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RESEARCH EFFORTS FOCUS ON ASTHMA-COPD OVERLAP

Source: Brigham and Women's Hospital
Date: 11/9/2023
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Asthma and chronic obstructive pulmonary disease (COPD) each affect millions of people in the United States. So it’s not unexpected that a subset of patients would have both lung conditions. Yet surprisingly, little is known about the science of what’s called asthma-COPD overlap, or ACO. Experts at Brigham and Women’s Hospital are focused on changing that.

“From a clinical perspective, primary care doctors, respiratory specialists and emergency departments see these patients all the time. They know how to recognize when someone has both conditions,” said Craig P. Hersh, MD, MPH, a specialist in pulmonology and critical care medicine at The Lung Center at the Brigham. “But from a scientific perspective, much less is known.”

Based on observational studies, experts believe anywhere between 15 and 45 percent of people with COPD have a previous asthma diagnosis. One effort that promises to help researchers get a better handle on those numbers is COPDGene, a National Institutes of Health-sponsored, multicenter study in which Hersh is a site co-principal investigator at the Brigham. The study has enrolled 10,000 smokers with and without COPD to follow them longitudinally.

Seeking a Clearer ACO Diagnosis

The first step in studying these patients is learning to identify them. “Right now, we don’t have a clear way to do that,” Dr. Hersh said. “As part of the COPDGene study, we’re collecting data on CT scans, lung function and blood samples, which we think will help to find markers that are unique to the subset of patients with ACO.”

The lack of clear diagnostic markers has been a major impediment to clinical research. In fact, Hersh noted, a suspected diagnosis of ACO has traditionally been a disqualifier for clinical trials: Patients with an asthma diagnosis are excluded from COPD trials, and patients with a COPD diagnosis are excluded from asthma trials. Because people with a history of asthma were not excluded from COPDGene, the effort provides a unique opportunity.

Using what Dr. Hersh called a “fairly strict” definition, investigators have discovered that about 12 percent of people enrolled in the observational study have asthma-COPD overlap. “We’ve found that it’s more common in women, which we already knew,” he said. “But we’ve also found that it’s more common in African Americans. That frequency wasn’t known, and it’s an important new finding.”

COPDGene Study: A Move Toward Precision Medicine

As the name suggests, the COPDGene study is also seeking genetic variants that could be linked to a predisposition to COPD. “We know that both asthma and COPD have genetic or hereditary influences, so we’ve been studying that overlap as well,” Hersh said. “To do these kinds of studies, you need very large patient populations, so we’re not there yet. But we do have some suggestive findings already.”

Another focus of COPDGene is to look for particular antibodies in the blood, although specific markers for ACO have not been found yet.

“There have been a lot of promising new treatments with asthma biologic therapies over the last several years, and there’s a lot of interest in figuring out if these medications would be useful for patients with ACO,” Dr. Hersh said. “If we can learn to define ACO based on biomarkers found on CT scans or in the blood, we may be able to more accurately apply precision medicine, offer these biologics or develop potential new medications for this important group of patients.

Dr. Hersh added that even before specific clinical trials for ACO are launched, having better diagnostic guidelines will have an impact on clinical care. “We could start using these biomarkers in clinical practice right away,” he concluded.

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Inherited Cancer Risks: New Insights from MSK Presented at 2023 ASCO Meeting

Source: Memorial Sloan Kettering - On Cancer
Date: 06/05/2023
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Researchers from Memorial Sloan Kettering Cancer Center (MSK) revealed new findings about hereditary cancers and genetics at the recent 2023 American Society of Clinical Oncology (ASCO) annual meeting.

Genetic mutations that are passed down through families cause a significant percentage of cancers — between 5 and 10%, and as high as 15 to 20% in people with advanced cancers. Patients with certain hereditary cancers may especially benefit from many of the latest cancer treatments, including targeted drugs and immunotherapies. Their families also may benefit from being monitored for early signs of cancer.

Among the recent advances in MSK’s research into understanding how inherited DNA mutations affect cancer development and treatment, four presentations at the ASCO meeting highlighted new analysis of early-onset disease, hereditary cancers in transgender people, a new gene linked to lung cancer, and the importance of genetic testing for younger people with gastrointestinal cancers.

What Defines Early-Onset Cancers and How Should They Be Treated?

Amid growing concern about an increase in cancers occurring in younger people, clinical geneticist and gastrointestinal oncologist Zsofia Stadler, MD, presented research that found the age for so-called “early-onset” cancer can vary widely depending on the type of cancer. Dr. Stadler stressed the need to have clear criteria to define early-onset cancers, because her research also found these cancers are more likely to be linked to an inherited genetic mutation. Knowing whether a cancer is caused by a hereditary mutation is important because it can make a difference in choosing the right treatment. It’s also a signal that members of a patient’s family should consider genetic testing.

“We know the incidence of early-onset cancer is increasing for some tumor types, but when we think about what early onset means, we realize it’s actually poorly defined,” says Dr. Stadler, Clinical Director of MSK’s Clinical Genetics Service. “These cancers are usually defined as those arising before the age of 50 for any type of solid tumor. But the fact is, there is a dramatic variation in the average age of onset across different tumor types.”

The research had two aims: The first was to determine what age should be considered early onset for a variety of solid tumors. The second was to determine how often different types of early-onset cancers were likely caused by inherited genetic mutations.

First, the investigators used a National Cancer Institute database to determine the average age at which patients typically developed 32 types of solid tumors. Based on those ages, researchers then used a formula to calculate what age would be considered early onset for each of these cancers. That age ranged from the late 30s for cervical and thyroid cancers to about 60 for mesothelioma and bladder cancer. “If we considered 50 the cutoff age for every type of solid tumor, there are a lot of early-onset cancers that we would miss,” Dr. Stadler explains.

