Leukemia as a Child Then Again as an Adult

Jan xxx, 2018, by NCI Staff

Credit: National Cancer Institute

UPDATE: Content about a related study, published Feb 28 in Nature, has been added to this post. Encounter the blue box at the bottom of the page.

An NCI-funded study has found that, at the genetic level, acute myeloid leukemia (AML) differs greatly between younger and older patients.

"AML in younger patients and AML in older patients are entirely singled-out diseases," said the written report'south senior investigator, Soheil Meshinchi, M.D., Ph.D., of Fred Hutchinson Cancer Enquiry Center. "It's almost like comparing chest cancer to colon cancer."

The findings, published in the January 2018 issue of Nature Medicine, come from a genomic analysis of nearly 1,000 children and immature adults with AML. The study is part of the Therapeutically Applicative Inquiry To Generate Effective Treatments (TARGET) initiative, a collaborative effort between NCI and the Children's Oncology Group (COG) to better understand the biological science of several loftier-risk or difficult-to-care for pediatric cancers.

"This [written report] tin can inform where therapeutic evolution should focus in social club to ameliorate target pediatric AML," said Yana Pikman, Thousand.D., a pediatric oncologist at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, who was not involved in the study.

Therapies that are tailored to the biological science of AML in children may be the best promise for treating the disease, the researchers believe. They take already used some of the early study findings to influence clinical trials of potential targeted therapies for AML.

Challenging Assumptions nigh AML

Acute myeloid leukemia, a cancer of the bone marrow and claret, occurs most oft in adults over the age of threescore. Though it is rare, AML also develops in younger adults and children, sometimes as early equally a few days later on birth.

The treatment options for young patients with AML include intensive chemotherapy and os marrow transplantation. In the early on 1980s, approximately 30% of children with AML survived five years after their diagnosis, and in more recent years, the rate has increased to around 65%.

Despite this improvement, there has been limited progress in identifying effective targeted therapies due to "an inadequate agreement of the biological science of childhood AML," the TARGET investigators wrote.

"More often than not, people call up that AML in children is the same illness every bit in older adults, merely less common," explained Dr. Meshinchi. "And then, until now, most of the studies, discoveries, and treatments [for AML] have been adult in older patients. The assumption is that whatsoever we discover in an older population can exist used to care for younger patients," he continued.

But earlier studies by Dr. Meshinchi and his colleagues showed that some of the virtually mutual genetic features of adult AML are completely absent in childhood AML, suggesting that the biological characteristics of this leukemia may differ by patient age.

Toward a Better Understanding of Childhood AML

For the TARGET projection, the researchers analyzed the genomic (DNA, RNA, and epigenetic) features of cancer cells from infants (less than iii years old), children (3–14 years old), and adolescents and young adults (fifteen–39 years old) with AML.

In add-on to identifying pocket-size Deoxyribonucleic acid mutations, the investigators also took notation of large changes in chromosome construction (known as structural alterations), such as the loss, amplification, or relocation of a chunk of a chromosome.

The genomic characteristics of childhood AML differed broadly among study participants, the researchers discovered. For case, but a handful of the same mutations and structural alterations were nowadays in more than than five% of patients in the study.

The depression frequency of recurring mutations and alterations represents "a substantial challenge to advancing therapies for pediatric AML," noted Andrew Brunner, G.D., and Timothy Graubert, M.D., of Massachusetts General Hospital, in a commentary that accompanied the TARGET written report.

Because the genetic features of each child's AML are unique, "no single handling strategy is likely to be effective for all pediatric AML [patients]," the TARGET researchers wrote.

The squad also identified many fusion genes, which can form when chromosome pieces shift and have been found to drive the growth of many blood cancers. The fusion proteins produced by such fusion genes are platonic drug targets because they are exclusive to cancer cells, so drugs that target them are less likely to harm normal cells, Dr. Meshinchi explained.

"The critical question is: Is information technology possible to target these fusion proteins straight?" he asked. Dr. Meshinchi and his team are exploring this possibility, also as the potential for targeting fusion proteins indirectly by going after the genes and proteins that they regulate.

