YOUR FUTURE STARTS WITH HOPE YOUR FUTURE STARTS WITH HOPE Making Sense of Genetic Associations with Childhood Leukaemia Risk Sandeep K. Singh 1, Philip J. Lupo 2, Michael E. Scheurer 2, Anshul Saxena 1, Amy E. Kennedy 3, Ertan Kanbur 4, Mehmet Fatih Okcu 2, Mehmet Tevfik Dorak 4 1 Florida International University, Miami, FL, USA; 2 Baylor College of Medicine, Houston, TX, USA; 3 National Cancer Institute, Bethesda, MD, USA; 4 School of Health Sciences, Liverpool Hope University, Liverpool, U.K. Childhood Cancer 2016, London, U.K.
BACKGROUND Earlier studies were candidate gene studies Most candidate gene study results could not be replicated Genome-wide association studies (GWAS) are hypothesis-free, and provided unbiased results GWAS could not replicate most of the candidate gene study results The novel GWAS results are very robust, but have not been translated to clinical use We also generated a novel GWAS result for sex-specific risk for childhood ALL
AIM To assess the most frequently reported GWAS findings for functionality and gain mechanistic insight To do the same for the statistically most significant result from our GWAS on sex-specific risk marker for childhood ALL
MATERIAL Published GWAS results were obtained from GWAS catalogue, GRASP and Phenoscanner Our GWAS was a case-only study in childhood ALL based on samples from Baylor College of Medicine (n = 237)
RESULTS All GWAS conducted to date in European populations found SNPs in ARID5B and IKZF1 as risk markers ARID5B (AT-rich interaction domain 5B) Chromosome 10 rs , rs , rs , rs , rs , rs , rs IKZF1 (IKAROS family zinc finger 1) Chromosome 7 rs , rs , rs , rs , rs
Non-independence of Reported Results 1KG EUR data
Non-independence of Reported Results 1KG EUR data
Functionality of Reported Results ARID5B rs rs rs rs rs rs rs rs rs rs rs CADD scores
Functionality of Reported Results IKZF1 rs rs rs rs rs rs CADD scores
Functionality of Reported Results rs (freq=0.316) rs rs (freq=0.346) 13.6 (freq=0.233) Not included in any GWAS chip Have not been examined in any disease Can be imputed May yield stronger associations (higher OR)
ARID5B and IKZF1 expression in ALL
ARID5B rs as an meQTL
ARID5B risk markers Notable features: Correlate with ARID5B expression (which is upregulated in leukaemia) Correlate with ARID5B methylation level Also associated with height (positive correlation) and schizophrenia
ARID5B and the Environment
IKZF1 and the Environment
GWAS for Sex-specific Risk Markers A case-only study (Baylor, n = 237) Top hit was RASSF2 rs (protective for males, risk for females; P = 4 x 10 -6) RASSF2 (Ras association domain family member 2) is a tumour suppressor RASSF2 binds and inhibits KRAS (which is frequently mutated in childhood ALL); affects cell cycle and apoptosis; has a suppressive effect on NF B
GWAS for Sex-specific Risk Markers rs is a strong meQTL for cg within RASSF2 (positive correlation)
GWAS for Sex-specific Risk Markers cg is hypomethylated in ALL
GWAS for Sex-specific Risk Markers rs correlates with RASSF2 expression levels rs also correlates with RASSF2 methylation levels The CpG site affected by rs is critical one in childhood ALL development RASSF2 has two binding sites for Y-linked transcription factor SRY RASSF2 is targeted by the oncomir Oncomir is induced by MYC, which is induced by oestrogen RASSF2 and MIR17HG levels show inverse correlation in all leukaemia subtypes (MILE study)
RASSF2 rs : Potential Mechanism RASSF2 RAS Tumour suppressor Proto-oncogene mir rs (-) (+) MYC Oestrogen (+) (-) Positive eQTL and meQTL for RASSF2 SRY (+) NF B (-)
Existing GWAS markers act by altering expression levels of their respective genes (ARID5B, IKZF1 and RASSF2) There may also be environmental counterparts of genetic effects observed in GWAS The sex-specific risk marker rs provides insight into the potential mechanism of the gender effect in childhood ALL Mechanistic studies are best done by a combination of wet laboratory experiments and existing bioinformatics resources CONCLUSION
YOUR FUTURE STARTS WITH HOPE YOUR FUTURE STARTS WITH HOPE