Putting glioblastoma in its place

Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer, with a median survival time of just one year following diagnosis. Treatment is complicated by the considerable variability in GBM tumors – what works for one tumor often fails to work for another. Selecting the most appropriate treatment may soon, however, be easier, thanks to an improved GBM classification system, developed by Mount Sinai and Sema4 scientists and published in Cancer Research.

A team of researchers, led by Sema4’s Head of Data Sciences Jun Zhu, PhD, reasoned that an improved GBM classification system could help clinicians to select the most pertinent therapy – a case of “know your enemy”. Some GBM tumors are dependent on the mitotic spindle checkpoint molecule BUB1B for their survival, so his team mined complex datasets to produce an innovative computational method to classify tumors based on their BUB1B dependency. In doing so, they uncovered new tumor subtypes and found that while BUB1B-sensitive tumors had a significantly worse prognosis, they were also predicted to be more responsive to many of the cancer drugs already in clinical use.

The molecular subtypes identified in this new study appear to provide a more accurate estimate of prognosis and therapeutic response than existing classifications. One reason that previous classifications have failed to lead to effective personalized treatments is the high degree of intratumoral heterogeneity in GBM. Cells from different parts of the tumor may belong to different molecular subtypes and, therefore, subtype-specific therapies fail to eradicate all the cancerous cells. The BUB1B classification system, however, does not suffer the same defect.

“It was a pleasant surprise to us that our subtype is stable for heterogeneous tumor cells within a GBM tumor and, thus, it is possible to kill all tumor cells instead of just a subgroup,” says Dr. Zhu. “Preliminary results indicate that the stability is associated with certain genomic features, but more data are needed to understand why. More importantly, we also need to work out how to leverage the subtype information to develop mechanism-specific therapies.”

“These findings underscore the significant potential we see to improve patient outcomes by investing in predictive modeling of even the most complex types of cancer,” explains Eric Schadt, PhD, Sema4’s CEO and Dean for Precision Medicine at Icahn School of Medicine at Mount Sinai.

The study was the result of a multidisciplinary collaboration between computational scientists and clinicians – a characteristic of many Sema4 research projects. Information generated from our integrative studies – such as the GBM project and a recent examination of lung cancer mutations – is the first step towards designing improved diagnostic tests and optimizing personalized cancer therapies. Currently, Sema4 offers the Oncology Hotspot Panel, which provides information on over 200 mutational hotspots associated with a range of cancers. As our knowledge of cancer genomics increases so too will our ability to expand this number, leading to improved diagnosis, treatment, and survival rates for cancers including glioblastoma. “We look forward to building on this collaborative project and moving toward development of a diagnostic test that could help physicians better understand and treat their patients’ glioblastoma cases,” says Dr. Schadt.

Sema4 and Mount Sinai study identifies novel lung cancer mutations

Nearly quarter of a million Americans will be diagnosed with lung cancer in 2018, according to new estimates published by the American Cancer Society, and lung cancer will be responsible for more deaths than the next three most common cancers (breast, prostate, colon) combined.

Cancer arises due to genetic mutations – changes in the patient’s DNA. By figuring out precisely which genetic variants instructed their patient’s lung cells to change from normal to cancerous, doctors can select personalized therapies targeted to these mutations and minimize non-specific side-effects.

Sema4 and Mount Sinai scientists recently profiled the range of mutations found in non-small cell lung cancer (NSCLC), the most common form of lung cancer. They examined DNA from 932 NSCLC tumors and found nearly 3,000 mutations in cancer-associated genes, demonstrating the clinical utility of targeted next-generation sequencing with a focused oncology hotspot panel in NSCLC. The study, published in Genome Medicine, provides a comprehensive overview of not only the genetics but also potential treatment options for NSCLC, as actionable mutations were present in 65% of the patients.

In addition to detecting known mutations, the Sema4 team also identified novel lung cancer mutations by combing through the large volume of sequencing data generated during panel analysis. An activating somatic mutation was detected in the JAK2 gene in one in every 100 patients. This genetic variant would be expected to cause over-activity of the JAK-STAT cell signaling pathway, so the Sema4 researchers trawled publicly available pharmacogenomic data to investigate potential therapies, and found that the mutation could confer sensitivity to both JAK inhibitors and anti-PD1 immunotherapy. They also detected activating germline mutations in the JAK3 gene, in 7% of patients, that would be predicted to render tumors susceptible to anti-PD1 treatment.

