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The Prizes 44th session awards eminent figures in each of its Arabic Language & Literature and Service to Islam categories

King Faisal Prize Award Ceremony 2022

King Faisal Prize Award Ceremony 2022

King Faisal Prize Award Ceremony 2022

King Faisal Prize Award Ceremony 2022

Riyadh, March 29, 2022 (GLOBE NEWSWIRE) -- Two mathematicians and a scientist were among this years King Faisal Prizes seven laureates who received their prizes on 29 March in Riyadh, Saudi Arabia, for having enriched humanity with key and invaluable achievements and discoveries, and excelled in the fields of Medicine, Science, Arabic Language & Literature, and Serving to Islam.

The Medicine Prize was awarded to Professor David Liu, Richard Merkin Professor and Director of the Merkin Institute of Transformative Technologies in Healthcare, who invented the first gene base editor in 2016.

This technology laid the foundation for possibly treating thousands of genetic diseases like sickle cell disease and muscular dystrophy. Professor David Liu used base editors in mice to correct the genetic mutation behind progeria, a rare condition characterized by premature aging, retarded development, and early death. Still, more work needs to be done before gene base editors can be used in humans.

Initiating a revolution in genome editing, base editors have received great global demand. They were distributed over 9,000 times to more than 3,000 laboratories around the world. Scientists were able to publish more than 300 papers on this technique, used in different organisms ranging from bacteria to mice.

Base editing is a precise genome editing method; like a genetic pencil, that rewrites DNA base letters, which cause genetic mutations and potentially genetic diseases. This technology, which is in constant development, chemically rewrites one DNA base to another by rearranging the atoms of one DNA base to resemble a different base. In 2019, Professor David Liu created with his team prime editing which offers more targeting flexibility and greater editing precision.

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With over 75 issued U.S. patents, Professor Liu was referred to as the Gene Corrector by Nature magazine topping its list of Ten People Who Mattered This Year in 2017 and was included in the Foreign Policy Leading Global Thinkers list. He is also a biotech entrepreneur, cofounding Editas Medicine, which uses CRISPR therapies (tool for editing genomes) to discover, develop, manufacture, and commercialize transformative, durable, and precise genomic medicines for a broad class of diseases.

The Science Prize (Mathematics) was awarded jointly to Professor Martin Hairer, Chair in Probability and Stochastic Analysis at Imperial Colleges Department of Mathematics, and to Professor Nader Masmoudi, a distinguished Professor of Mathematics at the New York University of Abu Dhabi and head of his Research Center on Stability, Instability and Turbulence.

Professor Martin Hairer developed the theory of regularity structures which gave a precise mathematical meaning to several equations that were previously outside the scope of mathematical analysis. He published his theory in 2014 providing tools and manuals for solving many previously incomprehensible equations called the stochastic partial differential equations (SPDEs). These equations involve chance and describe how randomness throws disorder into different phenomena like coin tossing, stock price changes, wind movement in a tunnel, or forest fire growth. He transformed the area of SPDEs by introducing fundamental new techniques and was able to solve equations like KPZ equation which describes the evolution of the boundary at which two substances meet over time.

Professor Hairer is a world leader in probability theory and analysis and has authored a monograph and over 100 research articles. His work has been distinguished with several prizes and awards, most notably the LMS Whitehead and Philip Leverhulme prizes in 2008, the Fermat prize in 2013, the Frhlich prize and the Fields Medal in 2014, a knighthood in 2016, and the Breakthrough prize in Mathematics in 2020.

As for Professor Nader Masmoudi, he was able to unlock the mystery around many physics problems which remained unsolved for centuries. He found a flaw in Eulers mathematical equations which for more than two centuries described the motions of fluids under any circumstance. He discovered that Eulers equations do not apply to all circumstances, as previously thought, and proved that they could break or fail under certain conditions related to fluids. His work helped solve and understand many problems related to fluid-modeling like weather predictions and airplane turbulence.

For the past 20 years, Professor Masmoudis research has been at the forefront of Partial Differential Equations, Fluid Mechanics, and Dynamical Systems. He has been cited by more than 8000 papers for his works in pure and applied mathematics. He has been recognized with numerous awards, including the Best Scientific Paper Award in Annales de lInstitue Henri Poincar, a Chair from the Fondation Sciences Mathematiques de Paris, The Fermat Prize, and the Chair Schlumberger from the IHES in Paris.

