In this interview, News Med is talking to Gabriela Saldanha about DNA Fragmentation and Sanger Sequencing.
What are Sanger sequencing and DNA-fragment analysis? Where are these analyses used?
Sanger sequencing by capillary electrophoresis is the gold standard for DNA sequencing, even with the advent of next-gen sequencing (NGS). The assay and its interpretation are simple and targeted and are best used for DNA fragments that are 75‒1,000 bases long. The current best practice in many labs is to confirm NGS results with Sanger sequencing, and Sanger sequencing is the most cost-efficient method for sequencing single samples.
Fragment analysis separates and analyzes fragments of DNA amplified by PCR. Short tandem repeat (STR) analysis is a subset of fragment analysis and, in the past, has most often been used in forensic and paternity analyses. However, STR analysis can also support non-forensic applications such as cell line authentication, MLPA, microsatellite analysis and mixed-sample deconvolution.
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What instrumentation is required for Sanger sequencing and fragment analysis? Will most researchers have these instruments in their labs, or will they outsource the work?
A single-base resolution capillary electrophoresis system is standard equipment for carrying out these analyses. In the past, many labs would send samples to core labs for analysis because the equipment was often too big or expensive for labs that only needed to…
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Tumors have significant differences depending on the person affected, even if they are the same cancer, such as breast cancer. Therefore, precision oncology targets specific genetic characteristics of a tumor and incorporates them into treatment. In this way, existing therapies can be “tailored” to avoid side effects and save money on expensive treatments. This represents the cancer treatment of the future.
Dr Dilara Akhoundova, medical oncologist at the University Hospital Bern and postdoctoral researcher at the University of Bern, and Prof Mark A. Rubin, director of the Department for BioMedical Research (DBMR) and the Bern Center for Precision Medicine (BCPM), have now summarized and reviewed the most recent advances in multi-omics tumor profiling. In their review, published in the leading journal Cancer Cell, they provide a critical view of the current state of translational validation of the reviewed technologies and analyze their potential for integration into precision treatment.
These new technologies take us to a depth of understanding of tumors that has never been seen before. It is as if with the standard tools, we were told that Switzerland is a country with higher altitudes than the Netherlands; with these new technologies, we can see the 3-D landscape of mountains, valleys, and lakes.”
Mark A. Rubin, Director of the Bern Center for Precision Medicine
Integrating novel technologies into the clinic as fast as possible
However, there…
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Test tube with DNA molecule on abstract background
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Genetic testing once was offered only to people with rare genetic conditions, or strong family histories of disease that spanned generations. But genetic testing is now being offered to healthy people, to detect if they carry a genetic change (often referred to as a “variant” or “mutation”) that may place them at high risk to develop preventable conditions, including some cancers and cardiac conditions.
In theory, population genetic testing makes sense. Instead of waiting for a person to die of a heart attack at a young age, we can learn of some of those risks ahead of time and mitigate them. This approach works not only for the person having testing and their family members – who may also be at risk – but also for our medical system, employers, and overarching health care costs that we, as a society, want to minimize.
But in practice, are we there yet? Cristi’s story illustrates that we still have a long way to go to make population genetic testing a win for the patient and their family members. Cristi is a certified genetic counselor who, like many of us, knew that several members of her family had developed cancer. But the cancers in Cristi’s family did not fit into a known hereditary cancer syndrome. Cristi’s mom had genetic testing based on her personal history of a brain tumor and melanoma, and family history of breast and prostate cancer, and no mutations were found in her DNA. So when Cristi signed up for genetic testing to check the customer experience of a population-based screening program offered by her company, she was surprised to learn that she carried a pathogenic variant in a gene called RET.
People who carry a RET variant have a syndrome called Multiple Endocrine Neoplasia 2A (MEN2A) and are considered to have an almost 100% chance of developing an aggressive type of thyroid cancer called medullary thyroid cancer. For this reason, people with MEN2A have traditionally been counseled to remove their thyroid gland preventively, often in childhood, before they develop cancer. MEN2A is also associated with a high risk of developing pheochromocytomas (tumors on the adrenal glands) and tumors of the parathyroid glands. Recommendations for people with MEN2A include specialized screening for these tumors each year, consisting of blood work and ultrasound imaging.
At first, Cristi’s healthcare team thought her genetic results must be a…
The genes involved in coronary heart disease, the most common form of heart disease, appear to be nearly the same for everyone, according to a VA study.
Roughly one-third to one-half of everyone’s chances for developing this type of heart disease are rooted in their genes. This genetic risk seems to be the same across all major racial and ethnic backgrounds, including people of European, African, Japanese, and Indigenous ancestries, the VA study found.
Some groups, such as African Americans, are more likely to suffer from heart disease, and our findings indicate that’s not because they have a higher genetic risk for the disease. It confirms that other factors are responsible for more heart disease in those populations, such as access to health care and different lived experiences,” she adds.
Dr. Catherine Tcheandjieu, study author, genetic epidemiologist, VA Palo Alto Health Care System and University of California San Francisco
The genetic study-;the largest to date on heart disease-;was published August 1, 2022, in Nature Medicine. It looked at nearly a quarter of a million cases of coronary heart disease, including more than 100,000 U.S. Veterans with the disease.
Coronary artery disease is the leading cause of death in the United States, responsible for one in every five deaths. It occurs when major blood vessels to the heart muscle become narrowed or blocked, which can lead to heart attack.
The study was led by investigators at the Palo Alto VA and involved researchers from several other VAs across the nation.
Research into the genetics of heart disease, like many other areas of health research, is mostly based on data from white people because of higher participation.
