Childhood Cancer Research Topics

Germline genetic variation is known to contribute to an individual’s risk of developing diseases such as cancer. Common genetic risk variants have been identified through genome-wide association studies (GWAS) that scan the genome for basepair changes in DNA which occur at significantly different frequencies in cases than in controls.

There have been several GWAS of childhood acute lymphoblastic leukemia (ALL) to date, which have discovered at least 15 genetic risk variants in different genes.

Our group has discovered several of these risk variants in multi-ancestry GWAS of ALL, including cases and controls from our California-based studies.

We have a particular interest in the increased risk of ALL in children of Hispanic/Latino ethnicity, who have the highest incidence of ALL in the United States. GWAS of ALL in Hispanics/Latinos in California, as well as including large numbers of Hispanic/Latino ALL cases and controls in our multi-ancestry genetic studies, have helped us to identify novel genetic risk genes and to pinpoint the likely causal variants at several childhood ALL risk loci.

In ongoing research, we are combining existing and new GWAS data to perform comprehensive genetic analyses of ALL in Hispanics/Latinos, including GWAS, admixture mapping, and polygenic risk score analysis, to try to understand the genetic contribution to this disparity in disease incidence.

We are also involved in a global collaborative study through the Childhood Leukemia International Consortium (CLIC) to perform the largest multi-ancestry GWAS of ALL to date. In addition, we have developed a California-based study of familial cancers to investigate the contribution of less common, or rare, germline variants with stronger impacts on childhood leukemia risk.

Our ultimate goal is to have a full understanding of the genetic contribution to childhood leukemia development, which may enable us to identify children most at risk of disease and to guide precision prevention strategies.

A rich and consistent set of research has shown that patterns of infection influence childhood acute lymphoblastic leukemia (ALL) risk. For instance: being a first born child carries a higher risk of ALL as the younger children are exposed to more infections brought home by the older children.

Also, a normal course of vaccinations provides decreased risk of leukemia (compared to unvaccinated children), showing that immune “exercise” decreases risk.

Read more about Infections and childhood leukemia…

Childhood leukemia is a disease of many different subtypes. We study one of them named “acute promyelocytic leukemia” (APL) that has unique features:

(i) the disease is more common in Latino countries than other parts of the world, and

(ii) the disease occurs sometimes as secondary cancer (after prior chemotherapy), suggesting a chemical cause.

Read more about acute promyelocytic leukemia in children…

One of the earliest identified risk factors for childhood leukemia was Down syndrome (DS).

Children with DS, who are born with an extra copy of chromosome 21 (i.e. trisomy 21), have ~20-fold increased risk of developing B-cell acute lymphoblastic leukemia (B-ALL) and ~500-fold risk of acute megakaryoblastic leukemia (AMKL, which is usually very rare in the general population).

Experimental studies have shown that trisomy 21 affects the normal development of blood cells.

Read more about Down Syndrome and leukemia…

Patterns of infections and antigenic exposures were long theorized to contribute to the development of childhood leukemia presumably through dysregulation of the immune system at an early age. Recent evidence implicates cytomegalovirus (CMV) as a specific infectious risk factor in the development of childhood ALL. This is the first time a specific infectious agent was implicated.

CMV is part of the Herpesviridae family, and is a common infection in the general population, infecting 30-60% of pre-pubescent children and up to 90% of the population by the age of 50 years.

Primary CMV infection can go unnoticed with mild clinical symptoms; however, even immune competent hosts cannot eradicate the virus, and CMV establishes lifelong latent infection within the host. CMV distorts host innate and adaptive immunity by interfering with cytokine activity, natural killer cell function, T cell response, chemokine activity, and inhibiting apoptosis.

CMV also can dysregulate the immune response to subsequent antigenic exposures. Though CMV is not proven to be an oncogenic virus directly contributing to hematopoietic malignancies, it has been shown to promote tumor growth in other malignancies, most notably glioblastoma multiforme, and exhibits characteristics that overlap with many of the hallmarks of cancer.

In our prior work, we found that children newly diagnosed ALL cases were more likely to have detectable CMV DNA in the bone marrow at diagnosis compared to AML patients who are equally as immunocompromised. In two separate cohorts we showed that children with CMV exposure in utero or early childhood are more likelihood to develop ALL in childhood.

We also found CMV to be associated with certain subtypes of ALL, specifically B-ALL and the high hyperdiploid subtype, that an inflammatory gene expression signature is associated with CMV-positive lymphoblasts, and an association between ALL predisposition genes and CMV-status at ALL diagnosis. The immune dysregulatory properties of CMV in combination with the growing body of evidence associating CMV with ALL lead us to the hypothesis that CMV exposure in utero or early childhood results in immune dysregulation in response to subsequent childhood infections allowing for the expansion of pre-leukemic clones and ultimately leading to overt leukemia.

CMV also provides for us a potential target for therapy, which we will explore in the future.

All body cells carry the same DNA – but each cell has a distinct purpose. How does a blood cell differ from a muscle cell or brain cell? The answer lies in the “epigenome” which is essentially the “operating system” of the genome, running a different program in each cell type. These programs are under tight regulation and are set down early in tissue development.

The most primal epigenetic characteristic is DNA methylation placed upon “C” residues on the DNA stand both at specific sites and across multiple genes and genomic regions.

Here, we study these DNA methylation patterns. Cancer is a product of both genetic and epigenetic changes that promote uncontrolled growth of a tissue. In this project we study both the DNA methylation changes that differentiate childhood ALL cells from normal precursor blood cells – while also identifying those epigenetic changes that have already altered from the normal at the time of the birth of the child.

Most DNA methylation patterns are laid down in the first days and weeks of gestation – the most vulnerable time for aberrations to occur. Environmental factors, such as parental smoking, nutrition, pesticides and air pollution, all may impact DNA methylation at this vulnerable time, establishing cells with altered DNA methylation impacting leukemia risk (without causing DNA mutations).

We try to link up these early changes with DNA methylation patterns in the leukemia cells with this “meet in the middle” approach – further delineating the mechanisms by which environmental factors may induce risk to childhood ALL.

Children can get brain tumors and for the most part, we still don’t understand why. For adults, mutations took decades to accumulate, and when key genes (oncogenes or tumor suppress genes) are affected, the chance of getting brain tumor increases. However, in children, there is not much time for detrimental mutations to accumulate, they could still develop a variety of brain tumors, some of them very aggressive.

Here we investigate why children develop brain tumors, for example gliomas. By combining a variety of data including DNA sequences, key chemical modifications of DNA, and exposures to chemicals from the surrounding environment, we aim to identify risk factors of brain tumors and their disease inducing pathways.

For example, we recently discovered that a variant in the mitochondria is associated the risk of childhood glioblastoma, one of the most malignant brain tumors with very poor prognosis. This variant was previously reported to affect height and hearing, but was never tied to cancer risk. This gave us new insights into how energy pathways could play a role in glioblastoma initiation.

Work is ongoing in our lab to deepen the understanding of etiology of childhood brain tumor, and how we can better predict its risk.