To answer the study’s second major question, the researchers then used these new classifications to analyze how often early-onset cancers were linked to an inherited genetic mutation. (This is an alteration in DNA that is passed on by a parent and present in every cell in the body.)

Overall, researchers found that early-onset cancers were much more likely to be linked to hereditary mutations — 19% versus 15.5% in people whose cancers developed at an average age. For hereditary mutations defined as “high penetrance” (meaning they were extremely likely to cause cancer), the difference was even more dramatic: 13% of early-onset cancers were linked to inherited mutations versus 5% of cancers occurring at an average age.

Researchers arrived at this conclusion using data from about 29,000 patients whose DNA was analyzed with MSK-IMPACT®, a test that identifies genetic mutations linked to cancer. It can find mutations that are only in tumors as well as inherited mutations that may increase the risk of developing cancer.

“The diagnosis of an early-onset cancer is an impetus for doing genetic testing to look for inherited risk factors,” Dr. Stadler says. “The findings from this study illustrate how important it is that early-onset cancers be correctly classified.”

Caring for Transgender Patients With Hereditary Cancer Syndromes

Genetic counselor Megha Ranganathan, MS, CGC, participated in a panel discussion focused on caring for transgender patients with inherited mutations in the BRCA1 and BRCA2 genes. Mutations in these genes can increase the risk for several cancers, including breast, ovarian, and prostate cancer.

“There are more than 1.6 million people in the United States who identify as transgender, and that number is likely an underestimate,” Ranganathan says. “The data is so limited that many providers are often unsure how to best manage cancer risk in these people, especially those at higher risk due to an inherited genetic predisposition.”

Ranganathan and her co-presenters discussed two cases demonstrating the challenges for these patients. The first case involved a transgender woman (a person who is assigned male at birth but identifies as a woman). After her mother was diagnosed with ovarian cancer, genetic testing revealed the transgender woman had a BRCA2 mutation. “At that point, the patient had already been receiving gender-affirming estrogen therapy for about 10 years,” Ranganathan said. “We know that prolonged estrogen exposure is a risk factor for breast cancer, but it is unknown how much it increases her risk, especially because she has a BRCA2 mutation.

“Despite the lack of reliable data, increased breast cancer surveillance or risk-reducing surgery may be reasonable options,” she added. “We encourage these patients to talk to their doctors to determine the best option for them depending on their gender-affirming goals.” Another issue for this patient: Because she was assigned male at birth, she has a prostate, and this gene mutation puts her at increased risk for prostate cancer as well.

The second case involved a young transgender man (a person who is assigned female at birth but identifies as a man). He had a BRCA1 mutation and was considering top surgery (surgery to remove breast tissue and make the chest look more masculine). Would having top surgery reduce his risk for breast cancer? The panel suggested more extensive surgery such as a full mastectomy could be considered to prevent breast cancer in this situation.

Ranganathan and her co-presenters also discussed several ways healthcare providers can create a more inclusive environment for gender-diverse people. The panelists explained key concepts and terms, how to represent someone’s gender and sex assigned at birth on family trees, and how to request a patient’s chosen name and pronouns.

“Many transgender people avoid the healthcare system altogether because they fear discrimination and stigmatization. Research is lacking on how best to care for them,” says Ranganathan. “As an institution that is dedicated to reducing healthcare disparities, we at MSK want patients to be aware that this is something we’re thinking about and that we aspire to provide excellent care for all patients, regardless of gender identity.

A New Gene Potentially Linked to Inherited Risk of Lung Cancer

Pediatric oncologist and clinical geneticist Michael Walsh, MD, presented new research that found for the first time that mutations in the cancer predisposition gene POT1 are associated with increased rates of lung cancer. Previously, mutations in POT1 have been associated with sarcoma, certain types of leukemia, and clonal hematopoiesis, a blood condition linked to aging.

“Compared with other cancers like breast, ovarian, and prostate cancers, we know less about the inherited risks of lung cancer,” Dr. Walsh says. “We know that lung cancer is strongly linked to environmental causes like smoking. These findings shine a light on potential inherited factors that may also play a role in causing lung cancer.”

Dr. Walsh and his team were able to make this discovery thanks to the cancer genetic test MSK-IMPACT. In addition to sequencing patients’ tumors, MSK-IMPACT can also analyze the genetics of normal tissue, so experts can determine whether a cancer is linked to an inherited genetic mutation or developed at random. In this case, a study of data from patients’ normal DNA allowed investigators to undercover new findings about inherited mutations in POT1.

“POT1 has been added to the list of genes detected by MSK-IMPACT relatively recently, so it hasn’t been studied as well as some other cancer genes,” Dr. Walsh explains. “But when we looked at data for about 7,000 patients, we found that the incidence of lung adenocarcinoma in people with this inherited mutation was much higher than expected.”

After the MSK-IMPACT analysis, Dr. Walsh and his colleagues found that other large databases of cancer genes supported their findings. They will continue studying the link.

Dr. Walsh says one day this discovery might provide insights leading to new treatments for cancer.

Increasing Genetic Testing for Younger People with Gastrointestinal Cancers

In response to the alarming increase in colorectal cancer cases in younger people, MSK clinical geneticist and family medicine physician Alicia Latham, MD, MS, urged more testing to determine possible inherited risks of cancer.

“As MSK offers genetic testing to more of our patients, we’re finding that some of these gene mutations are more common than we previously believed,” says Dr. Latham, who spoke at an ASCO session focused on gastrointestinal (GI) cancers. “But there are questions about whether these mutations are truly related to the cancer or are instead incidental findings.”

Dr. Latham specializes in treating people with Lynch syndrome. This hereditary condition carries an increased risk of certain types of cancer, including colon cancer and rectal cancers. Lynch syndrome cancers are characterized by a feature called microsatellite instability, which makes them especially responsive to immunotherapy drugs called checkpoint inhibitors.