In addition to Medicine and Science, King Faisal Prize recognized this year the achievements of outstanding thinkers and scholars in the field of Arabic Language & Literature, and honored exemplary leaders who played a pivotal role in serving Islam, Muslims, and humanity at large.

The Arabic Language and Literature Prize about Arabic Literature Studies in English was awarded to Professor Suzanne Stetkevych, Chair of the Department of Arabic & Islamic Studies at Georgetown University, and to Professor Muhsin Al-Musawi, Professor of Arabic and Comparative Literary Studies at Columbia University.

Professor Suzanne Stetkevych was awarded the prize for her extensive research and work analyzing Arabic literature with unmatched depth from the pre-Islamic period to the revivalist period. Her research approach resulted in the renewal of the critical perspective and methods of studying classical Arabic poetry.

Professor Muhsin Al-Musawi received the prize for being a well-established authority in the field of Arabic literature demonstrating his encyclopedic knowledge in both classical and modern Arabic literature. His research and studies have made great impact on students and researchers in the field of Arabic studies, both in the Arab world and the West. He handled Arabic literature as a world literature.

The Service to Islam Prize was awarded to the former Tanzanian President His Excellency Ali Hassan Mwinyi and to Professor Hassan Mahmoud Al Shafei. His Excellency Ali Hassan Mwinyi actively participated in Islamic advocacy, spreading the spirit of religious tolerance, educating Muslims, and translating many Islamic resources and references into Swahili language. In parallel, Professor Hassan Mahmoud Alshafei served Islamic sciences through teaching, writing, authenticating, and translating, and has contributed to the establishment of the International Islamic University in Islamabad and the development of its colleges curricula.

The Islamic Studies Prize for this year on Islamic Heritage of Al- Andalus was withheld because the nominated works did not meet the criteria of the prize.

Since 1979, King Faisal Prize in its 5 different categories has awarded 282 laureates from 44 different nationalities who have made distinguished contributions to different sciences and causes. Each prize laureate is endowed with USD 200 thousand; a 24-carat gold medal weighing 200 grams, and a Certificate inscribed with the Laureates name and a summary of their work which qualified them for the prize.

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Gene-Editing Technologies, Fluid Mechanics Breakthroughs, and Solutions to Unfathomable Mathematical Equations Recognized by King Faisal Prize - Yahoo...

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Groundbreaking cancer research helps shed light on recently identified syndrome

Ayden Isaacs, 15, (middle) walks along the Mississippi River in St. Louis County with his mother, Jennifer Isaacs, and his father, Michael Isaacs. Ayden Isaacs was diagnosed with DNMT3A Overgrowth Syndrome in 2015 at Washington University School of Medicine in St. Louis. Children and young adults with the rare genetic disease may have physical and intellectual disabilities and an increased risk for blood cancers, including acute myeloid leukemia (AML). Aydens clinical samples have helped researchers learn more about his condition and AML.

In 2008, a team of scientists at Washington University School of Medicine in St. Louis became the first to decode the DNA of a patients cancer cells and trace the disease to its genetic roots. The patient, a woman in her 50s, suffered from acute myeloid leukemia (AML), an aggressive and often deadly cancer of the blood and bone marrow. The findings garnered the research team worldwide acclaim and paved the way for more personalized approaches for the treatment of cancer based on the clusters of mutations in patients tumors.

One of the most unusual mutations discovered in that patients AML cells was in the gene DNMT3A. The gene had never been linked to cancer, so the significance of the genes mutations was unknown. But it was a fascinating candidate gene to consider. DNMT3A was known to encode an enzyme that can methylate DNA at very specific places in the genome, a process that can change patterns of gene expression and that was known to be very important for normal development.

In the year that followed, the Washington University team sequenced the DNMT3A gene in 280 additional AML patients and found that it was indeed one of the most common initiating mutations for this disease and that mutations in one particular site, at the 882nd amino acid in the DNMT3A protein, was more common than all of the others. This hot spot for mutations suggested that something special was going on there, and further studies from the lab of Timothy J. Ley, MD, clarified what that something was. Ley, the universitys Lewis T. and Rosalind B. Apple Professor of Medicine and chief of the Section of Stem Cell Biology in the Division of Oncology, helped lead the first sequencing of the AML patients genome.

