Childhood cancer genetics: A legacy of groundbreaking work drives St. Jude forward

The discovery that cancer is a genetic disease was a revolutionary idea when the first human oncogene was discovered in the 1980s. Although our understanding of our genetics in cancer has come a long way, even today, some 40 years later, there is still much to learn about the nuances of genetics and how our genes can underly disease. At St. Jude and other institutions, genetic research has opened new universes of understanding about cancer.

“Large-scale genomic sequencing projects have revealed volumes about why childhood cancer arises, spreads and resists treatment,” said James R. Downing, MD, St. Jude president and CEO. “At the same time, these initiatives have produced an unthinkable amount of data, much of which has yet to be parsed. With each discovery, we find a new path to pursue. Some of these directions will be dead ends, but others will hold the potential to advance understanding and, ultimately, cures. In many ways, genomics is curiosity-led work—and for scientists, it’s an immensely rewarding challenge.”

Genes determine the color of a person’s eyes or hair, their height, their propensity to develop allergies, their ability to taste certain flavor and much more. DNA is the chemical sequence that makes up genes, made up of four bases: adenine (A), thymine (T), cytosine (C) and guanine (G). Variations in the sequence of these pieces of DNA throughout the 3 billion base-pair human genome are responsible for many of the differences between people.

Cancer is, at its core, a genetic disease. Cancer results from mutations (often multiple) in a patient’s DNA that cause activity in cells to go awry. If researchers can understand how these mutations lead to or impact cancer growth, they may be able to find more effective treatments. But studying cancer genetics is complicated – with chromosomes gained or lost, pieces of DNA switching locations and novel mutations.

In 2010, St. Jude Children’s Research Hospital and Washington University School of Medicine launched an ambitious project to understand the genetics of pediatric cancer. The appropriately named Pediatric Cancer Genome Project (PCGP) was the first attempt to define the landscape of childhood cancer. At the time, all such genetic-related work had focused on adult cancer. The PCGP sequenced 800 patients, providing a wealth of information that pushed forward our understanding of cancer in children.  These new, advanced understandings helped pave the way for generations of researchers to make discoveries that will lead to more effective treatments.

Inherited genetics

Think of DNA as an instruction manual for putting together a bookshelf. Most of the instructions will be the same for all shelves, akin to how DNA is similar in all humans. But the model of shelf will alter specific aspects of the instructions (genetic variants). Sometimes an instruction manual will have a misprint, like an inherited (germline) mutation in DNA. While most germline mutations don’t alter the instructions enough to cause a problem, in rare cases the incorrect letter leads to incorrect instructions, which can translate to poor outcomes – like nailing the shelf to a wall unintentionally.

Germline mutations are passed on through germ cells – eggs and sperms. Any offspring can inherit a parent’s germline mutations. Understanding germline mutations can help explain why certain cancers appear more frequently in specific families.

• The PCGP found that 1 in 10 pediatric cancer patients have a germline mutation in a gene known to predispose individuals to cancer, published in the New England Journal of Medicine.
• This was a surprisingly high percentage to researchers, as family histories had indicated a much smaller heritable cancer predisposition.
• The results provided credence to the idea that looking at germline mutations from whole genome sequencing could give better and more detailed information about cancer predispositions than existing assays.
• The St. Jude Cancer Predisposition Clinic was developed to use this information to counsel families with a higher-than-normal risk of cancer.

Somatic mutations – an evolving tumor

Cancer cells accumulate mutations in their DNA as they multiply. These ‘somatic’ mutations are present only in cancer cells – not in normal cells. Soma, meaning body in Greek, is a reference to how these mutations are restricted to within a person’s body and will not pass down to their children. If germline mutations are akin to small misprints in the instruction manual, somatic mutations can vary from small misprints, to repeated pages, to adding pages from an entirely different manual in a different language. The impact can be drastic.

Cancer cells accumulate many changes to their DNA – some help the cancer thrive, called drivers. Some mutations are neutral, called bystanders. The challenge for those looking at these mutations is identifying which are drivers and which are bystanders – a complex process that is an intense area of research.

Sometimes these mutations create new proteins that increase the fitness of cancer cells. These proteins are made by instructions from two different genes. They are therefore termed ‘fusion’ proteins. Identifying fusion proteins can facilitate development of new therapeutics.

• The PCGP led to the identification of multiple mutations in tumors that explain what drives certain cancers and suggested ways these tumors may be vulnerable to drugs.
• Genetic basis of high-risk childhood cancer points to possible new drug treatment strategy.
• Two new genes linked to amyotrophic lateral sclerosis (ALS) and related disorders.
• Tumor suppressor gene TP53 mutated in 90 percent of most common childhood bone tumor.

Genetics and epigenetics: the value of sequencing

By taking cells from the body, isolating the DNA, and reading the A, T, G, C sequence, we can decode genetic information. Only certain regions of DNA, called exons, encode genes. To look at these gene-coding regions, scientists conduct whole exome sequencing.

Today, scientists know that almost all DNA contains information and instructions, even those regions that do not encode genes. For example, certain DNA regulatory elements control levels of gene expression. Enhancers are regions of DNA that increase gene expression in another part of DNA, while repressors decrease gene expression. The study of how gene expression is controlled by factors other than changes in the genetic code is called epigenetics.’ One way scientists study epigenetics is with whole genome sequencing.

• St. Jude is a leader in large-scale sequencing of pediatric cancer patient samples. These large sequencing project have led to many discoveries, including how epigenetics impact cancer development and care.
• Gene sequencing project finds new mutations to blame for a majority of brain tumor subtype.
• Gene sequencing project finds family of drugs with promise for treating childhood tumor.
• Gene sequencing project discovers mutations tied to deadly brain tumors in young children.
• Researchers find a ‘critical need’ for whole genome sequencing of young cancer patients.

St. Jude and freely available sequence data and analysis tools

Genetic and epigenetic sequencing generates vast swaths of data. St. Jude has created the infrastructure for scientists around the world to explore this data and deploy visualization tools to more effectively find the gems of knowledge amongst the mountains of results.

• St. Jude Cloud contains all the sequence data used to publish studies from sequencing projects, survivorship and other diseases.
• It also includes free-to-use data analysis and visualization tool like the “Pediatric Cancer Variant Pathogenicity Information Exchange” (PeCanPIE) and the Genomics platform.
• With the German Cancer Research Center, Heidelberg, St. Jude published a method to search for potential drug-susceptible mutations in Nature.
• The tumor samples used in the research and the data collected are free to the scientific community as part of the Childhood Solid Tumor Network, also published in Nature.

Continue to explore cancer genetics

St. Jude is leading the way in numerous aspects of cancer genetics.