The Nature Medicine study, on the other hand, examined the genes of more than 27,000 Black and 12,000 Hispanic people with coronary artery disease. Most of these were Veterans, who agreed to share their genetic and health information for research as part of VA‘s Million Veteran Program, also known as MVP.
With data from MVP, VA researchers in this study confirmed for the first time that many genetic variations known to heighten heart disease risk in white people have the same effect in people of African and Hispanic ancestry. Additionally, researchers found nearly 100 new locations on the human genome where variations appear to increase risk of coronary artery disease.
To find these locations in the human genome that are linked to heart disease,…
Several decades of nutrition research have shown us that no one-size diet fits all and since we are all unique, healthcare nutrition which applies to all doesn’t fit everyone. Many factors come into play as to why it may happen but the main reason has something to do with our genes or genetic makeup.
Genomic testing determines the interplay between genes, nutrition and health. It helps personalise the diet and nutrition and provides you with a blueprint for optimal health and wellness.
What do genomic tests evaluate?
Genomic tests identify the specifics of our DNA, in terms of change in our chromosomes, associated genes and/or protein . Nutrigenetic DNA tests examine the genes and variants of these genes involved in specific nutrients and their metabolism.
What can genomic testing tell you?
Genomic testing can reveal a wide range of information, from your ancestry to your health and family history. For instance, genetic testing can screen and diagnose complex diseases, find out the risk and predisposition to disease, identify hereditary disease patterns and even help in creating a course on treatment, revealing a proclivity for nutrient deficiency or toxicity, food sensitivities and even whether you’re at risk for nutrition-related diseases.
In an interview with HT Lifestyle, Dr Saima Naz Khan, Senior Manager- Scientific Affairs at Genes2Me Pvt Ltd, revealed, “Every individual requires a balanced diet which should comprise macronutrients (carbohydrates, proteins, fats and fibers) and micronutrients (minerals and vitamins) but no individual neither requires nor responds to the exact amount of these nutrients; therefore, there’s no one-size-fits-all diet. While several factors are at play, genetics plays a crucial role in our nutrition. Genomic testing can reveal why…
A baby who dies before 28 weeks of pregnancy is referred to as a miscarriage while babies who die at or after 28 weeks are stillbirths but the World Health Organization highlights that pregnancy loss is a taboo subject worldwide, linked to stigma and shame and many women still do not receive appropriate and respectful care when their baby dies during pregnancy or childbirth. It states, “General advice on preventing miscarriage focuses on eating healthily, exercising, avoiding smoking, drugs and alcohol, limiting caffeine, controlling stress, and being of a healthy weight.”
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Another health tip by experts, to prevent miscarriages is genetic testing. In an interview with HT Lifestyle, Dr Jyothi Patil, Senior Consultant – Reproductive Medicine, Obstetrician-Gynaecologist at Bangalore’s Milann – Fertility & Birthing Hospital, shared, “The most common reason for miscarriage is some kind of chromosome abnormality that can be identified through genetic testing. It enables one to detect changes in genes, chromosomes, or proteins. Besides confirming or ruling out a suspected genetic ailment the test can also determine a person’s risk of developing or passing on a genetic disorder. Genetic testing is a personal choice that might have a positive or negative outcome.”
She added, “Unnecessary check-ups and screening tests can be avoided with a negative result. A positive outcome can point a person in the direction of available preventative, monitoring, and treatment choices. About half of all miscarriages in the first trimester are caused by chromosomal abnormalities in the foetus. In vitro fertilization and embryo genetic testing are available to couples who are suspected of losing children owing to recurring genetic disorders (preimplantation genetic testing or PGT). PGT has been shown to minimise the number of miscarriages.”
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Revealing that about 5 percent of pregnancies end in miscarriages because of recurrent pregnancy loss, Dr Saima Naz Khan, Senior Manager-Scientific Affairs at Genes2Me Pvt Ltd, said, “After several pregnancy losses, couples want to know the cause behind it because they want to know whether their action caused it or they could have done something to prevent it. However, we have seen that the genetic problem can cause these pregnancy losses.”
She suggested that if couples want to know the reason behind recurrent pregnancy losses, then genetic testing can be performed to avoid the loss. Dr Saima said, “We advise couples to undergo Microarray chromosomal testing. It is an advanced technology that can analyse thousands of DNA samples simultaneously. In this process, direct foetal samples are extracted from the DNA, and thus, it does not require cells from the foetus. Furthermore, the chromosomal microarrays have a high detection ability of chromosomal abnormalities.”
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She elaborated that because of its enhanced diagnostic yield than the rest of the traditional methods, chromosomal microarray has become a promising tool for chromosome analysis. She added, “After the genetic testing, you can talk to your genetic counsellor to understand the reason behind the miscarriage. Depending on your results, the fertility specialist can counsel you on what course of action you can take to prevent miscarriage and pregnancy loss.”
Discuss the results of genetic prenatal screening tests with a genetic counselor or other health care provider.
Date Issued: April 19, 2022
The U.S. Food and Drug Administration (FDA) is warning patients and health care providers about the risks of false results with genetic non-invasive prenatal screening (NIPS) tests, sometimes called noninvasive prenatal testing or tests (NIPT). Results from NIPS tests can provide information about the possibility of a fetus having certain genetic abnormalities that could result in a child being born with a serious health condition.
While health care providers widely use NIPS tests, none have yet been authorized, cleared, or approved by the FDA. The accuracy and performance of NIPS tests have not been evaluated by the FDA and these tests can give false results, such as reporting a genetic abnormality when the fetus does not actually have one. NIPS tests are screening tests, which means the NIPS test may only tell you the risk of the fetus having certain genetic abnormalities. They are not diagnostic tests, which are generally used to more definitively confirm or rule out a suspected genetic abnormality.
