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GWAS Explores Role of Inherited Variants in Childhood ALL

NEW YORK (GenomeWeb News) – Inherited genetic variants — including some found at variable frequencies in different human populations — can significantly bump up an individual's risk of developing acute lymphoblastic leukemia, according to a multi-population genome-wide association study out last night in the Journal of the National Cancer Institute.

"These findings indicate strong associations between inherited genetic variation and ALL susceptibility in children," senior author Jun Yang, a pharmaceutical sciences researcher with St. Jude Children's Research Hospital, and colleagues wrote, "and shed new light on ALL molecular etiology in diverse ancestry."

Through GWAS analyses involving nearly 2,500 children with ALL and almost 11,000 unaffected individuals, Yang and colleagues from St. Jude and elsewhere tracked down ALL-associated loci falling in four genes previously implicated in the disease and in one new chromosome 10 locus.

For those carrying mostly risk versions of the top ALL-associated SNPs in four genes, they found, ALL incidence was far higher than it was in those with no risk alleles or just one risk allele.

Moreover, the team saw examples of risk alleles that occur more often in the Hispanic population than in European or African-American populations — a pattern that study authors said may partly explain the elevated ALL rates described in Hispanic populations in the past.

Previous GWAS support the notion that ALL risk is at least partly inherited, Yang and colleagues explained. But so far variants in just a few genes have been linked to the disease through studies of individuals with European ancestry.

"Although accumulating evidence indicates inherited predisposition to ALL, the genetic basis of ALL susceptibility in diverse ancestry has not been comprehensively examined," Yang and his co-authors noted.

To begin exploring such questions in individuals from a variety of backgrounds, the group did a GWAS involving cases and controls from diverse ethnic populations, along with analyses focused on individuals with European, African-American, or Hispanic ancestry.

For the discovery stage of the study, the researchers used Affymetrix arrays to genotype 1,605 children from the Children's Oncology Group study who had been diagnosed with B-cell ALL. Genetic patterns in these patients were compared with those found in 6,661 unaffected control individuals enrolled through the Multi-Ethnic Study of Atherosclerosis.

The analysis uncovered candidate variants that seemed to coincide with ALL risk at one new locus on chromosome 10, along with four loci linked to ALL in the past.

The latter sites are located in and around the ARID5B, IKZF1, CEBPE, and CDKN2A/2B genes, authors of the study explained, while the newly associated locus fell in the vicinity of the BMI1 and PIP4K2A genes.

Following a series of validation studies in another 845 cases and 4,316 controls analyzed by ancestry, the team confirmed that the top SNPs in most of the genes shared ties with ALL regardless of ethnicity. But there was an exception: so far the top SNP in the vicinity of the CEBPE gene seems to have an ALL association that's specific to Europeans.

In addition, at least some of the ALL-associated variants — particularly those in the ARID5B and PIP4K2A genes — seem to turn up more or less often depending on the population considered.

For instance, the higher risk version of an ALL-linked SNP in PIP4K2A appears to occur with higher-than-usual frequency in the Hispanic population, researchers reported. In contrast, this variant was somewhat less common in the African-American population and intermediate in Europeans.

Such differences may be important, particularly since results of the study suggest that individuals who have inherited predominantly risk alleles at the top SNPs in the ARID5B, IKZF1, CEBPE, and PIP4K2A genes are some nine times more likely to develop ALL than those carrying one or no risk alleles.

"The genetic basis of ALL is most likely to be polygenic," Yang and colleagues explained. "However, it should be noted that carrying risk variants at merely four SNPs (ARID5B, IKZF1, CEBPE, and PIP4K2A) conferred a nine-fold increase in disease susceptibility."

Several of these genes, including ARID5B, IKZF1, and CEBPE, have been implicated in processes such as hematopoietic differentiation and development, study authors noted, which are processes that might be expected to be altered in leukemia.

"With these ALL susceptibility genes now on hand (ARID5B, IKZF1, CDKN2A/2B, CEBPE, PIP4K2A), we are armed with novel knowledge of which certain children develop ALL in the first place," Yang told GenomeWeb Daily News in an email message. "The fact that alterations in these genes lead to ALL raises the question of what would happen if we restore these pathways in ALL and also make them possible exciting therapeutic targets as well."

Nevertheless, those involved in the study explained that additional work will be needed, both to fine-map causal variants within the ALL-associated regions found already and to uncover additional genetic contributors to ALL risk within and across many different populations.

"The discoveries … are an important step forward in terms of understanding why children develop ALL in the first place, particularly for those with African or Hispanic ethnicity," Yang said in a statement. "However, this is probably still just a small part of the complete picture."