“These novel mutations define a unique disease mechanism that has not been previously described in lung cancer, therefore facilitating the development of personalized treatments for patients with these variants,” says lead author Dan Li, PhD. “Going forward, we will continue to perform integrative analyses of cancer genetic data and patient clinical data to discover novel predictive biomarkers for treatment response. We will also develop and implement improved cancer genetic testing platforms for diagnosis.” Sema4’s current testing platform, the Oncology Hotspot Panel, analyzes 207 mutational hotspots across the genome that are known to be associated with cancer.

The clinical implications of the novel mutations were identified through an integrative analysis of genetic, genomic, and pharmacogenomic data. Mining large, multidisciplinary data sets is a central element of Sema4’s research ethos and one that successfully uncovers information that can directly impact clinical decision-making, as shown by this study and another recent study on glioblastoma. Our team is committed to using this approach to improve diagnosis, treatment, and outcomes for cancer patients, including the one in 16 Americans who will be diagnosed with lung cancer in their lifetime.

Moving towards ending the diagnostic odyssey: how Sema4 research benefits rare disease patients

Today we celebrate Rare Disease Day, an international day of awareness that shines a light on rare diseases and their impact on patients’ lives. The day’s theme this year is one fundamental to Sema4’s mission: research. More than 7,000 rare diseases have been identified to date, 80% of which are caused by known genetic factors and, collectively, these diseases affect 30 million Americans, half of whom are children. While on a worldwide population level these diseases may be rare, in some population groups they are dramatically enriched. Reports from rare disease communities, biotech companies focused on rare diseases, and rare disease researchers indicate that it takes most rare disease patients on average five to eight years to obtain an accurate diagnosis, during which time irreversible damage can occur to their health. How, then, can we reduce the duration of that diagnostic odyssey and improve health outcomes?

Diagnosis is typically made after symptoms have manifested, but for many patients, the answer lies in their DNA from birth. We built on our expertise in medical and pediatric genetics, as well as our roots in the Mount Sinai Health System, to create Sema4 Natalis, a supplemental newborn screen designed to detect the strongest genetic risk factors of rare diseases even before the onset of symptoms. Until now, families have been likely to be caught off-guard by these early-onset diseases, and prognosis is often poor by the time symptoms have manifested, a problem compounded by the long wait for an accurate diagnosis. Natalis was developed to help address this issue of undiagnosed pediatric illness by using next-generation DNA sequencing and analysis to supplement traditional newborn screening.

Natalis screens for 193 childhood-onset diseases or disorders — more than five times the number on most standard state-mandated newborn screening tests — and also includes a pharmacogenetic analysis of how a child is likely to respond to 38 medications commonly prescribed in childhood. Our goal when designing Natalis was simple: to identify babies at risk for these 193 diseases, and allow pediatricians to reach a diagnose and deliver interventions – sometimes as simple as vitamin supplements – in time to make a real difference in the life of a child. Rare diseases included in Natalis, but not in most state-mandated screens, include spinal muscular atrophy (for which a recently FDA-approved drug offers treatment), atypical epilepsy (for which vitamin B6 supplementation can reduce or prevent seizures), and mutations that lead to certain childhood cancers at exceptionally high rates (where knowledge of such high risk can lead to more frequent monitoring).

We designed Natalis to provide results that are both accurate and medically actionable, based on years of research and clinical experience in molecular diagnostics. It was essential that Natalis meet three strict criteria: analytical validity, clinical validity, and clinical utility. Testing takes places in our CLIA-certified laboratory, using advanced next-generation sequencing technology that is >95% accurate, guaranteeing analytical validity. All positive test results are confirmed with a second sequencing technology. To ensure clinical validity, we only included diseases with “high penetrance,” meaning that if a patient tests positive for a disease-associated variant, there is a high probability (>80-95%) that he or she will develop symptoms of that disease. Finally, clinical utility was achieved by only including diseases for which there is a medical intervention available.

Although ordering Natalis can be initiated online, it is distinct from direct to consumer (DTC) tests in that the order must be approved by one of our independent physicians to ensure it is medically appropriate for the child. Parents can also opt to order the test through their own physician. These features, along with the inclusion of genetic counseling, set Natalis apart from DTC tests. We are hopeful that Natalis will be embraced by patients and physicians in as positive a way as hereditary cancer testing, which is available in DTC form and has markedly improved outcomes for patients despite looking for disease-associated variants with far lower penetrance than those in Natalis.