The FDA is aware of reports that patients and health care providers have made critical health care decisions based on results from these screening tests alone and without additional confirmatory testing. Specifically, pregnant people have ended pregnancies based only on the results of NIPS tests. Without confirming the results with a diagnostic test, there is no way to know whether the fetus actually had the genetic abnormality reported by the screening test. The FDA is aware of cases where a screening test reported a genetic abnormality and a confirmatory diagnostic test later found that the fetus was healthy.
Given the increased use of these tests and concerns raised in recent media reports, the FDA is providing this information to educate patients and health care providers and to help reduce the inappropriate use of NIPS tests. The FDA recommends that patients discuss the benefits and risks of NIPS tests with a genetic counselor or other health care provider before deciding to get these tests. Patients should also discuss the results of NIPS tests with a genetic counselor or other health care provider before making any decisions about their pregnancy. Health care providers should be aware of the risks and limitations of using these screening tests and should not use the results from these tests alone to diagnose chromosomal (genetic) abnormalities or disorders.
Recommendations for Patients
Talk with a genetic counselor or other health care provider before deciding to have prenatal testing and to discuss which tests to use, including genetic screening tests such as NIPS tests. Genetic counselors and other health care providers can help you understand the benefits and risks of these tests.
Do not use the results of screening tests such as NIPS tests alone to make decisions about your pregnancy because the results of these tests may not accurately reflect whether your fetus has a genetic abnormality. Additional testing may require invasive procedures to obtain a sample, such as amniocentesis or chorionic villous sampling (CVS), which carry a small risk of miscarriage. The diagnostic confirmatory tests performed on these samples may not have been reviewed by the FDA.
Discuss the results of genetic prenatal screening tests and what the results may mean with a genetic counselor or other health care provider. They can help you decide whether to get additional testing to confirm results from a screening test.
A positive screening test result means that the fetus has a higher risk of having a genetic abnormality compared with the average risk. It does not mean that the fetus definitively has a genetic abnormality, or a condition caused by a genetic abnormality.
A negative screening test result means that the fetus has a lower risk of having a genetic abnormality compared with the average risk. It does not rule out the possibility that the fetus has a genetic abnormality, or a condition caused by a genetic abnormality.
The ability of a NIPS test to correctly tell whether a fetus is at risk for a genetic abnormality depends on how common or rare the genetic abnormality is and on underlying risk factors. Disorders caused by a microdeletion (small missing piece of a chromosome) are rare. Because these conditions are so rare, a positive result may be more likely to be from a healthy fetus than one that actually has the reported genetic abnormality.
Recommendations for Health Care Providers
Review the Recommendations for Patients with your pregnant patients.
In addition to technical issues, multiple biological factors can influence NIPS results. For example, in some cases, a positive NIPS test result may accurately detect a chromosomal abnormality, but that abnormality is in the placenta and not in the fetus. In these cases, the fetus may be healthy. Additional confirmatory diagnostic tests should be performed to determine whether or not the fetus is affected.
Discuss with your patients the benefits and risks of prenatal tests, including genetic screening tests such as NIPS tests.
Do not use the results of screening tests such as NIPS tests alone to diagnose chromosomal abnormalities or disorders.
Ensure your patients receive the appropriate follow-up testing and care, including genetic counseling, as needed.
Test Description and Background
Noninvasive prenatal screening (NIPS) tests analyze small fragments of fetal DNA, called cell-free DNA, that are circulating in a pregnant person’s blood with the goal of determining the risk that the fetus has certain genetic abnormalities. When used appropriately, these tests offer a non-invasive approach for prenatal screening and may provide useful information to assess the risk that a fetus has (or does not have) a genetic abnormality. It is important for patients and health care providers to be aware that these are screening tests, not diagnostic tests, and to understand the benefits, risks, and limitations of these tests.
Many laboratories that offer these tests claim the tests are “reliable” and “highly accurate,” offering “peace of mind” for patients. The FDA is concerned that these claims may not be supported with sound scientific evidence. False claims may cause patients as well as health care providers to believe the test results are reliable and can be used alone to make decisions about the pregnancy. In addition, because some of the genetic abnormalities and disorders are so rare, in cases such as detection of a microdeletion, there may be a high chance that a positive result is actually from a fetus that does not have the genetic abnormality reported by the test.
The NIPS tests currently being offered are marketed as laboratory developed tests (LDTs). Most LDTs, including NIPS tests, are offered without FDA review. While LDTs are medical devices under the Federal Food, Drug, and Cosmetic Act, the FDA has had a general policy of enforcement discretion for most LDTs since the Medical Device Amendments were enacted in 1976. That means that FDA does not generally enforce applicable regulatory requirements for most LDTs. The FDA is continuing to work with Congress on legislation to establish a modern regulatory framework for all tests, including LDTs.
Additional Information for Health Care Providers
The FDA recommends that health care providers also be aware of the positions of relevant professional societies, including the American College of Obstetricians and Gynecologists (ACOG), the Society for Maternal-Fetal Medicine (SMFM), and the American College of Medical Genetics and Genomics (ACMG):
These medical professional societies recommend that prenatal genetic screening should be discussed and offered to all patients regardless of their age or risk for a chromosomal abnormality.
Patient education is emphasized in order to support informed decision making about whether to accept or decline screening. Emphasis is placed on education surrounding the positive predictive value of NIPS tests and the appropriate use of cell-free DNA tests as screening and not diagnostic tests.
ACMG specifically recommends against testing for aneuploidies (missing or extra chromosomes) other than those involving chromosomes related to Down syndrome (21), Edwards syndrome (18) and Patau syndrome (13).