Because these mutations have important implications for treatment, there is a move toward testing more patients with GI cancers for these genes, especially younger patients, Dr. Latham explains.

“This is a real change from what we’ve done in the past,” she says. “But because findings from these tests can have such important implications for treatment, we want everyone to be aware of these connections and the importance of testing.”

She adds that several collaborative advisory groups in North America and Europe are also backing the recommendations to test more patients for inherited conditions.

Dr. Latham leads MSK’s Comprehensive Assessment, Treatment, and Prevention of Cancers with Hereditary Predispositions (CATCH) program, which provides surveillance and monitoring for people who have genes that are linked to inherited cancer predisposition syndromes.

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MSK Opens New Clinic to Monitor People with a Genetic Risk for Developing Blood Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 01/23/18
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Most cancers arise by chance and, therefore, are hard to predict. But scientists and doctors are learning more about the genetic changes that cause cancer as well as those that signal a higher risk for it. Thanks to MSK-IMPACT™, Memorial Sloan Kettering’s diagnostic test that looks for genes associated with cancer, more people who carry cancer-related genes are being identified.

To take advantage of these new opportunities, MSK has launched the Precision Interception and Prevention Initiative. This program is focused not only on catching cancer very early but also on eventually preventing it from forming in the first place. One of the program’s components is a clinic for people with an age-related condition called clonal hematopoiesis (CH). MSK’s clinic, the first of its kind, is beginning to see people with CH this month.

“This initiative unites high-impact science and clinical medicine to actively identify and help a population of people who are either at a high risk of developing cancer or who already have cancer but don’t know it,” says Luis Diaz, head of MSK’s Division of Solid Tumor Oncology, who is leading this effort.

A person with clonal hematopoiesis has an increased number of blood cells that carry some of the same mutations that are found in blood cancers. CH occurs when hematopoietic stem cells (which give rise to all types of blood cells) form cells that are genetically distinct from the rest of the blood stem cells. Sometimes these distinct cells carry cancer-associated mutations.

“This is an exciting and quickly growing field, and it’s vital for us to learn as much about it as possible,” says physician-scientist Ross Levine, who will be heading the new clinic. “By launching this effort to monitor and care for people with CH, we will be able to advance our understanding about this important area of science.”

Clonal Hematopoiesis: A Common Phenomenon Linked to Aging

Dr. Levine was part of the research team that was the first to identify the genetic basis of CH and its connection to blood cancer. They first reported that relationship in 2012. Since then, many investigators have begun to study the condition and have shown that CH is very common. Researchers have found that it is linked to an increased risk of certain blood cancers, especially myelodysplastic syndrome and acute myeloid leukemia, as well as cardiovascular disease, heart attacks, and strokes.

The most common cause of CH is aging. Studies have suggested that between 10 and 20% of people over age 70 have signs of it in their blood. Smoking also increases the risk. “CH is very common. Millions of people have it,” Dr. Levine says. “But most people don’t know they have it, and doctors don’t know what to do with it. We thought it was important to do more research on this phenomenon so that we can start figuring out who may need intensive follow-up and treatment right away and who can be observed.”

“Right now we don’t have good ways to predict who is most likely to develop a blood cancer, so any new findings that come out of this clinic have the potential to make a big difference,” says Marcel van den Brink, Head of MSK’s Division of Hematologic Oncology.

In addition, certain types of chemotherapy and radiation therapy can increase the incidence of CH. This explains why cancer survivors carry a risk for secondary leukemia. The still-rare condition is happening more often because more people with cancer are surviving longer or are cured of their disease.

A study last year from Dr. Levine, MSK researcher Michael Berger, and their colleagues found that 25% of people with any type of cancer had CH, a higher number than had previously been observed. Of that group, 4.5% had specific mutations that are known to drive the formation of leukemia.

Treating Blood Cancer Earlier

Most people with CH will never develop blood cancer, but doctors are starting to understand which individuals with CH are at the highest risk. “This is one of the reasons this clinic is so important,” says MSK hematology fellow Kelly Bolton, who will be helping to run the new program. “We hope about 100 patients with high-risk forms of CH will participate in our first year.”

The MSK investigators who designed MSK-IMPACT, including molecular pathologist Marc Ladanyi and Dr. Berger, believed it was important to look for cancer-related genes in people’s normal tissue as well as in their tumors. This would help them determine whether a person’s cancer occurred completely by chance or whether inherited factors played a role. The easiest normal tissue to obtain is blood, and the gene mutations linked to CH started to show up as part of MSK-IMPACT testing.

As MSK launches its CH clinic, people who have undergone MSK-IMPACT testing for other cancers and have been found to have high-risk forms of CH in their blood will be contacted by their surgical or medical oncologist and invited to enroll in the program. MSK patients who are treated for low blood counts and found to have CH as part of their blood work will also be seen.

“In the past, CH has been just an incidental finding. When we were worried someone had an undiagnosed blood cancer, we would refer him or her to the Leukemia Service,” Dr. Bolton explains. “Now when we discover patients with high-risk forms of CH, we will have a clinic with experts in CH to manage and coordinate their care.”

For now, those who enroll in the clinic will have the opportunity to have their blood tested on a regular basis. People who are found to have a blood cancer will be able to start treatment immediately, when the disease is much easier to control.

Looking toward Future Treatments

In the future, MSK investigators hope to launch clinical trials of treatments that could block the progression from CH to active cancer. In addition, treatment for solid tumors may be tailored to protect people who already have an increased risk of developing a second cancer. But doctors don’t yet know enough about what drives the formation of CH to make any changes to treatment now.

