Date Published: June 10, 2019
Publisher: Public Library of Science
Author(s): Kateryna Petrykey, Sarah Lippé, Philippe Robaey, Serge Sultan, Julie Laniel, Simon Drouin, Laurence Bertout, Patrick Beaulieu, Pascal St-Onge, Aubrée Boulet-Craig, Aziz Rezgui, Yutaka Yasui, Yadav Sapkota, Kevin R. Krull, Melissa M. Hudson, Caroline Laverdière, Daniel Sinnett, Maja Krajinovic, Cinzia Ciccacci.
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.
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.
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.
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.
Acute lymphoblastic leukemia (ALL) is the most frequent childhood cancer  accounting for approximately 25% of all cases . The five-year survival rate of childhood ALL is currently greater than 85% due to the optimization of multi-agent risk-adapted treatment strategies [2, 3]. However, the exposure to specific chemotherapeutic agents and/or cranial radiation therapy during a susceptible period of child development results in late-adverse effects (LAEs) [4–6] including neurocognitive impairments . Clinically significant deficits among ALL survivors are most commonly found in attention [7–12], working memory , processing speed [9, 14, 15] and executive functions, such as verbal fluency and cognitive flexibility . Neurocognitive impairment in childhood ALL survivors persist for many years after treatment [17, 18]. Large survey studies like the Childhood Cancer Survivors Study (CCSS) as well as other studies conducted in childhood ALL survivors [7, 9, 19] have demonstrated higher risk of depression, anxiety, behavioural difficulties, distress, as well as post-traumatic symptoms compared to siblings [20–25]. Longitudinal follow-up in long-term survivors have indicated that frequency of distress evolves over time, with more than 10% of survivors experiencing significant increase in depression as well as in anxiety .
Functionally predicted germline common variants in MTR, PPARA, SLCO1B1, ABCC3, CALML5, CACNB2 and PCDHB10 genes were found to be significantly associated with deficits in neurocognitive tests performance, whereas a variant in EPHA5 gene was significantly associated with both anxiety and depression.
Our study has certain limitations. Its limited sample size may affect the accuracy of the results, particularly in the context of the stratified analysis. Other unmeasured factors in this study, for example, inflammation and oxidative stress, could modulate or potentiate association with genetic factors. The candidate gene approach may have missed genetic markers potentially involved in neurocognitive decline and mood disturbances that could have been detected through unbiased approaches. Among associations detected in the PETALE cohort only two showed a similar trend in SJLIFE cohort. Despite matching both outcomes and patients’ characteristics between the two cohorts, it is possible that small sample size, differences in treatment protocols or time of ALL diagnosis [117–120] contributed to the observed discrepancies. Likewise, stratification by risk group designation was not available for the SJLIFE cohort, precluding replication of the risk-based stratified analyses. Although the analyses in PETALE cohort were corrected for multiple testing, and confounding was reduced due to homogeneous population and uniform treatment, we cannot exclude that some of the associations have been obtained by chance.