The mutations at amino acid 882 changed the way the protein normally interacted with itself to make a functional enzyme, and reduced the activity of the enzyme by about 80% essentially rendering it inactive. When Ley and his then-trainees David Russler-Germain, MD, PhD, and David Spencer, MD, PhD, looked at the DNA methylation patterns in AML samples with this mutation, they found a very distinct signature, with pinpoint areas of reduced DNA methylation at very specific regions of the genome in every patient who had the mutation.

This knowledge framed an essential chicken vs. egg question: Were these areas with reduced DNA methylation important for causing AML, or were they just a byproduct of cancer transformation? The only way to find out would be to get a sample of blood cells from a person with the same exact DNMT3A mutation but who did not have AML, to see whether the changes in DNA methylation were already there.

But there was no obvious way to find such a patient.

On a bright winter afternoon in 2015, serendipity graced the investigators and the families of a group of patients with a rare genetic syndrome that had been discovered the year before.

As Ley sat in his office mulling over the conundrum that was confounding the field, his phone rang.

The caller Shashikant Kulkarni, PhD, then-head of the Department of Pathology & Immunologys Cytogenetics and Molecular Pathology Laboratory bombarded Ley with a staccato of facts: A patient at St. Louis Childrens Hospital. A 9-year-old boy named Ayden, with a newly described genetic syndrome associated with a mutation in the DNMT3A gene but his blood counts were normal. And, Kulkarni noted, the boy and his parents had consented to donating his blood and tissue samples for research.

I couldnt believe it, Ley recalled.

Shortly after that conversation, Ley received a call from Marwan Shinawi, MD, a professor of pediatrics in the Department of Pediatrics Division of Genetics & Genomic Medicine. Shinawi had just diagnosed Ayden with DNMT3A Overgrowth Syndrome, also known as Tatton Brown Rahman Syndrome (TBRS), a syndrome first identified in 2014 by a pediatric geneticist in London, Kate Tatton-Brown. The condition can cause individuals to be taller than average, overweight and have a large head circumference and distinctive facial features. People with the disorder also may have intellectual disabilities, behavioral difficulties and decreased muscle tone.

In 2014, there were only 13 patients in the world with a known diagnosis of the syndrome.

Youre not going to believe this, Shinawi told Ley over the phone, but the patient has the R882H mutation that youve been studying, and his father works here in pathology.

It was truly incredible, Ley said. There were 13 known patients in the world who had this syndrome. None of them to date had the mutation at position 882 that was so strongly associated with AML. This created a remarkable opportunity to learn more about how DNMT3A mutations contributed to TBRS and how they initiated AML.

Leys prior research on the mutation and blood cancers also triggered concern for Ayden. I worried that Ayden and these other children might be at increased risk of leukemia, Ley said. I knew that it was essential to monitor Aydens health while determining whether there is an increased risk of leukemia for patients with this syndrome.

Thanks to Aydens contribution to scientific research as well as similar contributions from dozens of other families from around the world the Washington University Medical Campus is now a global beacon for patient care and research for TBRS. Now, the syndrome is known to affect about 250 children and young adults worldwide, according to the TBRS Community, a family-led rare-disease organization founded by Jill Kiernan. Her daughter, Aevary, was one of the first to be diagnosed with the syndrome, in 2014.

The nonprofit, which emphasizes advocacy, education and research, is collecting information from families in a clinical registry to study the genetics, development and health of children with DNMT3A Overgrowth Syndrome and of their families.

Dr. Ley has been amazing about talking directly to families whose children have DNMT3A variants, Kiernan said. He says, Well do what we can. Well coordinate with their team. Well tell them what we know and what we dont know. And he does. Its not only Dr. Ley, but everyone weve worked with at Washington University has a sincere interest in helping these children and their families.

The childrens blood and tissue samples continue to be studied in laboratories across the School of Medicine, from oncology and genomics to neuroscience and pediatrics. In conjunction with the studies of clinical samples, genetically modified mouse models are proving to be an important new tool for understanding how DNMT3A mutations work. Mouse and human genomes share common genes that typically function in the same way. Such similarities make mice ideal for simulating human disorders to study how a single mutation can cause all of the features of a complex disease like TBRS. Remarkably, when the amino acid 882 mutation is created in mouse germline cells that make eggs and sperm, the animals develop virtually all of the features of the human syndrome including the reductions in DNA methylation noted in the AML patients. They also have an increased likelihood of developing blood cancers, including AML. These findings were published last year in Nature Communications.