Recent studies suggest that people with CH are at risk for cardiovascular diseases. However, testing for CH is not currently part of screening for them. “It’s important for people with CH to follow up with their primary-care doctors and make sure they have had the appropriate screenings for cardiovascular diseases,” Dr. Bolton says. “We will encourage everyone participating in our CH clinic to do this.”

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Findings from Two Patients Shed New Light on Drug Resistance in AML

Source: Memorial Sloan Kettering - On Cancer
Date: 06/27/2018
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Last summer, the US Food and Drug Administration approved enasidenib (Idhifa®) for the treatment of acute myeloid leukemia (AML). Enasidenib works differently than most cancer drugs. Rather than killing leukemia cells, it turns them into normal blood cells. Memorial Sloan Kettering hematologist-oncologist Eytan Stein led the pivotal clinical trial that resulted in the drug’s approval.

Now, a collaborative team of researchers is reporting that people who take enasidenib can develop resistance to it — and in a way never seen before. The findings are being reported in Nature.

“Everyone who studies precision medicine spends a lot of time thinking about why some people respond to certain drugs and why some stop responding or never respond at all,” says physician-scientist Ross Levine, who was one of the paper’s senior authors, along with Dr. Stein. “MSK has been one of the leaders in figuring this out.”

The discovery was made by a team of doctors, laboratory researchers, and pharmaceutical company scientists. They used cells from people who were being treated with enasidenib to uncover why the drug sometimes stops working. 

Targeting a Mutation Found in Several Different Cancer Types

Enasidenib is approved for people with AML that is driven by a mutation in a gene called IDH2. About 15% of people with AML have this mutation. IDH2 mutations and mutations in the related gene IDH1 are found in other types of leukemia as well as myelodysplastic syndromes, glioblastoma, and bile-duct cancer.

The proteins made from mutated IDH genes can drive cells to become cancerous. MSK President and CEO Craig Thompson conducted much of the fundamental research on IDH mutations and their relationship to cancer. He is one of the co-authors of the Nature paper.

Researchers had previously shown that only one of the two copies of the IDH2 gene needs to be mutated to drive cancer. The other one is usually normal. In the new paper, the investigators report that when cells developed resistance to enasidenib, the additional mutations that allowed the cells to resist the drug occurred on the normal copy of IDH2.

This stands in contrast to how resistance develops against most targeted cancer therapies. In those cases, an already mutated gene develops an additional mutation that allows the cancer cell to fend off the drug’s effects. “The finding about IDH2 suggests that genetic resistance is more complicated than we thought,” says Dr. Levine, who is a member of MSK’s Human Oncology and Pathogenesis Program (HOPP).

Just two patients were in the study, but the investigators learned a great deal. Experiments with laboratory models allowed them to study how the mutations work. The findings suggest that some people may develop resistance to IDH inhibitors due to a mutation on the same copy of the gene that carries the cancer-causing mutation.

Dr. Levine says that this prediction was confirmed when the researchers identified a third patient being treated with a similar drug that targets a mutation in IDH1. The IDH inhibitor stopped working in this person when a resistance mutation appeared on the copy of the IDH1 gene with the cancer-causing mutation. This suggests that the process may be universal to all IDH-blocking drugs. “It’s a small number of people, but we’re quite confident that we’ll see this same mechanism in others moving forward,” he adds.

Targeting IDH mutations is a growing area of cancer drug development. Earlier this month, Dr. Stein was a co-first author of a paper published in the New England Journal of Medicinethat looked at another drug that targets the IDH1 mutation in people with AML. The multicenter phase I trial reported data on 125 people whose cancer had stopped responding to other treatments. The researchers found that of those treated with the drug, ivosidenib, almost 42% responded. Nearly 22% had a complete remission, meaning that their cancer was no longer detectable. The overall survival was longer than what would be expected in people with this stage of AML and severe side effects were rare. The researchers plan to continue studying the drug in larger, placebo-controlled trials.

A New Biomarker for Drug Resistance

After the people in the study developed resistance, their tumors started growing again. Doctors were able to switch them to other drugs that worked in a different way, however, so they were not affected by the additional mutation. There are a number of other treatment options for people with AML. These include both FDA-approved therapies and experimental drugs being tested in clinical trials. Many people with AML ultimately receive stem cell or bone marrow transplants, which offer the opportunity for a cure. However, many people are not able to undergo transplants, which makes developing new drugs an important focus.

“Now that we know resistance to enasidenib can develop, we can start to monitor people for it by conducting blood tests,” says first author Andrew Intlekofer, who is also a physician-scientist in HOPP. “Over the course of therapy, we can use the protein as a biomarker for the formation of resistance. Then we’ll know we need to offer a different treatment.”

Far-Reaching Implications for Other Cancers

Understanding how resistance to enasidenib develops could lead to the development of additional drugs. Although, Dr. Intlekofer adds, more research is needed before new drugs can be identified. He also notes that the new discoveries about enasidenib could apply to other drugs that work in a similar way. Treatment of other cancers that are characterized by IDH1 and IDH2 mutations could be affected as well.

Dr. Levine highlights the importance of collaboration when conducting this kind of research. Working closely with scientists from Agios, the company that makes enasidenib, was of particular importance, he says. “To do this kind of work, it requires a great team. Everyone who worked on this study made important contributions. This work was one of the most satisfying research experiences I’ve ever had.”

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Double Jeopardy: Gene-Sequencing Test Uncovers New Clues about a Defect Seen in Many Tumors

Source: Memorial Sloan Kettering - On Cancer
Date: 07/18/2018
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Healthy cells contain two copies of each gene: one from your mother and one from your father. But cancer cells don’t play by the rules, and they can disrupt that arrangement.

