Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia

Abstract

Although five-year survival rates for childhood acute lymphoblastic leukemia (ALL) are now over 80% in most industrialized countries, not all children have benefited equally from this progress. Ethnic differences in survival after childhood ALL have been reported in many clinical studies, with poorer survival observed among African Americans or those with Hispanic ethnicity when compared with European Americans or Asians. The causes of ethnic differences remain uncertain, although both genetic and non-genetic factors are likely important. Interrogating genome-wide germline SNP genotypes in an unselected large cohort of children with ALL, we observed that the component of genomic variation that co-segregated with Native American ancestry was associated with risk of relapse (P = 0.0029) even after adjusting for known prognostic factors (P = 0.017). Ancestry-related differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy, indicating that modifications to therapy can mitigate the ancestry-related risk of relapse.

Figure 1. Principal Component Analysis of Genome-wide Germline SNP Genotypes in Children with ALL

Comparison of the top 3 axes of variation (PCs) among patients with ALL of different self-reported races/ethnicities and among different reference populations (CEU, N=60; YRI, N=60; CHB/JPT, N=90 samples from the HapMap and 105 Native American samples). Descriptions on X-axes represent self-declared designations. Boxes include data between the 25th and the 75th percentiles. Note that the first (PC1, Panel A), second (PC2, Panel B), and third axis (PC3, Panel C) reflect genetic variation characteristic of African, East Asian, and Native American ancestry, respectively. Also note that self-reported Asians consisted of both South Asians and East Asians (top and bottom cluster of far right bar in Panel B, respectively), with varying levels of East Asian genetic ancestry.

Figure 2. Genetic Ancestry and Risk of Relapse in Childhood ALL

A. Genetic ancestral composition of 2,534 children with ALL. Each patient’s ancestry is depicted as a column, whereas color represents the proportion of ancestry estimated for that patient (European, red; African, gray; Asian, green; Native American [NA], blue). Genetic ancestry was estimated using STRUCTURE. Patients were clustered using Ward clustering method, based on dissimilarity in genetic ancestry measured by 1-minus pair-wise correlation (see Supplementary Note). Higher levels of NA ancestry were linked to increased risk of relapse in all patients (B), and within the self-reported whites (C), and for those who did not receive delayed intensification (D), but not within those who did receive delayed intensification in the COG P9904/9905 trial (E). Although cumulative incidence of relapse is plotted separately for patients with <10% (red) vs ≥10% (blue) NA ancestry, all P values were estimated using Fine and Gray’s cumulative incidence hazard regression model treating NA ancestry as a continuous variable (see Supplementary Note for details on NA ancestry dichotomization).