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New Findings About the Genetic Risks of Childhood Cancer
A large study of childhood cancer long-term survivors found new variants of cancer susceptibility genes that could inform and improve genetic counseling.
The Challenge
Treatment and supportive care for childhood cancers has greatly improved over the last decades. That means an increasing number of adults have a history of childhood cancer.
These survivors are at risk for developing several late and long-term effects from their cancer treatment, including a risk of the cancer returning and a small risk of developing another type of cancer.
One thing that contributes to both the risk of developing a childhood cancer and the risk of having late and long term effects is whether or not the child Inherited certain gene variants in cancer-susceptibility genes from one or both parents.
Most pediatric cancers have only been associated with a subset of cancer susceptibility genes. It is not known if variants in other cancer susceptibility genes, including those related to adult-onset cancers, are present in childhood cancer survivors.
The Research
To better understand the genetic causes of childhood cancers, a large group of scientists, including Ryan Diver, MSPH, and Lauren Teras, PhD, in Population Science in the American Cancer Society conducted a comprehensive analysis of 5,451 long-term cancer survivors from the Childhood Cancer Survivor Study (CCSS) who were studied for more than 30 years. For a comparison group—people without a history of childhood cancer—the scientists used data from the American Cancer Society’s Cancer Prevention Study II.
I’m a childhood cancer survivor myself, and my family was screened for genetic variants related to my cancer. However, the genes identified in this study were not considered at the time my family and I were screened. Following up on these findings with more research is key for finding the best treatment for childhood cancer patients and better genetic counseling for them and their families.”
The researchers identified pathogenic or likely pathogenic (P/LP) variants in cancer susceptibility genes not previously associated with pediatric cancer. They found that pediatric cancer survivors were more likely to have P/LP variants than those who hadn’t had a pediatric cancer. Additionally, the pediatric cancer survivors with more P/LP variants had worse survival than pediatric cancer survivors with fewer variants.
Inheriting Cancer Risks: Some Basic Terms
Permanent changes in the DNA sequence of a gene are called gene mutations. Some scientists think that “gene variant” is a more accurate term because changes in DNA do not always lead to disease. Sometimes “gene mutation” and “gene variant” are used as synonyms.
Genetic variants can have a large or small effect on the likelihood of developing a particular disease. The term “pathogenic” refers to something that causes a disease. When genetic variants lead to disease, they’re called pathogenic variants or pathogenic mutations.
Genes that are vulnerable to cancer-causing variants or changes are called cancer predisposition genes or cancer susceptibility genes. In some cases, a cancer predisposition gene variant is inherited, or passed along from generation to generation. Several dozen cancer-predisposition genes have been identified, and about 5 to 10% of all cancers result directly from variants in those genes that are inherited from a parent.
For example, BRCA1 and BRCA2 are inherited cancer predisposition genes. Mutations in these genes increase the risk for developing certain cancers.
The type of gene changes that get passed from parents to a child are called “germline variations.” When BRCA1 and BRCA2 mutations are passed down by parents, they’re an example of what are considered germline pathogenic variations.
People who inherit certain changed genes that make them more likely to develop cancer are said to have a genetic predisposition or a genetic susceptibility to a cancer or certain types of cancer. Sometimes this is referred to as having a family cancer syndrome. But having this doesn’t mean that person will develop cancer. And if they do develop cancer, it may not be caused by the inherited genetic mutation.
The term penetrance is used to describe how many people carrying a mutation in a cancer predisposition gene will eventually develop cancer. If everyone who inherits a mutation develops cancer, that mutation is said to have complete penetrance. If some people don’t, it’s incomplete or reduced penetrance. If most people with an inherited mutation develop cancer, that mutation has high penetrance. For example, pathogenic variations on the BRCA1 and BRCA2 genes are high-penetrance gene mutations. Other gene mutations are in categories considered to be moderate- or low-penetrance.
“This is an important study because it shows that pediatric cancer patients may have genetic variants in other cancer-related genes that they’re not aware of," says Ryan Diver, MSPH, a data analysis within ACS Population Science.
Here are two more noteworthy findings from this study.
- Many of the cancer survivors were recruited more than 10 years after their diagnosis, which suggests that these variants may continue to influence the development of late effects for much longer than shown in previous research.
- Several of the gene variants identified in the pediatric cancer survivors are typically associated with adult cancers but not childhood cancers, such as BRCA2 in breast cancer.
Why it Matters
This large pediatric cancer study identified that pediatric cancer patients are more likely to have variants in cancer-susceptibility genes that have not previously been associated with the type of cancer they had.
Further characterization of variants in these genes is necessary to provide the most helpful genetic counseling for childhood cancer patients and their families. For patients, identification of additional gene variants could change treatment options and follow-up procedures. For older childhood cancer survivors, this new information may influence changes to the guidelines for genetic screening to improve the prevention of late effects, like the recurrence of the cancer or development of a second type of cancer.
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