A collaborative team of researchers from Memorial Sloan Kettering has found that a genetic state called whole-genome doubling is more common in cancer than expected. In addition, they were able to show a connection between this phenomenon and worse outcomes in people with cancer. The findings were published online July 16, 2018, in Nature Genetics. This research helps set the stage for a new way to categorize cancer and could ultimately help guide treatment decisions.

“This was a big surprise,” says senior author Barry Taylor, Associate Director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO). “It turns out that almost 30% of all cancers have this change, across all different types of cancer. That makes whole-genome doubling the second most common feature of cancer after mutations in the p53 gene.”

Unexpected Discoveries from Genetic Testing

Whole-genome doubling is just what it sounds like. It means that a cell has gone from having two copies of every gene in its genome to four. It’s one of the many different types of genetic errors that can enable cancer cells to grow out of control. Until now, it was unknown how often it occurs.

The new discovery was uncovered thanks to MSK-IMPACT™. This diagnostic test of tumor tissue looks for mutations in 468 genes that are known to drive cancer. The test is available to people being treated at MSK for advanced cancer. It helps doctors determine which therapies are most likely to offer a benefit, including experimental new drugs in clinical trials.

To ensure that the mutations detected by MSK-IMPACT are part of the cancer, pathologists also test some of the person’s normal tissue. This is usually a blood sample. Directly comparing the tumor genome to the inherited genomes in normal blood allowed the researchers in this study to tell the whole-genome doubling apart from other changes specific to the cancer.

Sequencing with MSK-IMPACT began in 2014. Since then, discoveries about genetic changes in normal blood have led to other important results. These include findings about how common inherited cancer genes are and the presence of a blood condition known as clonal hematopoiesis.

MSK-IMPACT also anonymously links the genomic data for each person to their clinical records. Investigators are then able to find connections that they wouldn’t be able to make with the genomic information alone.

“We looked to see whether people whose tumors had whole-genome doubling had different outcomes than those whose tumors did not,” Dr. Taylor explains. “It turns out they did. This genetic change was associated with lower survival rates in the people who had it, regardless of cancer type and other clinical and molecular features.”

Validating the Findings in Future Research

Because MSK-IMPACT testing is performed on advanced cancers, the researchers used another set of data to confirm their findings. They looked at The Cancer Genome Atlas (TCGA), a database of tumor information from more than 10,000 people with cancer. TCGA includes information on cancers that are newly diagnosed and at all stages, from I to IV. The researchers found that the rate of whole-genome doubling in these tumors was about the same as what was seen in the MSK-IMPACT data.

“This suggests that whole-genome doubling happens sooner in the development of cancer rather than later,” Dr. Taylor says. “We don’t think it’s an event that initiates cancer, but it occurs early in a tumor’s evolution.”

He adds that the findings help explain why people with advanced cancer that has spread often fare differently from one another. Some survive for years after their cancer has spread, while others do not. The variation in outcomes may be due to whole-genome doubling in the tumors. However, the causes behind these differences are not yet known.

More research is needed to validate the study’s findings before they can be used to influence patient care. But in the future, genome doubling could help guide personalized medicine, directing doctors to the people who need the most-aggressive treatment.

The co-authors on this study included MSK Physician-in-Chief José Baselga as well as CMO Director David Solit and Associate Director Michael Berger. The first author was Craig Bielski, a computational biologist in Dr. Taylor’s lab.

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Research Advances the Genetic Understanding of Pineoblastoma, a Rare Brain Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 07/20/2018
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In recent years, there have been many advances in treating children with cancer, but brain tumors remain a major challenge. For many pediatric brain tumors, the current treatments often are not very effective or are very toxic. Experts at Memorial Sloan Kettering are focused on learning more about the genetic and molecular underpinnings of these cancers.

Pediatric Neuro-Oncology Service Chief Matthias Karajannis is leading many of these efforts. Dr. Karajannis, along with a team from MSK and several other hospitals in the United States and Germany, published a paper in Nature Communications that focuses on a rare brain tumor called pineoblastoma. This type of tumor accounts for less than 1% of all primary brain tumors. The study reports that pineoblastomas in adults and children are distinct from each other — something that was not previously known. The findings also point the way toward developing better therapies for the disease.

“Over the past decade, we’ve made major progress in understanding the distinct biological differences in various pediatric brain tumors,” Dr. Karajannis says. “Now this research in the lab is starting to bear fruit and help us better diagnose and treat patients, especially those with rare tumors like pineoblastoma.”

Decoding the Alterations in a Rare Cancer

Pineoblastoma is a member of the class of tumors called primitive neuroectodermal tumors (PNETs). It usually occurs in children and young adults, but the tumors can sometimes appear in older adults. One of the findings from the new study is that the adult form of the disease more closely resembles other, less-aggressive PNETs, while the pediatric form is driven by a different set of molecular changes. These distinct changes make pineoblastoma in children more aggressive.

Pineoblastoma arises in the pineal gland. This pea-size organ in the brain produces and controls certain hormones, including melatonin, which affects sleep. The symptoms of pineoblastoma are similar to those of other brain tumors, including headaches, nausea and vomiting, and problems with eye movement and vision. It can also cause a buildup of fluid in the brain.

Sometimes pineoblastoma runs in families that have a certain inherited mutation. These inherited mutations lead to errors in one of the proteins that control small molecules called microRNAs. MicroRNAs monitor which genes get turned on and off. When errors aren’t property controlled, they can drive the formation of tumors. The new study found that in nonfamilial pineoblastoma, dysregulation of microRNAs occurs because of a different mutated gene, called DROSHA.

A Breakthrough in Understanding Brain Tumors

In the paper, the investigators report the latest discoveries based on the genetic and molecular analysis of 16 pineoblastoma tumors removed from patients, including 13 children. They looked at more than the changes in DNA that were connected with the disease, however. They also considered what is called the methylation profile. Methylation is one way that DNA gets modified without changing the DNA sequence. Earlier this year, another study from Dr. Karajannis and his collaborators reported a new system for distinguishing 100-plus types of brain tumors based on their methylation profiles.