To assess the attitudes of consumers toward genetic screening for newborns, Sema4 recently commissioned a Harris poll – just one component of our overall program to gain new insights into genomic health – which revealed that the majority of Americans are in favor of newborn genetic screening. 88% of Americans said that if they could find out just after their baby is born about their child’s genetic risk of getting a treatable early-onset disease, they would want to know. We are also in the process of launching a clinical study to explore the utility of supplemental newborn screening to both patients and physicians, including how individuals respond to this new type of actionable information, what actions they take as a result, and how this ultimately impacts health outcomes and healthcare utilization. Through our consumer research, clinical study, and Natalis itself, we seek to understand, in partnership with our patients and the scientific and medical communities, the benefits of obtaining supplemental genetic information at birth and whether DNA screening for treatable childhood disorders should become the standard of care.

As a parent, I understand all too well the emotions surrounding the birth of a child and the urge to keep them safe. When my first baby was born, I was consumed by fears, most of which I could allay through preventative measures: removing loose bedding, installing a baby gate, and keeping up to date with vaccinations. But, some things were out of my control: what if he would one day develop a genetic disease that not even I, an expert in genetics, could predict or fix? A test like Natalis back then would, I think, have provided tremendously empowering insights. Looking forward, I firmly believe Natalis will give other parents the advantage of early insight in support of the care of their children and am proud to be leading the way with Sema4 in this new age of genomic medicine.


Eric Schadt, Ph.D.
Founder and Chief Executive Officer

Sema4 Natalis: Giving parents the advantage of early insight

Imagine having a child with a disease so rare that doctors have no idea what is wrong and therefore how to help. This is the reality today for parents of children with rare diseases, a group of more than 7,000 diverse conditions, 80% of which are caused by genetic factors. Today is Rare Disease Day, an international day of awareness focused on rare diseases and the individuals affected by them, including 30 million Americans, half of whom are children.

It takes rare disease patients on average eight years to obtain an accurate diagnosis, during which time their health may have suffered irreversible damage. Earlier this month, we launched Sema4 Natalis, an extensive supplemental newborn screen that aims to provide parents with an accurate diagnosis, even before symptoms occur. Natalis screens for 193 treatable childhood-onset conditions — more than five times as many as the average state-mandated (“heel prick”) test — using advanced DNA sequencing technology. Rare diseases included in Natalis, but not in most state-mandated screens, include spinal muscular atrophy, atypical epilepsy, and certain childhood cancers, among many others. The test also includes a pharmacogenetic analysis of how a child is likely to respond to 38 medications commonly prescribed in childhood.

Natalis is the product of years of research and hard work at Sema4. We couldn’t be prouder to see it finally enter the world – it is, in effect, our own newborn! Natalis can detect genetic risk factors for rare diseases before the onset of symptoms, allowing pediatricians to reach a diagnosis and deliver interventions — sometimes as simple as vitamin supplements — in time to make a real difference. The availability of established medical treatments for all 193 conditions was an important guideline when designing our test to ensure that we only deliver medically useful information. Another vital factor was including only genetic variants highly likely to cause disease. While not every child born with one of these variants will get the disease, the probability is high enough (>80-95%) to merit attention.

Testing your newborn with Natalis couldn’t be easier. The kit can be ordered online during pregnancy, to make sure it is handy when baby makes his or her debut in the world. One of our independent physicians reviews each order to ensure it is medically appropriate for the child, and, if approved, the kit is mailed out to your home. Parents who do not want to order online can order the test through their doctor. DNA is collected from the baby’s mouth using a gentle swab and returned in the prepaid box to our CLIA-certified laboratory, where we use advanced DNA sequencing to analyze your baby’s genes with >95% accuracy. Analysis takes around two weeks, after which the results are available online in our patient portal. Every Natalis order also comes with a genetic counseling session to go over results and potential next steps.

We believe that Natalis will empower parents by giving them the advantage of early insight into their child’s health. It seems that the public agrees: 88% of Americans say that if they could find out just after their baby is born about their child’s genetic risk of getting a treatable early-onset disease, they would want to know, according to the results of a new Harris poll, commissioned by Sema4. For our part, we are thrilled to have brought Natalis into the world, and can’t wait to see the impact it will have on reducing the average time to a rare disease diagnosis as well as the associated heartbreak.

To learn more about Natalis and newborn screening, join us on March 7th from 1-1:45pm EST for a Facebook Live conversation with top reproductive health experts Dr. Alan Copperman (CMO of Sema4 and Medical Director of RMA of New York) and Dr. Joanne Stone (Director of Maternal Fetal Medicine at the Mount Sinai Hospital). In the meantime, you can find out more about Natalis here:

Celebrating genetic counselors on GC Awareness Day

November 9th is Genetic Counselor Awareness Day. Today, we recognize our amazing team and genetic counselors across the world for their countless contributions to providers, patients, and the research community. Genetic counselors play a critical role in the shifting healthcare landscape. They work directly with doctors, patients, and their families to help them understand genetic testing, guide them through the process, and help them make informed choices based on their results.