ACOG does not recommend the use of NIPS tests to detect microdeletions.
Published studies also strongly support the importance of performing confirmatory diagnostic testing to determine whether or not the fetus truly has a chromosomal abnormality following a positive screening test result. The scientific literature related to the use of NIPS tests from laboratories, including 25 peer-reviewed publications covering 13 studies evaluating more than 10,000 individuals undergoing NIPS, indicates that the NIPS tests evaluated generally perform well for ruling out disorders caused by chromosomal abnormalities. The scientific literature generally report high negative predictive values, greater than 99.9% when calculated, for the NIPS tests studied. This means that the fetus is very likely not to have a chromosomal abnormality if the test returns a negative result. However, the literature confirms that the reliability of positive screening results is limited, particularly for microdeletions. Reliability of positive screening results in these studies was best for Down syndrome, with a positive predictive value of about 90%, meaning that one in 10 positive results are not confirmed as Down syndrome. However, reliability of positive screening results was far lower for microdeletions, with the positive predictive value ranging from about 2% to 30%, depending on the condition. For example, Di George syndrome, which is caused by a microdeletion on chromosome 22, showed a positive predictive value of about 30%. This means that, out of 10 patients receiving a positive result for Di George syndrome on a screening test, it is not confirmed in 7 of those patients when diagnostic testing is performed with CVS or amniocentesis.
FDA Actions
The FDA is informing the public of the risks related to the use of genetic prenatal screening and the potential harm if NIPS test results are not used and interpreted appropriately.
The FDA encourages test developers to provide accurate, clear, and complete information about the performance of their tests, how they should be used, and what the results may or may not mean. The FDA also encourages test developers to work with the FDA toward authorization, clearance, or approval of their tests.
The FDA will continue to closely monitor safety issues around the use of NIPS tests and is committed to protecting public health. The FDA will keep the public informed if significant new information becomes available.
Reporting Problems with Your Device
If you think you had a problem with a non-invasive prenatal screening (NIPS) test, the FDA encourages you to report the problem through the MedWatch Voluntary Reporting Form.
Health care personnel employed by facilities that are subject to the FDA’s user facility reporting requirements should follow the reporting procedures established by their facilities.
Questions?
If you have questions, email the Division of Industry and Consumer Education (DICE) at [email protected] or call 800-638-2041 or 301-796-7100.
In this interview, we speak to Sheetal Parmar, vice president of medical affairs and head of clinical services at Natera, about their cell-free DNA (cfDNA) testing services and the future of genetic testing with science.
Please could you introduce yourself and tell us about your current role at Natera?
I’m Sheetal Parmar, a board-certified genetic counselor and vice president of medical affairs at Natera.
Natera is a global leader in cell-free DNA (cfDNA) testing. What are some of your aims and missions at Natera?
At Natera, we aim to make personalized genetic testing and diagnostics a part of standard care, and our mission is to change the management of disease worldwide. Our core cfDNA technology provides health information in the areas of reproductive health, oncology, and organ health.
Natera is revolutionizing the standard of care with next-generation, cell-free DNA testing
You analyze cfDNA to find insights about health and disease. What is cfDNA and what insights can you gain from analyzing it?
Cell-free DNA, or cfDNA, are small pieces of free-floating DNA found in the bloodstream. Everyone has cfDNA that originates from their own cells in their bloodstream. By analyzing the cfDNA from a blood draw, we can collect useful genetic information about a variety of conditions.
The first application of our cfDNA technology was in the reproductive health space. During pregnancy, there is cfDNA from both the pregnant individual and the placenta circulating in the bloodstream and we can analyze it to screen for chromosome conditions such as trisomy 21, trisomy 18, and trisomy 13.
We applied what we learned about analyzing cfDNA during pregnancy to oncology to detect molecular residual disease and monitor disease recurrence, and also use this technology in organ health, to assess for transplanted kidney, heart, and lung rejection.
Despite women’s health seeing more interest in recent years, there is still more that needs to be done. What do you currently believe to be some of the biggest challenges faced by women’s health and why should life sciences companies be placing a greater emphasis on it?
I agree that there is so much more we can do to address challenges in women’s healthcare. For example, despite all our scientific advances, there exist pregnancy complications such as preterm birth and preeclampsia that are associated with morbidity and mortality. Preterm birth affects about 10% of pregnancies and is associated with significant neonatal morbidity and mortality.
Preeclampsia, a condition where a pregnant person develops high blood pressure with protein in the urine and other problems affects approximately 3-8% of pregnancies. 10-16% of maternal deaths in economically advanced societies are due to preeclampsia. Many researchers and companies are focusing on health issues like these because they are significant and methods to identify pregnancies at risk are limited.
Natera has developed a variety of tests within the field of women’s health. Can you describe some of the tests that are available for women and what they test for?
Natera has a number of genetic tests that provide important health information from preconception through pregnancy. This includes Spectrum preimplantation genetic testing of embryos during the IVF process; Horizon carrier screening for individuals and couples to determine their risk for passing a genetic condition to their child; Panorama NIPT which screens for chromosome conditions in the pregnancy, Vistara NIPT which screens for single-gene conditions in the pregnancy, and Anora which is a test on miscarriage tissue to identify the cause of a pregnancy loss.
Additionally, we have a genetic test called Empower for those who want to know more about their risk for developing cancer, understand why it might be more common in their family, or want to inform treatment options following a cancer diagnosis. Empower screens for genes associated with an increased risk for common hereditary cancers and our multi-cancer panels include commonly screened-for genes associated with 12+ types of cancer.