“We were surprised to find these different molecular fingerprints between the adult and pediatric forms of the disease,” Dr. Karajannis says. “Another surprising finding was that, similar to what is seen in familial pineoblastoma, dysregulation of microRNAs appears to play a major role in the development of pineoblastoma that comes up sporadically. We also found that one of the genes involved in the formation of pineoblastoma is connected to brain development in embryos as well. This provides an intriguing link between the formation of this tumor and normal brain development.”

The investigators also identified repeated mutations in a gene called ARRB2. This gene has previously been linked to kidney and liver cancers. Very little is currently known about how ARRB2 functions, however.

“Further studies will be needed to assess the role of ARRB2 and the other genes we found to be recurrently mutated in pineoblastoma,” Dr. Karajannis concludes. “But our findings open up new avenues of research toward novel therapies that exploit the abnormal processing of microRNA that we’ve observed.”

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Studying a Forerunner of Pancreatic Cancer Reveals New Clues about How the Disease Develops

Source: Memorial Sloan Kettering - On Cancer
Date: 09/03/2018
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One universal truth about cancer is that the later it’s detected, the harder it is to treat. Pancreatic cancer is one form of the disease that is almost always found when it’s advanced, making it an exceptional challenge. Because it’s rarely caught early in its development, this also means that researchers know less about what drives its formation and spread than they do with many other kinds of tumors.

Understanding how a cancer develops and grows, however, has important implications. It allows researchers to create better targeted therapies and develop better detection and screening methods. Now a study led by Memorial Sloan Kettering physician-scientist Christine Iacobuzio-Donahue is shedding new light on a phenomenon that sometimes leads to pancreatic cancer. The results were published September 3, 2018, in Nature.

A Possible Lead-Up to Cancer

When surgeons remove a cancerous pancreas, they often find groups of abnormal cells called pancreatic intraepithelial neoplasias (PanINs) in other parts of the organ. PanINs are also common in older people who do not have pancreatic cancer.

Although they are not cancer, some PanINs eventually become cancer. Experts aren’t sure how often that happens. “I think of them sort of like moles on the skin,” says first author Alvin Makohon-Moore. “It may not turn into anything serious, but it’s clear that some sort of change has taken place that could further transform into cancer.” Dr. Makohon-Moore is a postdoctoral fellow in Dr. Iacobuzio-Donahue’s lab.

In the new study, the investigators identified eight people who had undergone surgery for early-stage pancreatic cancer who also had PanINs in other parts of their pancreas. The patients were treated at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, where Dr. Iacobuzio-Donahue and her colleagues worked when this research began. Several investigators from Johns Hopkins also contributed to the Nature paper.

The Search for Genetic Similarities — and Differences

The pancreas tissue was dissected under a microscope, and the cells from each PanIN were separated from the tumor cells in a very precise way. The DNA from each PanIN was then extracted, and the researchers conducted whole exome sequencing. This involves sequencing all the sections of the genome that are known to encode proteins. The tumors were also sequenced. For both types of cells, the investigators sorted out which mutations were likely to be directing cancer growth (called driver mutations) and which were just along for the ride (called passenger mutations).

“The goal of this research was to find mutations that the tumors and PanINs had in common and other mutations that the PanINs and tumors had acquired independently,” Dr. Makohon-Moore explains. “Based on this, we could create evolutionary trees for each patient, to figure out how their tumors had evolved.”

Based on the driver mutations found in the PanINs and tumors, the team was able to determine which cancer-causing mutations led to invasive cancer and which were acquired later. Unexpectedly, they also found that the PanINs could move through the system of ducts in the pancreas.

Potential for Further Research

There are several important next steps in the research. One is to look at a greater number of PanINs and tumors to determine if there are any repeated genetic patterns. That’s difficult to do with samples from only eight people.

Another step is to look for attributes beyond the DNA that may be driving the formation of tumors. This will include studies of the cells around the PanINs. This area is called the microenvironment. Researchers will also look for changes in gene expression that are not reflected in the DNA sequence — called epigenetic changes.

“Eventually, we hope this research will give us a framework for interpreting the events that happen early in the development of pancreas tumors,” Dr. Makohon-Moore says.

He adds that this inquiry may provide an explanation for why pancreatic cancer comes back so often after surgery. Even for people with early-stage disease whose tumors are completely removed, the disease returns in 60 to 70% of them. “It could be that these tumors are not as localized as we think they are and that they have the ability to move around within the pancreas,” he says. “Our research may help provide a biological context for why this cancer is so aggressive.”

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New Framework for Categorizing Inherited Cancer Genes Will Have Wide-Ranging Impact

Source: Memorial Sloan Kettering - On Cancer
Date: 11/01/2018
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Every gene is made up of thousands of As, Cs, Gs, and Ts, which spell out the instructions for making all the proteins in our cells. Errors in those instructions — known as mutations or variants — can occur anywhere in these long strings of code.

For genes linked to diseases, including cancer, researchers are focused on determining which mutations matter. Some don’t affect risk, but others actually change the functions of proteins and could have a negative effect in the body.

“Understanding the significance of the variants we find in cancer genes is important,” says Memorial Sloan Kettering clinical geneticist Michael Walsh. “We need to know if they are harmless or harmful, so when we learn that someone has inherited one of them, we can tell them what it means. Should they have more frequent cancer screenings? Should their family members get tested as well?” In addition, for those who already have cancer, inherited gene variants may influence what treatments they are given.

