion in vitro diagnostics in cases when the test has an FDA-approved or cleared indication for use in that patient's cancer. Clinicians can order investigational, non–FDA approved tests, but coverage isn't guaranteed.

Results must be provided to the treating physician for management of the patient using a report template to specify treatment options. The final decision also extends coverage to repeat testing when the patient has a new primary diagnosis of cancer.

So far, the NCD only applies to tests for patients with advanced cancers. Still, routine clinical use of genetic testing will generate large volumes of genomic data from these patients. Tracking and analyzing these data throughout treatment will help researchers and regulators further study the implications of genetic mutations.

In April 2018, the FDA also demonstrated their support for NGS-based tests by issuing recommendations to accelerate the development and review of NGS-based tests.13 The guidance describes how developers can use FDA-recognized databases to support the clinical validation of NGS-based, as well as providing guidance on the information the FDA will look for in pre-market submissions to validate a test.

"As disease detection technologies rapidly evolve, so too must the FDA's approach to reviewing these new innovations," said FDA Commissioner Scott Gottlieb, MD. "The new policies issued today provide a modern and flexible framework to generate data needed to support the FDA's review of NGS-based tests, and give developers new tools to support the efficient development and validation of these technologies."

Call the Counselor               

As NGS is being used more widely, in addition to somatic mutations, hematologists are also discovering germline mutations, which can have implications for other family members, as they can be heritable. That's where a genetic counselor can step in.

In addition to clarifying the benefits, limitations, and risks of genetic testing with patients, "counselors can also discuss the risk of finding mutations that have been known to cause other disorders or of variants that we do not know the significance of yet," Dr. DiPaola said.

He noted that the community has shifted recently toward more transparency with patients about these findings. Yet, "there are several caveats of known or uncertain significance that should be communicated to patients and their families," he said. "That's why any hematologist who wants to do genetic testing on a patient should definitely involve a genetic counselor."

Colleen McBride, PhD, Rollins Professor and Chair of the Department of Behavioral Sciences & Health Education at Emory University in Atlanta, agreed, emphasizing the importance of helping patients understand what a genetic test can and cannot tell them. "Because so much of genetic science has been – some would argue – oversold, people might expect more out of genetic testing than it can deliver," she said. "We have to align expectations with the realities of what this testing is."

The discovery of germline mutations can alter the lives of patients' family members: On the one hand, relatives can seek out their own counseling to decide if they should undergo genetic testing; on the other hand, patients can feel obligated to discuss results with estranged family members.

"When you start into the realm of genetic testing, there are many interpersonal issues – like paternity or sensitive family information – that can come up," Dr. McBride said.

The field of genetic testing is evolving so quickly that it is often difficult for genetic counseling services to keep up, though, Dr. Godley cautioned. For example, many people diagnosed with breast cancer may be tested for the presence of BRCA mutations; however, BRCA can also predispose people to leukemia.

"If you ask a sample of genetic counselors if they counsel BRCA mutation carriers about increased risk for BM malignancies, many would say that it's not part of their training," Dr. Godley said.

The Next Generation of NGS

All the interviewees acknowledged that to fully mine the clinical significance of NGS data, the information gained from these analyses needs to be better organized. Toward that end, the National Institutes of Health (NIH) has funded the Clinical Genome Resource, or ClinGen. The program is dedicated to building an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research.13

"This is a publicly available database where variants are given a designation as to the likelihood that they confer risk for disease or not," Dr. Godley said. "The American College of Medical Genetics and Genomics has put forth a very standardized approach to give variants designations as deleterious, likely deleterious, unknown, or benign."14

The problem today is that one lab may call something "benign" and a different lab will call it "deleterious," Dr. Godley said. ClinGen is trying to standardize that.

ASH is the first professional society or foundation to sponsor ClinGen Working Groups. The first group, co-chaired by Dr. Godley, will collate variants for genes that confer risk for myeloid malignancies. The second group, co-chaired by Dr. DiPaola, will collate variants known to be associated with and/or cause platelet disorders.

On April 5, ASH announced a partnership with the University of North Carolina at Chapel Hill, a ClinGen grantee, to develop a broad and accessible compendium of genomic data aimed at improving the diagnosis of these hematologic disorders.15

"We have invited people from all categories or disciplines involved in genetic testing, including scientists, clinicians, and genetic counselors," Dr. DiPaola said. "We, as a group, are going to determine the clinical evidence that each variant has within the genotype."

The results of this effort will be shared with the scientific community through ClinVar, a publicly available NIH database that houses data on genetic mutations submitted by laboratories nationwide.

ASH's participation in the effort is part of a larger Precision Medicine Initiative the Society has undertaken to improve genomic profiling of hematologic diseases and identify strategies to improve the use of molecular data in clinical care, research, and education (see SIDEBAR).