Image Credit: 10 FACE/Shutterstock.com
You have also applied your technology to noninvasive prenatal testing (NIPT). Can you tell us more about NIPT and why it is beneficial not only to the mothers but to research also?
For a pregnant person, knowing their baby’s risk for certain genetic conditions allows them to prepare. NIPT is a screening test and not a diagnostic test. This means it can tell you what the chances are for certain genetic conditions in the pregnancy. While this test is not diagnostic, having a low-risk result for the conditions screened can provide some reassurance.
For a high-risk result, a confirmatory diagnostic test is recommended and this can be done during the pregnancy or after delivery. Knowing that a pregnancy has a genetic condition can inform what type of hospital a person should deliver at, what medical specialists should be available after delivery, what treatments or interventions might be recommended, and gives people time to prepare emotionally. In some cases, it can prevent a long diagnostic odyssey. For example, the average years to diagnose 22q11. 2 deletion syndrome is 4 years. We can now screen for 22q11.2 with cfDNA.
From a research perspective, Natera is committed to peer-reviewed publications for all our tests. I’m proud to say there are over 100 peer-reviewed publications across all our products and 25 of those are specific to Panorama NIPT. We recently published the results of the SMART study which is the largest prospective NIPT study ever conducted in a general population.
One of the reasons we sponsored this 20,000 patient study was to confirm Panorama test performance in the general population, which we did. However, more importantly, this study provided information on the incidence and test performance of 22q11.2 deletion syndrome. Individuals with this condition can have heart defects, immune deficiency, low calcium levels, cleft palate, learning differences, and schizophrenia.
With this study, we confirmed that this condition is not rare, in fact, in this cohort we found that the incidence was approximately 1 in 1500 pregnancies, which is more common than other conditions routinely screened in pregnancy. This peer-reviewed published data supports offering screening for 22q11.2 deletion syndrome to all pregnant individuals.
You are currently pushing the boundaries of testing management within science. How important is innovation to the field of genetic testing?
Innovation is incredibly important to translating advanced genetic technologies into usable and informative tests for the general public. One example of innovation from Natera’s R&D team is the application of AI to the Panorama algorithm.
Through analyzing millions of tests, the Panorama AI algorithm was able to reduce the number of “no results” while maintaining high test sensitivity and specificity. We also applied algorithm improvements to NIPT for 22q11.2 deletion where we improved our detection of various deletion sizes and increased the positive predictive value of the test from 20% to 53%.
However, innovation applies to more than the tests. It’s important to the overall infrastructure of testing. How easy is it for a healthcare provider to order the test and get results? Do patients and ordering providers have access to education and information during the entire testing journey? We wanted patients to have access to our genetic education services 24/7, so our genetic counseling team worked with our user experience and engineering teams to build NEVA, Natera’s educational virtual assistant. This is a chatbot that can provide pre-test education as well as post-test result information across many of our products.
Patients can even schedule an appointment with a Natera genetic counselor through NEVA. About 30% of patients use this outside of normal business hours, which means NEVA helps patients access information when it’s most convenient for them.
Image Credit: Natali _ Mis/Shutterstock.com
What do you believe the future of reproductive genetic testing looks like? Are there any particular trends that you foresee?
We are moving towards having the ability to screen individuals and pregnancies for a larger number of conditions. We have seen this across preimplantation genetic testing, carrier screening, and NIPT. Of course, it’s critical that as expansion occurs, there is a high level of test performance and that genetic education and counseling be available to anyone interested in testing. Equitable access to testing is necessary as well.
Do you believe that with continued innovation at Natera, you will continue to change the ways that diseases are managed? What would this mean globally?
As Natera continues to explore the potential applications of cfDNA, this could definitely have an impact on disease management and treatment. There are several studies currently looking at the need for chemotherapy for colorectal cancer patients based on the presence of ctDNA, or tumor fraction of cfDNA, regardless of cancer stage.
Also, the Prospera transplant assessment test is able to monitor for solid organ transplant rejection more accurately than existing biomarkers. Since rejection is the most common cause of transplant failure, early, more accurate detection will have a significant impact. Globally, these tests could impact the treatment and monitoring of both cancer and transplant patients and optimize treatment.
What is next for Natera? Are there any exciting projects that you are involved in?
The women’s health division is collaborating with clinicians to engage in clinical research aimed at improving and expanding the Panorama NIPT product. We are also looking at ways to improve overall maternal/fetal health during pregnancy through early identification of potential perinatal complications. I’m also really excited about partnering with our newest business unit for early cancer detection.
Where can readers find more information?
Natera’s website has a wealth of information for both patients and clinicians. We run a women’s health blog, as well as host videos, peer-reviewed research, and webinars.
About Sheetal Parmar
Ms. Parmar is vice president of medical affairs and head of clinical services at Natera. She is a board-certified genetic counselor specializing in prenatal diagnosis and screening. Sheetal received her BA in Molecular and Cell Biology from UC Berkeley and her MS in Genetic Counseling from the University of Cincinnati, where she was a Albert C. Yates Scholar and Fellow. She joined Natera after working for 11 years as the lead prenatal genetic counselor at a high-risk prenatal diagnosis clinic and cytogenetic laboratory.
She has served on the Board of Directors for the National Society of Genetic Counselors (NSGC) and is currently a site visitor for the Accreditation Council of Genetic Counseling (ACGC). In 2020, Sheetal received the Leading Women Entrepreneur Force for Change Illuminator award for her contribution to Natera’s positive impact on the lives of others during the COVID-19 pandemic.
In this interview, News-Medical talks to Dr. Marlena Fejzo about a breakthrough in the understanding of hyperemesis gravidarum (HG), a severe pregnancy sickness, and how it could improve maternal health around the world.