The Tremendous Task of Finding Meaning in Gene Variants

The field of cancer genomics took off in the early 1990s. At that time, scientists, including geneticists Mary-Claire King and MSK’s Kenneth Offit, began to report details on some of the first genes connected to cancer. These genes, BRCA1 and BRCA2, are associated with an increased chance of developing certain cancers, especially breast cancer and ovarian cancer. But what predisposes people to cancer are specific alterations in the genes. These changes can cause the proteins to malfunction in such a way that cancer may develop.

As genomic sequencing has become easier and less expensive, it has become much more commonplace. Huge amounts of data are now being generated. New cancer genes and variants are frequently being discovered. When the dozens of variants in hundreds of genes linked to cancer are taken into account, the task of determining which variants are significant may seem Sisyphean.

To help address that challenge, a few years ago the American College of Medical Genetics and Genomics (ACMG) released recommendations on how to classify the variants found in inherited cancer genes. Variants found in any gene may be classified in one of five categories: benign, likely benign, uncertain, likely pathogenic, or pathogenic. What remains a problem are the many variants that fall under the “uncertain” grouping, also called “variant of unknown significance.”

Now the ACMG is releasing an updated framework for classifying inherited variants in cancer genes. It focuses on integrating both tumor data and biomarker data. Dr. Walsh, a member of MSK’s Robert and Kate Niehaus Center for Inherited Cancer Genomics, is the lead author of the new guidelines, which were published November 1, 2018, in the journal Human Mutation.

“In the past, the ACMG has provided guidance for testing labs, saying that people who get their genomes sequenced should be informed about which of their genes harbor variants. But in some ways that was like putting the cart before the horse,” Dr. Walsh says. “We didn’t know enough to determine what many of these variants meant.”

He explains that researchers are starting to make some headway in pulling together all the tumor and biomarker data that’s being collected. There may now be evidence about whether certain previously unknown variants cause harm.

A Rapidly Changing Field with Real Consequences

As the new guidelines are adopted by labs around the country, variants will continue to be reclassified. As a result, earlier genomic screening will need to be revisited on a regular basis.

“As labs begin to apply these new rules, there will be some people who had testing in the past who will need to be contacted with updated results,” Dr. Walsh says.

Even as the guidelines are still being phased in, the issues that they are expected to bring up are already apparent. A recent study from investigators at the University of Texas Southwestern Medical Center in Dallas found that nearly one-quarter of the variants that had originally been classified as being of “unknown significance” were later reclassified as being either likely or unlikely to be associated with cancer. The investigators reviewed the results from 1.45 million people who were screened for cancer genes with a test developed by Myriad Genetic Laboratories.

Dr. Walsh says that people who have had testing in the past should consider contacting the labs and clinics where the testing was performed. The incremental change in rule classification will impact few people overall, so it is important that appropriate channels are established between patients and providers, he adds. MSK encourages people who have been tested here to contact their doctor or genetic counselor at regular intervals to see if there are any updates pertaining to the tests they had.

“Communicating is key and delivery of information needs to be in such a way that the information is useful and not frightening,” Dr. Walsh notes. “These changes in gene classification can have meaningful implications for people’s lives.” Some people who learn that gene variants they carry are linked to cancer will likely want to explore questions surrounding screening guidelines, risk-reducing surgeries, and even family planning. Others who learn that their variants are harmless after months or years of worry may be able to breathe a sigh of relief.

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Something New Under the Sun: Study in Leukemia Finds Role for Helios Protein

Source: Memorial Sloan Kettering - On Cancer
Date: 11/21/2018
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Proteins are one of the fundamental building blocks of life, controlling many of the vital functions carried out by cells. These activities include cell growth, division, and death. Sometimes the same protein can have more than one job, depending on how it interacts with other proteins in a cell.

The latest example of a protein with a dual role is one called Helios. When it’s missing, Helios can contribute to a type of pediatric blood cancer called B-acute lymphoblastic leukemia (B-ALL). But researchers at Memorial Sloan Kettering are now learning that when Helios is abundant, it can actually drive the formation of a different and a more common type of blood cancer called acute myeloid leukemia (AML). The findings were published in Cell Stem Cell.

“There are not a lot of examples of this type of situation,” says senior author Michael Kharas, a cancer biologist in the Molecular Pharmacology Program in the Sloan Kettering Institute. ”Occasionally, there are proteins that have completely different activities in different kinds of cancer. In this study, we figured out the ways in which the protein works and showed how it turns different genes on and off.”

A Protein That Regulates Genes

Helios is the name for the ancient Greek god of the sun. (Genes and proteins are sometimes given whimsical names, and Helios is a member of a family of proteins that are all named after characters from Greek mythology.) The Helios protein acts as an epigenetic regulator, which means it can control which genes get turned on and which genes get turned off. It exerts control by regulating chromatin, the part of the cell that packages DNA. If you imagine DNA as long strands of yarn, chromatin is the spool that the strands wrap around. When DNA is tightly wound, it’s hard for proteins to get made because the machinery that’s needed to start the process can’t make contact with the DNA. But when it’s unwound, the DNA becomes accessible.

In the new study, investigators found that Helios unwraps DNA from chromatin in areas that are important for the survival of leukemia cells. It also winds up the DNA in locations that are important for blood stem cells to turn into specific cell types. This process is called differentiation.

In someone with AML, the bone marrow produces immature white blood cells called myeloblasts rather than healthy, normal blood cells. Myeloblasts are unable to function like normal blood cells. They grow out of control and crowd out healthy cells. High levels of Helios are present in leukemia stem cells, which are essential for leukemia to grow. These cells are also thought to be the cause for relapse. 

“In the case of AML, Helios controls the program that leukemia stem cells use,” Dr. Kharas explains. “In some areas of the genome, it keeps the chromatin open, and in other places, it keeps the chromatin closed. The genes that are important for the cells’ ability to keep growing are left on, and those that would drive normal differentiation are turned off.”

