A new Nature Genetics study published by researchers at St. Jude Children's Research Hospital shows a link between Native American ancestry and the probability of a patient's leukemia reoccurring — a finding that could be a new biomarker for the disease and could eventually influence a clinician's choice of treatment. Cancer Minute spoke with Jun Yang, the study's first author, for more information on the study and the findings.
Cancer Minute: What made you think to look for a link between Native American ancestry and relapse of leukemia?
Jun Yang: Although cure rates are high in childhood leukemia, some patients are not cured, and others have unacceptable adverse effects. In particular, racial differences in leukemia treatment outcome have persisted. Differences in inherited polymorphisms are highly associated with ancestry/race and these genetic variations are also likely to have an impact on why some patients respond differently than others. We are undertaking a series of studies to elucidate the germline polymorphisms associated with racial disparities in drug response (antitumor effectiveness and adverse effects) in childhood ALL.
CM: What method did you use to conduct the study?
JY: Our goal is to study all children with ALL — not just those of one race group or another. Also, we wanted to use a genome-wide approach to find associations between single nucleotide polymorphism genotypes and response, in order to obviate the biases inherent in candidate gene approaches. The first step in a genome-wide association study is to understand if population diversity (i.e. due to genomic diversity associated with race/ancestry) affects the associations of germline genotypes and the phenotype — here, relapse risk. When we used a non-biased clustering analysis — principal component analysis — to characterize genomic diversity in our patients with ALL, we found that the first three principal components were strongly associated with the "self-declared" racial/ethnic background of our patients, and the same components were strongly associated with the racial/ethnic background of the normal controls that constitute the HapMap population references. The third principal component of genomic variation was strongly associated with relapse in all of our patient groups, and this third principal component of genomic variation distinguished controls of Native American ancestry from those of European, African, or Asian ancestry.
CM: What is the effect of having these genes on the probability of relapse, and how important is a factor like this in determining treatment?
JY: In this study, we showed that higher proportion of Native American genetic ancestry is linked to higher risk of leukemia relapse. That is, children with more than 10 percent Native American ancestry had about a one-and-a-half-fold increased risk of leukemia relapse compared to children with less than 10 percent Native American ancestry. Also, we observed that the increase in relapse risk due to ancestry diminished by certain types of additional chemotherapy (delayed intensification). Therefore, these genetic factors are potentially important in determining treatment, but their importance is likely to depend on the treatment regimens.
CM: Should clinicians routinely test for these genes, and is this a test that can be done in the clinic today?
JY: Further studies are needed to determine the clinical utility of testing these genetic markers in children treated for ALL.