Please introduce yourself and tell us about how you began your research into hyperemesis gravidarum (HG)?
I am a Research Professor of Obstetrics and Gynecology at the University of Southern California, a Board Member of the Hyperemesis Education and Research Foundation, and a consultant for Materna Biosciences, Inc.
I have a Ph.D. in genetics and my work focuses on diseases of women. I started to research HG after being totally bedridden and unable to eat for 10 weeks, ultimately losing a baby at 15 weeks gestation to the disease in 1999.
Please can you explain hyperemesis gravidarum (HG) and how it can affect the health of both pregnant women and their infants?
Most pregnancies are affected by nausea and vomiting, but HG lies at the severe end of the clinical spectrum. People with HG start having severe symptoms of nausea and/or vomiting early in pregnancy that strongly limits their ability to eat and/or drink and function normally. HG usually leads to dehydration, nutritional deficiencies, electrolyte disturbances, and weight loss. There can be significant maternal and fetal morbidity and even mortality.
The people in my study have reported detached retinas, pneumothorax, esophageal tears, and rib fractures from the violence of the vomiting. Studies show 32% contemplate suicide and 18% have PTSD from the prolonged traumatic experience. Brain damage and maternal deaths continue to be reported secondary to severe nutritional deficiencies, electrolyte disturbances, thromboembolism, and thyrotoxicosis.
In addition, there is now substantial evidence to support adverse outcomes. Babies exposed in utero to HG have a 5-fold higher risk of being born small for their gestational age. This is a higher risk than prenatal exposure to cannabis, tobacco, amphetamine, cocaine, as well as maternal chronic hypertension, pre-gestational diabetes, preeclampsia, and autoimmune disease. Despite this, symptoms of HG continue to be trivialized and patients are often left undertreated. Babies exposed to HG are at increased risk of preterm birth, low birth weight, smaller head circumference, decreased brain size, neurodevelopmental delay, vitamin K deficient dysmorphology, and autism spectrum disorder. In the case of HG, the baby is not always getting everything it needs from the mom.
Image Credit: Yeexin Richelle/Shutterstock.com
Why do you think HG has been so poorly understood and treated? With research like yours making breakthroughs, is the future looking better?
In the 1950s and 60s over 10,000 mothers with severe pregnancy nausea and vomiting were treated with thalidomide and their babies were born with limb deformities. This tragedy understandably dissuaded researchers, pharmaceutical companies, doctors, and patients from studying, developing, prescribing, and taking medications in pregnancy. But there is also the problem of misinformation.
Doctors continue to this day to be taught outdated theories that are not backed by science. There is clearly a misogynistic component to it too- the idea of the “hysterical pregnant woman” persists, resulting in a disconnect between HG patients and providers that contributes to pregnancy termination of wanted pregnancies.
Our research identifying the gene coding for the nausea and vomiting hormone GDF15 as the greatest risk factor for HG provides validation for people suffering from this condition. But more than that, it gives us a direction to focus on to develop new and hopefully more effective treatments.
Previous theories for the cause of HG have been based on psychological explanations and the hCG hormone. What were these theories and have you discounted them?
People have often focused on the pregnancy hormone hCG because it rises and falls in the first trimester when nausea and vomiting normally occur. However, evidence continues to be controversial with many studies showing no correlation between circulating hCG and HG. Genome-wide and exome-wide association studies are unbiased with respect to all genes in the genome. These techniques were used to identify genetic variants that are significantly different between cases with HG and cases with normal or no nausea.
There are genes known to be associated with psychological disorders and there are genes coding for the hCG hormone as well as its receptor and these, like all genes, were included in the studies. None of the genes encoding the hCG hormone were found to be of significance. Two hundred and eighty-nine variants on chromosome 19 were of greater significance than the most significant variant coding for hCG, including the top GDF15 variant that was the focus of our new study as well as five additional variants in GDF15 that did not reach exome-wide significance. In addition, 2 studies measuring circulating levels of hCG and GDF15 in pregnancies affected by more severe nausea and vomiting/HG found a significant association between GDF15 and not hCG.
As for the psychological hypothesis, a search of 4220 GWASes for GDF15 associations did not identify any personality traits but did identify protein levels, periodontitis, and lupus. The GWAS catalog contains over 400 genetic associations for anxiety disorder and over 2000 genetic associations for depression, and none of these are in the GDF15 locus.
Anxiety and depression may be a consequence of prolonged illness and starvation in pregnancy, but suggesting this is the cause of HG, rather than a consequence, can be harmful and is not supported by our studies. It is time to stop wasting resources on hCG and psychological factors as causal and focus on the GDF15 pathway.
How could abnormalities in the GDF15 gene be resulting in HG?
We are now in the process of studying this, as there are many ways genetic changes can contribute, for example via increasing circulating levels of GDF15 or increasing signaling by the hormone. Of note, a GWAS study of variants associated with increased serum levels of GDF15 found the same common variant we recently identified associated with HG. The placenta normally produces a huge amount of GDF15. Therefore, the variant may lead to an increase in the GDF15 hormone levels produced by the placenta that then travels to the brainstem and over activates the nausea and vomiting center of the brain.
We also know that GDF15 is a cellular stress signal that is increased when organs are under physical stress, when people are nutrient deficient, and when people have thyroid dysfunction. These are all states that can be consequences of HG pregnancies. Therefore, one can imagine that if you carry a genetic predisposition to slightly increased GDF15 levels, this can ultimately result in a downward spiral toward extreme nausea and vomiting.
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How did you identify the link between the GD15 gene and HG and how has your work confirmed and built on the previous breakthrough in this area?
