CHICAGO (GenomeWeb News) – Researchers are tracking down genetic variants that they hope will help identify childhood cancer patients at increased risk of treatment-related health complications later in life, City of Hope researcher Smita Bhatia reported at the annual American Society of Clinical Oncology meeting here yesterday.
In a pediatric oncology session on the genetics of cancer survival and survivorship, Bhatia described findings from a series of studies aimed at detecting genetic variants contributing to the risk of heart failure, or cardiomyopathy, after treatment with the cancer drug anthracycline in childhood. She also discussed studies focused on SNPs associated with risk of secondary leukemia following treatment for conditions such as Hodgkins and non-Hodgkins lymphoma.
By identifying the suite of genetic and non-genetic factors that can contribute to such processes, investigators hope to find ways of predicting and ultimately preventing these so-called "late effects," Bhatia said.
Past studies have revealed a dose-response relationship between anthracycline exposure and later risk of heart failure, she explained — an effect that appears to be related, in part, to the myocyte muscle cell damaging alcohol metabolite formed from anthracycline.
Anthracycline-related cardiomyopathy risk remains variable between individuals exposed to the same drug dose in childhood due to differences in children's age when they're exposed to the drug, their gender, lifestyle, the amount of time the drug is administered, and so on, Bhatia noted.
But genetic factors also appear to contribute to individuals' risk of anthracycline-related cardiomyopathy — reflecting differences in drug metabolism, internal dose, and other biological responses to the treatment.
For example, Bhatia noted that variants in genes coding for the carbonyl reductase enzymes affect the activity of the enzyme, which convert anthracycline to a cardiotoxic alcohol metabolite.
In a 2012 study in the Journal of Clinical Oncology, she and colleagues from the Children's Oncology Group described a relationship between a variant in the carbonyl reductase gene CBR3 that dials up cardiomyopathy risk at low- to medium- anthracycline doses.
Candidate gene studies have helped in identifying still more variants involved in anthracycline metabolism and related genes involved in producing and dealing with reactive oxygen species.
More recently, researchers have taken to applying genome-wide approaches to finding anthracycline-related cardiomyopathy risk factors, Bhatia explained, such as variants in the HAS3 gene, which codes for a protein with antioxidant activity that is involved in synthesizing hyaluronic acid.
On the secondary cancer risk side, meanwhile, Bhatia presented information from a prospective longitudinal study done at City of Hope that identified gene expression shifts in CD34+ immune cells from Hodgkins and non-Hodgkins lymphoma patients who went on to develop treatment-related leukemia.
That differentially expressed gene set included a 38-gene signature that subsequently classified secondary cancer risk with 95 percent specificity and more than 87 percent sensitivity in an independent set of cases and controls, she noted.
Bhatia cautioned that additional research is needed to validate and continue fleshing out the sets of variants involved in these and other late effects for childhood cancer patients.
Ideally, though, she argued that appropriate genetic factors may flesh out risk models based on non-genetic factors to predict individuals' absolute risk of complications over a specified period of time so that childhood cancer patients can be screened before receiving cancer treatments.