The key to understanding genetic conditions such as TBRS is having both clinical data and samples, as well as mouse models, explained the papers first author, Amanda M. Smith, PhD, a former researcher in Leys lab who led the development of the mouse model with the amino acid 882 mutation.

Harrison Gabel, PhD, an assistant professor in the Department of Neuroscience, has created additional DMNT3A mouse models and focused on how they affect brain function. Were looking at it from a molecular level, how genes get turned on and off, and how that affects development to drive the overgrowth, obesity and neurologic dysfunction that occur in the disorder, he said. The collaborative environment and resources at Washington University position us to attack this particular disorder from all sides. Dr. Ley and I are working side by side, studying the gene in blood cells and in the brain. Combining our efforts with Dr. Shinawi, who understands the clinical aspects of this disorder, and adding in the remarkable relationship with patients and their families, it all adds up to a powerful synergistic approach.

Gabel is a member of the TBRS Communitys scientific advisory committee, and Ley and Shinawi serve on the medical advisory board. This nonprofit recently secured a three-year, $600,000 grant from the Chan Zuckerberg Initiative. It is a total game changer for our little organization thats been fueled by parent volunteers, said Kerry Grens, the groups vice president and the Department of Neurosciences new marketing administrator. Her son Adrian was diagnosed with TBRS in 2019, when he was 3 years old.

Shortly after Adrian was born, Grens and her husband noticed their son was delayed on milestones such as holding up his head and sitting. He also had strabismus (crossed eyes) and a congenital heart defect. We saw a lot of doctors before we came to Washington University, underwent genetic sequencing and received an official diagnosis from Dr. Shinawi, Grens said. It can feel hopeless to have a child with an incurable rare disease, and volunteering with the organization gives me a chance to feel like Im making progress, making a difference. A lot still needs to be answered about this genetic mutation and the associated risks for other diseases such as leukemia.

Research led by Margaret Ferris, MD, PhD, an instructor of pediatrics at Washington University and an oncologist at St. Louis Childrens Hospital, recently confirmed the scientists initial concerns: Patients with TBRS are at an increased risk about 250 times more than the general population for blood cancers, including acute myeloid leukemia. The study was published in November in Blood, the journal of the American Society of Hematology.

This can be difficult news to tell the families, obviously, but its the truth, and they need the truth, said Ley, the studys senior author. Do we need to monitor these children for early signs of the development of leukemia? The answer is, clearly, yes, we do.

Aydens dad, Michael Isaacs, said the truth, no matter what it may be, gives him hope. Not knowing is the biggest burden, said Isaacs, director of informatics and of external affairs for the Department of Pathology & Immunology. Knowing, and having a diagnosis, help set expectations for what the future may look like, but most of all, it gives me hope. The research being done, the dedication of the parents, and the collaborations at Washington University all give me hope.

Washington University School of Medicines 1,700 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, and currently is No. 4 in research funding from the National Institutes of Health (NIH). Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Serendipity unites physicians, researchers, families to fight rare genetic disease in kids Washington University School of Medicine in St. Louis -...

A recent study published by researchers at Baylor College of Medicine and Texas Childrens Hospital, in collaboration with the German Center for Infection Research, identified two main subtypes or endotypes of tuberculosis according to the persons immune response to the infection. They found that one subtype had a better prognosis for curing tuberculosis than the other. Their findings, published in the European Respiratory Journal, could improve personalized treatment options for the disease in the future.

We conducted this research under the assumption that tuberculosis is not a uniform disease, that there are many pathways by which a person could develop the condition and that the outcome depends on the immune response produced by the infected person, said Dr. Andrew DiNardo, assistant professor of medicine infectious diseases at Baylor and Texas Childrens.

For people who contract tuberculosis, the course of the disease can vary significantly. Most people do not become ill after infection with Mycobacterium tuberculosis, the bacterium that causes the disease. However, people can develop chronic pneumonia and some also have disease in the lymph nodes, bones or the central nervous system. Some TB patients have suppressed and exhausted immune responses, while others have an overacting response that makes the condition worse.