Originally we partnered with the personal genetics company 23andMe and performed a genome-wide association study (GWAS) on their customers who volunteered to participate in a pregnancy survey. We compared the DNA between 1,306 cases with HG and 15,756 unaffected controls. In that study, we identified the novel association between HG and DNA variation around the gene that codes for the nausea and vomiting hormone GDF15.
Paradigm-changing findings often require additional evidence to gain broad acceptance in the field. Our new study, recently published in BJOG, used a different genetic technique, whole-exome sequencing (WES), on a different population of pregnant people (926 HG cases and 660 unaffected controls), and in the WES, a genetic variant in GDF15 was again identified, confirming previous results. The WES study also included patients of different ancestries, whereas the GWAS only included participants of white European descent.
In addition, WES can be used to identify rare mutations in genes. And in the WES study, the only gene with a mutation in 10 or more patients was a mutation in GDF15. In related studies, we, and others, have shown that in maternal serum, GDF15 levels are significantly increased in hospitalized HG cases, in patients with second-trimester vomiting, and those prescribed antiemetics. Lower levels of GDF15 are associated with no nausea and vomiting of pregnancy, which is also uncommon.
Variants in GDF15 have been associated with familial and recurrent HG, and with the level of circulating GDF15. The hormone is shown to cause taste aversion, appetite loss, and weight loss through the activation of the nausea and vomiting center of the brain in animal models. Taken together, there is now more evidence that GDF15 is involved in the etiology of HG than anything else.
How does this mechanism relate to cancer cachexia and how could this relationship benefit the future of HG treatment?
About 20% of cancer patients die from cancer cachexia, which is a condition with strikingly similar symptoms to HG, characterized by appetite loss, weight loss, and muscle wasting. GDF15 is produced by some tumors, circulates at abnormally high levels in patients with cancer cachexia, and causes cachexia in animal models. There are currently several drugs in development and clinical trials in cancer patients that block the GDF15 signaling pathway. If successful and safe in pregnancy, these drugs may be a game-changer for HG.
Via practices such as genetic testing, this knowledge could be used to improve the prediction and diagnosis of HG. How do you think this could all be implemented into the clinical setting, and how could it affect pregnancies around the world?
Pregnant patients often don’t see their doctor early in pregnancy when HG starts, and generally, doctors do not screen for HG during prenatal visits. Some patients are unaware that their symptoms require treatment until they end up in the hospital severely dehydrated and malnourished. Tools to predict and diagnose HG can be useful so that patients at increased risk can have earlier and more consistent care, which may lead to less need for emergency room visits, hospitalization, and limit adverse maternal and child outcomes.
In addition, 4 out of 5 people with HG have a recurrence. The high recurrence risk and severity of disease often disrupts family plans. If we can use genetic markers to predict who is more likely to have a recurrence, this may be very helpful in planning and preparing for subsequent pregnancies. However, these tests are a ways off because resources are scarce for creating and getting approval for use in a clinical setting.
What implications could this research and improved understanding of HG have on HG sufferers and their infants in the future?
In the short term, understanding that there has been progress toward understanding the biological basis of HG can be comforting to patients and their families. In the long run, I hope that it will lead to better tools to predict, diagnose, and treat the disease, ultimately resulting in healthier mothers and babies.
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Achieving adequate maternal health and ending preventable maternal deaths is a fundamental goal in improving healthcare around the world. How does your research support the global agenda to improve maternal health for all?
Approximately 70% of pregnancies are affected by nausea and vomiting, and HG has been reported to occur in 0.3-10.8% of pregnancies. Maternal deaths secondary to HG have been reported in this century in the US and UK. Progress in understanding the etiology of HG will hopefully lead to better prediction, earlier diagnosis, and treatment, and limit avoidable maternal deaths.
In addition, the research sheds light on a mechanism that results in undernutrition in pregnancy. One can imagine that in the future, similar to prenatal vitamins, medications targeting the GDF15 pathway, may work to improve overall nutrition in early pregnancy, leading to healthier mothers and babies.
Where can readers find more information?
About Dr. Marlena Fejzo
Marlena Schoenberg Fejzo, Ph.D., is an American medical scientist and professor of research on women’s health. She received her undergraduate degree from Brown University in Applied Math in 1989 and a Ph.D. in Genetics from Harvard University in 1995. After her postdoctoral studies on breast cancer at UCSF, she had joint appointments at the University of Southern California and the University of California, Los Angeles where she worked in the laboratory of Dr. Dennis J. Slamon until 2020.
Currently, she researches HG at the University of Southern California, is on the Board of the Hyperemesis Education and Research Foundation and is a consultant for Materna Biosciences, Inc. She has published peer-reviewed scientific articles on many diseases of women including ovarian cancer, breast cancer, multiple sclerosis, and discovered the first genes for uterine fibroids, nausea and vomiting of pregnancy, and hyperemesis gravidarum.
She was an invited speaker at a congressional briefing during women’s health week and multiple international conferences and has been interviewed for documentaries, podcasts, radio shows, and news outlets around the world about her work on HG.
An MUSC Hollings Cancer Center study sheds light on better ways to prevent and treat colorectal cancer, which often is found at advanced stages when it’s much harder to treat.
MUSC Hollings Cancer Center director and researcher Raymond DuBois, M.D., Ph.D., discovered the connection between a series of pathways, actions among molecules that lead to a change in the cell, which showed how cancer cells and the immune system interact. This work, published online on Feb. 2 in Cancer Prevention Research, provides strong evidence for a new therapeutic approach to aid the immune system in fighting cancer.
