Genetic markers correlated with Native American ancestry are associated with a higher risk of relapse among children treated for acute lymphoblastic leukaemia (ALL), finds a study in Nature Genetics. The US investigators found that ancestry-related differences in relapse could be overcome by the addition of a single extra phase of chemotherapy.

Although five year survival rates for childhood ALL are now over 80% in most industrialised countries not all children benefit. Racial and ethnic survival differences in childhood ALL have been reported in many clinical studies, with poorer outcomes observed for African Americans or those with Hispanic ethnicity compared with Europeans, Americans or Asians.

In the study Mary Relling and colleagues from St Jude’s Children’s Research Hospital, (Mephis, TN, and USA) analyzed genetic variation in 2,534 children with ALL. For the study the investigators used a library of 444,044 common genetic variations known as single nucleotide polymorphisms (SNPs), to search each subject’s DNA for evidence for a link between ancestry and relapse.

The investigators found that cancer was 59% more likely to return in patients whose genetic makeup reflected at least 10% Native American ancestry. Around 25% of patients in the study met the 10% threshold. The researchers also found that Hispanic patients, who have a high percentage of Native American ancestry, were more likely than other patients to carry a version of the PDE4B gene that was strongly associated with relapse. The PDE4B variant was also linked with reduced sensitivity to glucocorticoids, medications that are used in ALL treatment. “This is just one example of how ancestry could affect relapse risk. It is likely that many other genes are involved,” said Relling.

The investigators also found that ALL patients with greater Native American ancestry who received additional chemotherapy benefitted more from the extra treatment than other children. “Our data illustrate that giving additional chemotherapy can overcome the negative prognostic impact conferred by a set of ancestry-related polymorphisms and thereby mitigate ethnic disparities in the outcome of childhood ALL,” write the authors.

One of the authors, Stephen Hunger from the University of Colarado, adds, “These are important steps on the way to personalised cancer care, whereby treatment can be tailored to provide maximal benefit to patient subgroups, and someday, individual patients.”

Reference

J Yang, C Cheng, M Devidas et al. Ancestry and pharmacogenetics of relapse in acute lymphoblastic leukemia. Nature Genetics. Doi 10.1038/ng.763.