"It is so clinically important to standardize what labs are doing across the country and to provide a resource for physicians," Dr. Godley said. With the information gleaned from the ClinGen project and other efforts, "when physicians find that a patient has a variant on a panel for leukemia, they will be able to go to a public database to discover what that variant could mean. We really are only at the tip of the iceberg, and my suspicion is that many more genetic syndromes will be identified in the next five to 10 years." —By Leah Lawrence


  1. National Human Genome Research Institute. "The Human Genome Project Completion: Frequently Asked Questions." Accessed March 28, 2018, from
  2. National Human Genome Research Institute. "The Cost of Sequencing a Human Genome." Accessed March 28, 2018, from
  3. Forbes. "Illumina Promises To Sequence Human Genome for $100 – But Not Quite Yet." Accessed March 9, 2018, from
  4. National Cancer Institute. "A Story of Discovery: Gleevec Transforms Cancer Treatment for Chronic Myelogenous Leukemia." Accessed March 28, 2018, from
  5. Rossi D, Gaidano G. The clinical implications of gene mutations in chronic lymphocytic leukaemia. Br J Cancer. 2016;114:849-54.
  6. Amin AD, Peters TL, Li L, et al. Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer? Cold Spring Harb Mol Case Stud. 2017;3:a001719.
  7. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9-16.
  8. Genovese G, Kahler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477-87.
  9. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377:111-21.
  10. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488-98.
  11. Gillis NK, Ball M, Zhang Q, et al. Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol. 2017;18:112-21.
  12. Centers for Medicare & Medicaid Services. "CMS finalizes coverage of Next Generation Sequencing tests, ensuring enhanced access for cancer patients." Accessed March 26, 2018, from
  13. Clinical Genome Resource. "About ClinGen." Accessed March 22, 2018, from
  14. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24.
  15. American Society of Hematology. "ASH Announces Partnership with the University of North Carolina, a ClinGen Grantee, to Curate Genomic Data for Blood Disease Research." Accessed April 6, 2018, from

When President Barack Obama announced the launch of the Precision Medicine Initiative in 2015, ASH applauded this effort and defined a new set of research priorities with genomic profiling and chemical biology at the top of the list.1,2 It also created its own Precision Medicine Initiative and the ASH Task Force on Precision Medicine to explore new ways in which ASH could work with the NIH and other organizations to address gaps within genomically designed, precision medicine trials.3,4

"In the context of hematology, precision medicine is thinking about how genetic information and testing can inform clinical care," said Charles G. Mullighan, MBBS (Hons), MSc, MD, co-leader of the Hematological Malignancies Program at St. Jude Children's Research Hospital, chair of the ASH Committee on Scientific Affairs, and co-chair of the ASH Task Force on Precision Medicine. "ASH sees the Precision Medicine Initiative as a huge opportunity to meet an unmet challenge in the field."

The task force has identified three areas related to precision medicine that would be useful to its membership in the short- and medium-term, Dr. Mullighan explained.

First, the initiative should help researchers and clinicians gain a better understanding of what mutations mean in each particular gene. "There is a huge amount of research done in this area, but it is not done with a systematic approach," Dr. Mullighan said. "We need a method that reviews all the mutational data available and can tell us what each mutation means in the disease and whether it is relevant or druggable."

The second focus is data housing. Dr. Mullighan noted that the interpretation of genomic data is only as good as the genetic reference where the data were derived. "Sequencing a cancer in isolation can mean very little, but in the context of 1,000 genomes together, it can mean a lot," he said. "Our challenge is that much of our data is siloed. We have to try to house as much genetic information as possible in one place."

The third focus is continuing to support research that fills in knowledge gaps. "A lot of sequencing has been done, but there is still much more work to do," he said.

In 2005, the National Cancer Institute and the National Human Genome Research Initiative launched The Cancer Genome Atlas (TCGA), an effort to generate "comprehensive, multidimensional maps of the key genomic changes in 33 types of cancer."5  The TCGA project produced 2.5 petabytes of data describing tumor tissue and matched normal tissues from more than 11,000 patients, and, though it is an incredible resource, Dr. Mullighan noted, many hematologic diseases have not been studied at all or have not been studied comprehensively.

"ASH is in the process of initiating a project that will solicit applications for people to apply to sequence certain tumor types in sample cohorts to answer important scientific questions," Dr. Mullighan said.


  1. The White House of President Barack Obama. "FACT SHEET: President Obama's Precision Medicine Initiative." Accessed March 28, 2018, from
  2. American Society of Hematology. "ASH Agenda for Hematology Research." Accessed April 16, 2018, from
  3. American Society of Hematology. "ASH Precision Medicine Initiative." Accessed April 16, 2018, from
  4. The Hematologist. "President's Column. Leading the Charge for Precision Medicine." Accessed March 28, 2018, from
  5. The Cancer Genome Atlas. "Program Overview." Accessed April 16, 2018, from

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