Influence of genetic factors on long-term treatment related neurocognitive complications, and on anxiety and depression in survivors of childhood acute lymphoblastic leukemia: The Petale study

BACKGROUND: A substantial number of survivors of childhood acute lymphoblastic leukemia suffer from treatment-related late adverse effects including neurocognitive impairment. While multiple studies have described neurocognitive outcomes in childhood acute lymphoblastic leukemia (ALL) survivors, relatively few have investigated their association with individual genetic constitution. METHODS: To further address this issue, genetic variants located in 99 genes relevant to the effects of anticancer drugs and in 360 genes implicated in nervous system function and predicted to affect protein function, were pooled from whole exome sequencing data of childhood ALL survivors (PETALE cohort) and analyzed for an association with neurocognitive complications, as well as with anxiety and depression. Variants that sustained correction for multiple testing were genotyped in entire cohort (n = 236) and analyzed with same outcomes. RESULTS: Common variants in MTR, PPARA, ABCC3, CALML5, CACNB2 and PCDHB10 genes were associated with deficits in neurocognitive tests performance, whereas a variant in SLCO1B1 and EPHA5 genes was associated with anxiety and depression. Majority of associations were modulated by intensity of treatment. Associated variants were further analyzed in an independent SJLIFE cohort of 545 ALL survivors. Two variants, rs1805087 in methionine synthase, MTR and rs58225473 in voltage-dependent calcium channel protein encoding gene, CACNB2 are of particular interest, since associations of borderline significance were found in replication cohort and remain significant in combined discovery and replication groups (OR = 1.5, 95% CI, 1-2.3; p = 0.04 and; OR = 3.7, 95% CI, 1.25-11; p = 0.01, respectively). Variant rs4149056 in SLCO1B1 gene also deserves further attention since previously shown to affect methotrexate clearance and short-term toxicity in ALL patients. CONCLUSIONS: Current findings can help understanding of the influence of genetic component on long-term neurocognitive impairment. Further studies are needed to confirm whether identified variants may be useful in identifying survivors at increased risk of these complications.