The role of genetic counselors has evolved over the years. Traditionally, a laboratory genetic counselor was “behind the scenes” using their expertise to ensure a requested test is patient-appropriate, interpreting the results, and compiling reports for providers. There was usually little or no direct patient contact. Today, Sema4’s genetic counselors and those at other labs are committed to open communication at all levels. “While the doctor is still at the center of the process, the goal at our diagnostic labs is to establish a direct line of communication with the patient,” explains Lama Elkhoury, MS, CGC, Sema4’s Director of Genetic Counseling Services. “Our team proactively calls patients with positive genetic testing results to explain the results and provide compassionate guidance on care options. Patients are also welcome to contact us directly with questions.” One area Lama’s team is currently involved with is counseling users of Sema4’s Expanded Carrier Screen, which tests prospective parents for more than 280 genetic diseases, and advising them about what their results could mean for their future children.

Genetic counselors are also serving as an increasingly valuable resource for physicians, educating them on genetic diseases, helping them select the most appropriate genetic tests and interpreting results. Given the rapidly growing complexity and applicability of genetic testing, that level of laboratory access is more important to physicians today than ever before. More and more non-genetic professionals, like cardiologists, pediatricians, and neurologists, are ordering genetic tests to help determine what role family history and background might play in a disease and its treatment for patients. Genetic testing is now expanding well beyond routine prenatal and oncologic risk assessments. “With the move to personalized medicine,” notes Lama, “completely healthy individuals are now deciding to take a peek at their genomes to see how they can promote healthier lifestyles.”

The ability of Sema4 and its team of highly-trained and experienced lab counselors to tangibly help this widening universe of consumers is what makes Lama particularly excited about the period ahead. “I’m a patient advocate above all else,” she declares, “and nothing gives me greater satisfaction at the end of the day than to see how everyone’s hard work positively impacts so many individuals.”

Welcome to Sema4—Our vision of a healthier future

Over the course of just a few decades, we have become consumers and generators of a massive amount of digital data. From billions of search queries every day, to the growing number of gaming interactions around the globe, to countless videos streaming on our wired and mobile devices, the amount of data zooming across the internet this year alone will exceed one zettabyte. (That’s a 1 followed by 21 zeroes.) To give you a sense of the magnitude of this number, one zettabyte is equivalent to the amount of data that can be stored on 7.8 billion 128 gb iPhones or close to the number of stars in the universe.

This dramatic rise in the scale of our digital data is paralleled by rapid advances in information science, which has accelerated our ability to analyze these vast oceans of data. In both large and small ways, the insights derived from big data now influence our daily experiences—from how we book a flight or manage our finances, to the films and music we choose. Yet, while big data has already transformed life as we know it, this is just the very beginning.

As we look to the future of healthcare, health data at scale may hold the key to revolutionizing how we diagnose, treat, and prevent diseases. The vast wealth of health and personal data now available to us can give us greater insight into what constitutes disease—from the genes we are born with and the genetic makeup of the trillions of bacteria that inhabit our bodies, to our lifestyle habits and the myriad of environmental factors we encounter daily. We believe that, by sharing and analyzing this data, we can build better predictive models to guide how we approach and affect our health.

The launch of Sema4 is our next step in realizing this vision. Originating from the Icahn Institute for Genomics and Multiscale Biology and the Department of Genetics and Genomic Sciences at Mount Sinai, Sema4 is differentiated by a strong foundation of clinical expertise, world-class academic research, and pioneering information science. Our interdisciplinary team also brings diversity in both expertise and perspective to these efforts. From scientists, doctors, and genetic counselors, to engineers, designers, and bioinformaticians, the Sema4 team, itself, is a powerful network that is uniquely poised to drive innovation in this space.

Maybe you are starting your family and hoping for better health for your children. Perhaps you are facing a chronic illness and looking for answers. Or maybe you are a clinician invested in improving outcomes for your patients. For every one of us, harnessing health data can revolutionize how we define, understand, and create wellness. Our work at Sema4 is our commitment to making this possibility a reality. We believe that, together, we can channel the combined powers of science and technology to bring about meaningful change in our healthcare. Today, with the launch of Sema4, we are excited to start this journey toward a healthier future with you.


Eric Schadt, Ph.D.
Chief Executive Officer