Same Name, Different Disease

When the team compared the genomic characteristics of pediatric AML to those of developed AML, equally identified past a report from The Cancer Genome Atlas (TCGA), they discovered significant differences.

The most critical difference, noted Dr. Meshinchi, was: Whereas mutations were much more mutual than structural alterations in adults with AML, the opposite was true in children. For example, the researchers found nearly ten times more than structural alterations than Dna mutations in infants with AML.

The finding suggests that, in young children, structural alterations are stiff enough to cause cancer on their own, he explained. In adults, AML is acquired by the accumulation of multiple mutations and alterations over the form of a lifetime.

The researchers as well institute that the few Deoxyribonucleic acid mutations that were present in pediatric AML were different from those in adult AML—both in terms of where and how frequently the mutations occurred. For example, mutations in the NRAS gene (a factor that controls cell growth and death) were much more common in pediatric AML than adult AML. There was some overlap in Deoxyribonucleic acid mutations identified in adult and pediatric AML patients, however, particularly between the adolescent and young adults group and older adults.

Said Dr. Pikman, "people often say that kids are not little adults, and I think that this [written report] very conspicuously shows that."

Together, the study results underscore the fact that many AML treatments that are developed for adults with the promise that they tin "trickle down" to children and young adults may non be effective for pediatric AML, Dr. Meshinchi stressed.

The study findings provide a "better understanding of what initiates or sustains these cancers," which will help guide the evolution of new treatments, said report investigator Daniela Due south. Gerhard, Ph.D., of NCI's Office of Cancer Genomics.

In fact, TARGET and COG researchers are already planning several clinical trials based on these findings. For case, the researchers plant high levels of a poly peptide chosen mesothelin—which is sometimes expressed by lung cancer cells—in some younger patients with AML. Dr. Meshinchi and his colleagues are working with Bayer to bring a mesothelin-targeting drug the company has adult for lung cancer into clinical trials for children and young adults with relapsed AML.

Researchers at COG are also planning a clinical trial that volition investigate whether comprehensive genetic tests such as those used in the TARGET study can help guide treatment pick and improve patient outcomes.

The next pace is to keep "mining the data" from the TARGET study to identify patterns, associations, and potential drug targets, Dr. Gerhard said. And because the data are available to qualified researchers (in ways that protect patient privacy), more researchers have the opportunity to build on these initial results.

Dr. Pikman, who leads a multi-institutional study investigating the efficiency of genomic tests for matching patients with leukemia to targeted therapy, is already using some of the data to guide her enquiry.

Differences between Childhood and Developed Cancers Constitute in Multiple
Cancer Types

A study published Feb 28 in Nature past many of the same TARGET researchers has establish that several cancer types are genetically dissimilar in children and adults.

According to the study authors, the findings reinforce the belief among some researchers that drugs adult and approved to treat cancers in adults may not ever be effective or appropriate for children with the aforementioned cancer types.

To perform the "pan-cancer" report, Jinghui Zhang, Ph.D., of St. Jude Children's Research Infirmary, and her colleagues analyzed samples from nigh ane,700 patients, anile xx or younger, looking at all noninherited, or somatic, genetic alterations. Patients in the TARGET study had common childhood cancers, including acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, Wilms tumor, and osteosarcoma.

The researchers identified 142 altered genes that drive the evolution of these cancers (driver mutations), of which simply 45% are found in adult cancers. Well-nigh of the genetic alterations (62%) cruel into 2 categories: copy number variants and structural alterations.

The findings "provide a comprehensive genomic architecture for [pediatric] cancers and emphasize the need for [pediatric] cancer-specific development of precision therapies," the researchers wrote.

This report, and a similar one published in the same issue of Nature, provide "a remarkably complete picture show of childhood cancer," NIH Managing director Francis Collins, M.D., Ph.D., wrote in a recent blog post.

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Source: https://www.cancer.gov/news-events/cancer-currents-blog/2018/genetic-differences-childhood-adult-aml

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