Colorectal cancer (CRC) is one of the most common types of cancer and the second leading cause of cancer deaths. CRC cases have been increasing in young people across the U.S., but researchers are not quite sure why. “The rise in CRC cases in younger individuals is an area of concern for South Carolina and Hollings. In general, this region has a large number of sedentary individuals with high rates of obesity and smokers, which are known to promote cancer,” said DuBois, who is also a Distinguished University Professor in MUSC’s College of Medicine.
DuBois said that the low five-year survival rate is unacceptable for CRC patients with stage 4 (advanced) disease. Despite promising improvements in cancer treatments, immunotherapies, which help the immune system to fight cancer, such as checkpoint inhibitors, have had disappointing clinical results in many solid tumors, including CRC.
To find more effective options for patients, scientists have studied several molecular pathways to find new drug targets. However, much of this research is done with late-stage CRC, when there is already metastasis, or spread of the disease.
Looking at cancer and immune cell interactions in the early stages of cancer development may provide more answers for the field. Currently, there is very little understanding of what is going on in the immune system in the premalignant stage.”
Raymond DuBois, M.D., Ph.D., MUSC Hollings Cancer Center director and researcher
Last summer, DuBois published data that identified how a certain gene mutation, or change, allows tumors to evade detection by the immune system in CRC patients. This new publication builds upon that foundation and adds pieces to the “big-picture” puzzle that will ultimately lead to better solutions for cancer patients.
Piecing together immune evasion in CRC
Cancer cells can thrive in a person’s body when they hide from the immune system. The immune system is designed to kill and remove mutated cells: cytotoxic CD8+ T-cells kill the cancerous cells, and phagocytic macrophages clean up cellular debris. However, cancer often outsmarts the intricate immune system mechanisms. In a journey through signaling pathways, DuBois and colleagues pieced together the mechanism underlying immune evasion in early CRC.
“The mechanisms of how PD-1 is regulated in CD8+ T-cells and macrophages in the tumor environment is still mostly unclear,” said DuBois. Using mouse models of CRC and complex genetic techniques, DuBois’ team and his collaborator Jessica Lang, Ph.D., at the University of Wisconsin-Madison, identified that the EP4-PI3K-NFκB-PD-1 pathway was responsible for CRC immune evasion.
First, the researchers found a novel role of the prostaglandin PGE2 in tumor immune evasion. Prostaglandins are hormone-like fatty molecules that are released early in response to inflammation. PGE2 is the most abundant prostaglandin found in human cancers, including CRC. Additionally, high levels are associated with a poor prognosis.
“We discovered that the inflammatory mediator PGE2 turns on PD-1 expression by a series of intermediary pathways. The result is that the CD8+ T-cells and macrophages do not effectively attack the developing cancer cells,” said DuBois.
Identifying a new cancer treatment target
Next, the research team identified that blocking the molecule EP4 could “free” the immune system and restore the cancer-fighting functions. “In a mouse model of CRC, we found that blocking EP4 with a new class of receptor inhibitor restored the CD8+ T-cell cytotoxicity,” said DuBois. He explained that interrupting the pathway through EP4 reduced the levels of PD-1 on both CD8+ T-cells and macrophages, which increased the immune cells’ cancer-fighting functions in the intestines.
In CRC and other cancers, high levels of specific molecules, such as PD-1, are associated with worse survival. However, the biological reason was previously not apparent. “Our data shows that the proof of concept is there, and the negative PD-1 effect can be reversed,” said DuBois. In the future, there may be several options for the use of EP4 inhibitors, including combining them with checkpoint inhibitors in patients with more advanced cancers.
Since the data shows that blocking EP4 is potentially effective as an early treatment for CRC, the research team plans to further these findings by looking at subsets of the pathways and performing studies in metastatic disease. They also plan to look at the role of this pathway and inhibitor in other cancers.
Cancer prevention
While the current study focused on understanding the pathway for cancer treatment, the EP4 inhibitor could also be pursued as a cancer prevention agent. “People who have a very high risk for cancer are put on aspirin since it has been shown to delay cancer. The problem is that aspirin can be bad for the GI system. If EP4 receptor pathways work as we saw in our research, then perhaps this approach could be used instead of aspirin,” said DuBois.
Cancer prevention is a central theme at Hollings, where, as director, DuBois creates the vision for the center’s future. “We are really interested in growing our cancer prevention team. This includes cancer screening. Drs. (Marvella) Ford and (Gerard) Silvestri play lead roles with that work. Finding a pan-cancer blood test with proper sensitivity and specificity would be amazing.”
Hollings’ current goals are also in line with the recently announced Cancer Moonshot initiative, which aims to reduce the death rate from cancer by at least 50% over the next 25 years.
The current CRC screening guidelines recommend testing beginning at 45 years of age. “Patients can choose colonoscopy, CT colonography or stool tests,” DuBois explained. “Any test is better than no test, especially since CRC is now affecting younger individuals.” Hollings researchers Marvella Ford, Ph.D., and Kristin Wallace, Ph.D., are studying this troubling finding.
As MUSC works to change what is possible in cancer prevention and treatment, leaders have launched the community health research program In Our DNA SC. In partnership with Helix, a leading population genomics company, the program aims to enroll 100,000 participants in genetic testing to develop a secure genetic and research database. DuBois said this sequencing would help us to find those most at risk for developing cancer.
Wei, J., et al. (2022) The COX-2-PGE2 pathway promotes tumor evasion in colorectal adenomas. Cancer Prevention Research.doi.org/10.1158/1940-6207.CAPR-21-0572.
Assay, Bases, Cell, Cell Line, dna, DNA sequencing, Electrophoresis, Genetic, Genotyping, laboratory, Research, Sanger sequencing
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