By contrast, in the pediatric blood cancer B-ALL, it’s the absence of Helios that causes trouble. Earlier research found that Helios was lost in about half of people with a type of B-ALL called hypodiploid B-ALL.

In this study, however, investigators found that knocking down, or deleting, Helios can reduce the number of leukemia stem cells. Furthermore, Helios is required for leukemia cells to survive, and when it’s removed, leukemia cells stop growing and differentiating, and ultimately die.

To confirm that Helios contributes to AML development, the investigators also transplanted human leukemia cells into mice models. They found that when Helios was deleted, the mice had a greater reduction in leukemia cells and lived longer.

What’s Next? Targets for Drug Development

Based on the findings, the researchers hope to develop drugs that target Helios as a treatment for AML. Dr. Kharas doesn’t believe there is any danger in causing B-ALL by blocking Helios, since several other mutations are needed to drive the formation of that cancer. In addition, the mice that had Helios blocked in their blood cells didn’t show any signs of other cancers, including B-ALL, and had normal blood stem cell function. But until further research is conducted, investigators won’t know for sure.

Dr. Kharas notes that other researchers have discovered that Helios plays a role in the proper functioning of a type of white blood cell that affects immune response. This suggests that drugs that influence Helios could also be used to boost immune therapies for cancer.

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What Was MSK’s Role in TCGA, the Groundbreaking Cancer Genomic Study?

Source: Memorial Sloan Kettering - On Cancer
Date: 01/04/2019
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When The Cancer Genome Atlas (TCGA) launched in 2005, the understanding of the genetic changes that drive cancer was much less developed than it is today. TCGA was a joint project funded by the National Human Genome Research Institute and the National Cancer Institute. (The initials of project’s name also represent the four chemical building blocks in DNA: thymine, cytosine, guanine, and adenine.) The study sought to accelerate the field.

In the summer of 2018, after yielding dozens of scientific papers on more than 30 different kinds of cancer, TCGA officially drew to a close. As part of the conclusion of the initiative, investigators published a series of papers on what is called the Pan-Cancer Atlas in April 2018. These studies used genomic data from all of the cancer types that were included in the project. The comprehensive report details how, where, and why tumors form throughout the body.

“TCGA generated the gold standard for how to analyze cancers. It laid the foundation for clinical cancer genomics as we understand it today,” says Memorial Sloan Kettering physician-scientist Marc Ladanyi. In TCGA’s pilot phase, Dr. Ladanyi led one of the project’s seven Cancer Genome Characterization Centers, which was housed within MSK’s laboratories. Each center focused on performing a different kind of analysis. Dr. Ladanyi also made important contributions to the study of several types of cancer within the project.

“Now when we study patients’ tumors, we can go back to these data sets,” he adds. “They help us interpret what we find.”

Laying the Groundwork for Clinical Testing and Research

With data from TCGA, scientists were able to develop tests that help doctors analyze patients’ tumors. These tests include MSK-IMPACT™. This next-generation sequencing-based panel matches patients with the existing therapies or clinical trials that are most likely to benefit them. Data from TCGA suggested to researchers which genes should be included in the test. Eventually, 468 genes were selected in the panel. MSK-IMPACT obtained authorization from the US Food and Drug Administration in 2017.

One important aspect of TCGA is that all of the data from the project were immediately available to other researchers and the public, says MSK computational biologist Nikolaus Schultz. He was involved in TCGA from its earliest stage. “If you look at the number of times that publications from this project have been cited, it illustrates how important its contributions have been,” Dr. Schultz notes.

Funding from TCGA enabled the establishment of the cBioPortal for Cancer Genomics. This online platform allows scientists to review the data through various visualization and analytical tools. The cBioPortal currently hosts more than 200 data sets from large-scale genomic studies, including all of the data from TCGA. Users can probe data across genes, samples, and data types, thereby making important contributions to research not only at MSK but at other centers around the world.

Mesothelioma: Last but Not Least

The final TCGA paper, on malignant pleural mesothelioma, was published in the December 2018 issue of Cancer Discovery. Malignant pleural mesothelioma is a rare cancer. It affects the lining of the chest cavity and is usually linked to asbestos exposure. There are few good treatments for this cancer. Having an improved molecular understanding of what drives it is likely to lead to better therapies.

“We found several things that were quite interesting and novel,” says Dr. Ladanyi, who was a senior author on the study. The researchers performed in-depth analysis of 74 tumor samples. Many of the tumors carried changes that suggested they might respond to types of immunotherapy still under development.

An editorial that accompanied the publication of the paper noted that the study provided the scientific rationale for new targeted therapy options.

MSK’s Prominent Role in Leading and Contributing to The Cancer Genome Atlas

From the beginning, MSK investigators played a leading part in TCGA. Harold Varmus, who was president of MSK at the time TCGA launched, led the National Institutes of Health during much of the Human Genome Project — the effort to sequence the human genome. He was also a member of the working group that recommended the formation of a similarly wide-ranging project that would focus on cancer genes. That project became TCGA.

In addition to running a TCGA Cancer Genome Characterization Center, MSK contributed samples for 21 different kinds of tumors. In all, 7.2% of the more than 10,000 samples that were ultimately studied as part of the project were from MSK. Researchers at MSK also made major contributions to genomic sequencing and analysis efforts for many individual cancers, including ovarian, endometrial, gastric, colorectal, and prostate, as well as sarcoma, glioblastoma, and mesothelioma.

“It’s noteworthy that such a large number of samples were profiled in so many different ways. It helped us better understand all the different kinds of changes that can contribute to cancer,” says Dr. Schultz, who was senior author of the flagship Pan-Cancer Atlas paper related to oncogenic signaling pathways.

“The scope of TCGA may not be replicated again anytime soon,” he concludes. “It’s such a valuable data set that continues to become more and more valuable over time.”