Endotype discovery based on gene expression profiles has revolutionized our understanding of cancerand tailored patient therapy. We hypothesized that a similar approach could identify distinct and clinically relevant TB endotypes, and the results exceeded our expectations, said senior author Dr. Cristian Coarfa, associate professor of molecular and cellular biology at Baylor and member of Baylors Dan L Duncan Comprehensive Cancer Center.

DiNardo said that researchers in the field are looking for new therapies for the disease, as current therapies require six months of antibiotics. To identify new treatments, researchers have been studying the human immune response to tuberculosis bacteria to better understand what it takes to build protective immunity against this disease. This approach can lead to the development of personalized precision medicine therapies.

Led by Coarfa, the team applied cutting-edge unbiased bioinformatic techniques to analyze large patient datasets to look at immune responses to tuberculosis and identified two main clusters or endotypes of the disease. They then looked at these specific endotypes in two different patient cohorts and found that one endotype had a higher risk of treatment failure and death than the other. Using computer models, they then predicted what types of drugs could be used to treat each tuberculosis endotype.

When we compared different drugs as potential personalized therapy, we found that one therapy could be inconsequential or detrimental to one TB subtype, but beneficial to the other, DiNardo said.

The results of this study will pave the way for personalized therapies, with great potential to improve treatment outcomes for the deadliest of all bacterial infectious diseases, adds Professor Jan Heyckendorf, a DZIF tuberculosis researcher from Borstel and Kiel and one of the studys lead authors.

Whereas gene expression or transcriptomic-based TB endotypes are already informative, future work will incorporate other informative omics, such as metabolomics (metabolites present) and epigenomics or the regulation of gene expression via DNA methylation, leading to further refinement of endotypes and personalized therapy, said Coarfa.

Researchers will now implement clinical trials to treat tuberculosis in a stratified personalized therapy approach, similar to the approach that oncologists take when treating different subsets of cancers.

The following researchers also took part in the study Tanmay Gandhi, Sandra L. Grimm Kimal Rajapakshe, Tomoki Nishiguchi, Maja Reimann, H. Lester Kirchner, Jaqueline Kahari, Qiniso Dlamini, Christoph Lange, Torsten Goldmann, Sebastian Marwitz, DZIF-TB cohort study group, Abhimanyu, Jeffrey D. Cirillo, Stefan HE Kaufmann, Mihai G. Netea, Reinout van Crevel and Anna M. Mandalakas.The authors are affiliated with one or more of the following institutions: Baylor College of Medicine; Texas Childrens Hospital; German Center for Infection Research (DZIF); University of Lbeck; Baylor-Swaziland Childrens Foundation; Texas A&M Health Science Center, Bryan; Max Planck Institute for Infection Biology; Texas A&M University, College Station; Radboud University Medical Center; University of Bonn; Max Planck Institute for Biophysical Chemistry and University of Oxford.

The study was funded by NIAID (grant K23 AI141681-02), the Cancer Prevention Institute of Texas (CPRIT) grants (RP170005, RP200504 and RP210227), NIH/NIAID grants (1U19AI144297, R01AI14578), NIH/NCI P30 shared resource grant CA125123, and NIEHS grants (P30 ES030285 and P42 ES027725). Further support was provided by the German Center for Infection Research, the Texas A&M University System and National Institutes of Health grant AI104960, an ERC Advanced Grant (#833247), a Spinoza grant of the Netherlands Organization for Scientific Research,NIH grants (R01AI14578, R01AI137527, U01GH002278) and DoD grant W81XWH1910026.

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Two distinct tuberculosis subtypes IDed implications for personalized therapy - Baylor College of Medicine News

Yale researchers have further elucidated the mechanism of metformin, a widely used type 2 diabetes medication that, despite its long history of being safe and effective, works in a way that has remained elusive to scientists.

On March 1, Gerald Shulman, MD, PhD, George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology, published his labs findings on how metformin works to suppress gluconeogenesis through inhibiting Complex IV activity. Now, a different study led by Yingqun Huang, MD, PhD, professor of obstetrics, gynecology & reproductive sciences, builds upon Shulmans findings and further illuminates how the drug works. Her team published its findings in Proceedings of the National Academy of Sciences on March 28. Our research not only discovered a new mechanism of metformin, but also identified potential therapeutic molecular targets, says Huang.

