Features
FEATURE
Genetic Testing
Just Scratching the Surface
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 .”
He 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 .
ASHClinicalNews . org ASH Clinical News
59