Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in developed nations, affecting between 30 and 45 out of every one million kids.  But not much is known about the genetics of the disease.

Two research groups set out to learn more by looking for common genetic variations associated with the disease.  Their results, published online this week in Nature Genetics, provide new insight into the development of ALL.

British researchers led by Elli Papaemmanuil studied a total of 907 ALL cases and 2,398 controls with European ancestry.  They identified three genetic variants associated with increased risk for the disease.

The strongest of these, rs4132601, is near the IKZF1 gene, which encodes a protein involved in the development of white blood cells.  Deletions of the region of DNA containing this gene are common in forms of ALL that have a poor prognosis.  Each copy of a G at rs4132601 increases the odds of ALL by 1.69 times.

The second most strongly associated SNP was rs7089424 in ARID5B, a gene previously linked to a different form of blood cancer called acute promyelocytic leukemia.  Each copy of a G at rs7089424 was associated with 1.65 times increased odds of ALL.

Finally, Papaemmanuil et al. found that each copy of a G at rs2239633 was associated with 1.34 times increased odds of ALL.

(23andMe customers can check their data for all three SNPs using the links to the Browse Raw Data feature above.)

All three SNPs were even more strongly associated with ALL when the researchers restricted their analysis to a subtype of the disease called B-cell ALL.  Within this form of the disease, rs7089424 in ARID5B seems to be highly associated with a further subtype called hyperdiploid ALL.  This form of the disease has a better response to methotrexate chemotherapy than other subtypes of ALL.

The authors conclude that the variations they identified underlie approximately 64% of all cases of ALL.

“Our findings provide the first unambiguous evidence that common genetic variation influences the risk of developing pediatric ALL and strong rationale for searching for additional risk variants through further GWA [genomewide association] scans,” the authors write.

In a separate study of 441 ALL cases and 16,912 controls, Lisa Trevino and colleagues from the United States also found evidence for the involvement of variants in and around the ARID5B gene in B-hyperdiploid ALL.  The riskier versions of SNPs closely related to rs7089424 were not only correlated with disease risk, but also with a response to methotrexate that at least partially underlies its greater efficacy in B-hyperdiploid ALL.

“The data…suggest that the same genetic variation that predisposes to B-hyperdiploid ALL may underlie the superior response of this subtype to chemotherapy.  Thus, genomic variation may affect not only disease risk but treatment outcome as well,” they write.

Photo: VashiDonsk

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Treatment advances have dramatically increased the cure rate for acute lymphoblastic leukemia (ALL), the most common diagnosed cancer in children, from less than 10% in the 1960’s to more than 80%.

But even in those children who are cured, the response to treatment varies from patient to patient. For some, just a couple of weeks of chemotherapy can drastically reduce the number of leukemia cells in their bone marrow, while others continue to have high levels of disease even after six weeks of intensive therapy.

Now, researchers have discovered that these differences may depend on a patient’s genetics.

Much of the previous work aimed at understanding the variability in responses to cancer treatment has focused on differences between the cancer cells themselves. But researchers from St. Jude’s Children’s Research Hospital and the Children’s Oncology Group have taken a different approach, focusing on genetic variations inherent to the cancer patients and present in all cells of their bodies.

“Although the acquired genetic characteristics of tumor cells play a critical role in drug responsiveness, our results show that inherited genetic variation of the patient also affects effectiveness of anticancer therapy….Such variation may be factored into treatment decisions in the future,” the authors write.

Their study, published online yesterday the Journal of the American Medical Association, identified more than 100 SNPs linked to the number of leukemia cells that survive after initial treatment. A significant number of these same variations were also associated with early response, relapse and drug metabolism.

Children receiving different types of chemotherapy were studied to increase the chances that the SNPs identified by the study would be associated with treatment response in general, and not just response to a specific drug. A total of 487 kids, each receiving one of three different treatment regimens for ALL, were genotyped at more than 400,000 SNPS.

In all, 102 SNPs were associated with “minimal residual disease” (MRD), a measure of the number of leukemia cells that survive after the initial phase of treatment. Some of these SNPs are very close to each other and are likely markers of the same effect, but the researchers say that they identified 72 unique regions of the genome associated with this trait.

There are differences in ALL prognosis between different racial groups. For example, African American children have been shown in some studies to have lower survival rates than white children. The researchers suggest that this could be due to differences between the two groups in the frequency of the protective versions of SNPs identified in this study. In the future, the researchers write, findings like theirs could lead to “race-neutral” treatment decisions that are based on an individual’s unique DNA make-up instead of unreliable assumptions based on ancestry.


Photo of bone marrow cells from an ALL patient by Furfur.

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