Shulmans findings over recent years supporting an oxidation-reduction (redox)-dependent mechanism of metforminin which cytosolic redox is increasedintrigued Huangs lab. But while Shulmans lab has focused on how inhibition of the mitochondrial enzyme Complex IV promotes an increased cytosolic redox state and inhibition of gluconeogenesis [glucose production from glycerol, lactate and amino acids], Huang is interested in how increased redox changes hepatocytes [liver cells] further downstreama mechanism researchers are now debating.

In 2020, Huangs lab published a paper in Nature Communications that found that the expression of a gene known as TET3 was increased in mice and humans with diabetes. In turn, the expression of a specific fetal isoform of the HNF4A gene was also increased. In healthy adult livers, the adult form of HNF4A is predominantly expressed. In patients with diabetes, however, the fetal isoform is chronically increased because TET3 is also chronically increased. This fetal isoform also increases gluconeogenesis by regulating key enzymes involved in the process.

In our published paper two years ago, we identified that the upregulation of TET3 and the HNF4A fetal isoform in humans and mice with diabetes contribute to unabated gluconeogenesis in the liver, says Da Li, professor at China Medical University and co-author on both studies. Now, through its latest work, Huangs lab has discovered that when metformin induces an increase in cellular redox, this in turn increases let-7, a small microRNA molecule. When let-7 increases, it binds to and downregulates TET3, suppressing the HNF4A fetal isoform and also gluconeogenesis mproving diabetes

In the livers of diabetes, let-7 is depressed, explains Di Xie, associate research scientist in Huangs lab and first author of the study. Metformin brings let-7 back to normal levels and inhibits gluconeogenesis.

Unabated glucose production from the liver is one of the key mechanisms of diabetes. Through better understanding how metformin works to suppress gluconeogenesis, Huang hopes her work will lead to more effective drugs with fewer side effects. The study also identified potential therapeutic targets including let-7. Scientists could potentially use a vector such as a mild virus known as adeno-associated virus, for example, to specifically deliver a let-7 mimic to the liver of patients with diabetes to enhance let-7 expression and treat the condition. Huang hopes to develop such a vector for delivering therapeutics like a let-7 mimic in future research.

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Yale Researchers Continue to Unravel the Mystery of Metformin - Yale School of Medicine

Background

What are immune checkpoint inhibitors (ICI)? When a foreign tumor cell presents itself, it can talk with cells and instruct the human immune system to not kill the cancer, functioning as brakes. Immune checkpoint inhibitor therapies (ICI) function by releasing these natural brakes of the human immune system (Figure 1). By blocking this communication, ICIs allow the immune cell to perform its function and kill the foreign tumor cell.

Selecting who to treat with ICIs. Currently in clinic, we look at a tumor and decide who is going to receive ICIs by measuring the amount of a specific protein called programmed cell death ligand 1 (PD-L1). However, using this criteria for selection, only 1/5 patients with non-small cell lung cancer (NSCLC) who receive ICIs have a good response, as measured by improved survival. This means that only looking at the expression of PD-L1 is not sufficient for determining who to treat.

This proposed research aims to find an alternative way to identify which persons with NSCLC will respond, and not respond, to this kind of treatment.

Tissues from patients with NSCLC treated with ICIs from 2011 to 2020 were retrospectively collected. Tissues were pre-ICI treatment to allow to look at tissues that have not been altered by ICI treatment. The tumor-specific areas of these tissues were selected and analyzed using a research use only version of a clinical test. This is an inexpensive, simple diagnostic assay that is easy to operate. It measures mRNA levels. We looked at the mRNA of 4 target immune genes, CD274 (PD-L1), PDCD1LG2 (PD-L2), CD8A, and IRF1 (depicted in Figure 1) and a control gene. Gene expression levels were analyzed for associations with response.

PD-L1 protein is associated with survival (TPS >50) and is weakly correlated with PD-L1 mRNA

Lower PD-L1 mRNA is associated with worse outcome (decreased overall survival and no benefit at 24 months; Figure 2 below) and a high negative predictive value (92% NPV, meaning a negative test has a 92% chance of being associated with no benefit).

This assay, because of its high NPV, has the potential to identify patients who are not likely to benefit from ICIs and could be spared the risk of immune-related adverse effects.

Submitted by Renee Gaudette on March 30, 2022

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PD-L1 and PD-L2 mRNA are Associated with Outcome and High Negative Predictive Value in Immunotherapy-treated Non-small Cell Lung Cancer - Yale School...

