Ancient DNA May Uncover Ethnic Differences in Childhood Cancer

Researchers have harnessed ancient DNA to trace a genetic variant – one that increases the risk of a type of childhood cancer – back to the first people who migrated into the Americas approximately 13,000 years ago.

The research is published in Cell Genomics.

Understanding health disparities

B-cell acute lymphoblastic leukemia (ALL) is a form of leukemia in which the bone marrow produces large amounts of abnormal B lymphocytes, a type of white blood cell, making it difficult for healthy cells to fight off infection.

ALL is more common in Hispanic/Latino children compared to white non-Hispanic Latino children in the US, but it was not understood why this was the case.

To find out why, researchers from the Dana-Farber Cancer Institute used genetic analysis to investigate whether there is a genetic basis for this racial/ethnic disparity in ALL risk.

"We were able to use genetic studies in diverse populations to identify this new risk factor that explains some of the population differences in ALL risk," explained Dr. Vijay Sankaran, lead author of the study and a physician-scientist at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center.

Variant identified in ancient Indigenous American DNA

Using data from 1,878 cancer cases and over 8,000 controls from the California Cancer Records Linkage Project, the researchers conducted a genome-wide association study (GWAS). This determines if genetic variants are associated with specific traits, in this case, investigating mutations that increase the risk of B-cell ALL.

They identified a genetic mutation that is found at a much lower frequency in non-white Hispanic/Latino children. This variant reduces the expression of the IKZF1 gene that encodes a protein called Ikaros, which is required for B-cell development. Functional data suggests that this mutation slows the maturation of B cells and makes it more likely for them to develop cancerous mutations.

Further analysis found that this variant arose from Indigenous American groups and that it was almost absent in those of European ancestry. This may go some way to explaining why the mutation is more common in countries such as Mexico, where there is greater Indigenous American ancestry, compared to other countries such as Argentina, where there is less so.

But when did this variant arise in human history? This is where the researchers turned to the analysis of ancient DNA. Analysis of DNA sequenced from the oldest known Indigenous American individual, found in Anzick in Montana, revealed the presence of this variant. This suggests that the variant was present in the first people to migrate to the Americas as many as 13,000 years ago.

The researchers suggest that this variant could have been promoted by natural selection due to IKZF1’s role in the immune system, as the mutation may have protected against infection.

"Exploring ancient DNA provides insights into the roots of modern-day health differences, bridging the gap between our past and the pressing health challenges facing our society today," Sankaran said.

The study's findings may provide insights into the higher rates of treatment resistance and relapse observed in Hispanic/Latino children with ALL, but additional studies are required to understand the effects of this variant further. For example, this knowledge may lead to ways of preventing leukemia development in those who carry the variant.

"I hope our work will ultimately pave the path towards preventing this disease," Sankaran added.

Reference: de Smith AJ, Wahlster L, Jeon S, et al. A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children. Cell Genomics. 2024;0(0). doi: 10.1016/j.xgen.2024.100526

This article is a rework of a press release issued by the Dana-Farber Cancer Institute. Material has been edited for length and content.