Germline genetic testing where clinicians test for inherited mutations is essential for patients with colon cancer, as the results may not only help guide their treatment options but can also let them know if they or their family members are at an increased risk for other cancers.

However, current recommendations call for screening of patients and then deciding if they are appropriate candidates for germline testing, which could lead to some patients with genetic mutations or inherited cancer syndromes falling through the cracks and not being identified, according to Rachel Pearlman, a genetic counselor at The Ohio State University College of Medicine.

In a recent interview with CUREs sister publication, CancerNetwork, Pearlman discussed her research in genetic testing in patients with colon cancer, and why germline testing for all should be the way of the future.

Question: Can you explain your research regarding colon cancer genetic testing, and how it can help both patients and their family members?

Pearlman: The Ohio Colon Cancer Prevention Initiative, which we affectionately referred to it as the OCCPI study was exactly what the name implies. It was a statewide initiative in Ohio that was created to prevent colon cancer.

We know that individuals who are born with a germline pathogenic variant in a cancer predisposition gene have increased risk to develop specific types of cancer. Obviously the types of cancer depend on which gene isn't working correctly. By identifying individuals with colon cancer who have these germline pathogenic variants, we could then hopefully prevent them from getting different cancers in the future, and we could help their family members reduce their risk for cancers too.

The OCCPI study is the largest study to date that performed universal tumor screening on everyone in the study. And we also did germline genetic testing with multi-gene, pan-cancer panels for those who met our germline testing criteria. And then we also did tumor sequencing for those with unexplained mismatch repair deficiency.

We also provided genetic counseling locally for those who tested positive for a germline pathogenic variant and no cost cascade testing and genetic counseling for the relatives of those found to have Lynch syndrome.

What were some of the highlights that came out of that research?

Importantly, we found that one in 14 (or 7%) of individuals with colon cancer will have at least one gene mutation increasing cancer risk. And we know that this is actually an underestimate of the true prevalence, because only our high-risk patients receive germline testing. In our study, the true prevalence is probably closer to 10 to 15%, as shown by some other studies.

We also found that one in 25, (or a little bit over 4%) of patients with colon cancer actually have Lynch syndrome, which is a higher frequency than what we had previously reported, which is likely due to improved technology with both the universal tumor screening and germline testing and it truly being universal being done on all-comers rather than targeted (and) based on your diagnosis or family history.

Also importantly, we found that 3% had a pathogenic variant and a non-Lynch syndrome gene, the most commonly being in ATM, which is thought it was a breast and pancreas gene (mutation). (We also saw mutations in the CHEK2 gene) which is thought of as a breast and colon (cancer) gene. APC, which is known to cause polyposis. Interestingly, (there were) BRCA 1 and 2 (mutations), which increases risk for breast and ovarian cancer.

So we were finding gene mutations that we weren't necessarily expecting based on their colon cancer diagnosis. And for some of them, we weren't expecting them based on the family history either.

We also have some really interesting data in our young-onset cohort. We found that 16% of individuals diagnosed with colon cancer under the age of 50 had at least one gene mutation. We had published that a few years earlier. About 8% of those individuals have Lynch syndrome and 8% had no different hereditary syndrome.

The most import (finding), to come out of this research was that if universal tumor screening, which is recommended for every person who's diagnosed with colon cancer, had been the only method used to screen for hereditary cancer syndrome, then almost 40%, so 38.6%, of our patients identified to have a mutation would have been missed. (Thats) including 6.3% of those who are identified to have Lynch syndrome. We found that we're missing Lynch syndrome and mismatch repair proficient patients, and we found unexpected mutations in both the proficient and efficient mismatch repair patients.

What is on the horizon for genetic testing in colon cancer?

Hopefully genetic testing or germline genetic testing will be recommended for all individuals with colon cancer, which is a pretty big shift from our current guidelines, which are really based mostly on mismatch repair deficiency status, or age at diagnosis or family history criterion. There's a lot of burden on the practitioner trying to figure out who is the appropriate person to offer genetic testing to.

Once germline genetic testing is recommended for all colon cancer patients, or if that were to happen, that would certainly eliminate a lot of the burden on trying to figure out who is the right person to test. We know that everybody who has colon cancer is appropriate for testing.

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Universal Genetic Testing Should be Recommended for All Patients With Colon Cancer, Says Expert - Curetoday.com