1 / 27

Making Sense of Genetic Associations with Childhood Leukaemia Risk

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

htina
Download Presentation

Making Sense of Genetic Associations with Childhood Leukaemia Risk

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Making Sense of Genetic Associations with Childhood Leukaemia Risk Sandeep K. Singh1, Philip J. Lupo2, Michael E. Scheurer2, Anshul Saxena1, Amy E. Kennedy3, Ertan Kanbur4, Mehmet Fatih Okcu2, Mehmet Tevfik Dorak4 1Florida International University, Miami, FL, USA; 2 Baylor College of Medicine, Houston, TX, USA; 3National Cancer Institute, Bethesda, MD, USA; 4School of Health Sciences, Liverpool Hope University, Liverpool, U.K. Childhood Cancer 2016, London, U.K.

  2. 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

  3. 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

  4. 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)

  5. 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 rs7923074, rs7090445, rs7896246, rs7089424, rs4245595, rs10821936, rs10821938 IKZF1 (IKAROS family zinc finger 1) Chromosome 7 rs6964969, rs4132601, rs11980379, rs11978267, rs1110701

  6. Non-independence of Reported Results 1KG EUR data

  7. Non-independence of Reported Results 1KG EUR data

  8. Functionality of Reported Results ARID5B rs rs rs7090445 rs4245595 rs7923074 rs10821936 rs7896246 rs10821938 rs7089424 rs4506592 rs7087507 CADD scores 7.1 2.0 9.3 8.1 12.4 10.5 2.6 15.2 13.6 rs rs

  9. Functionality of Reported Results IKZF1 rs11978267 rs11980379 rs4132601 rs6964969 rs1110701 rs62445869 3.6 3.0 6.8 2.3 CADD scores 7.7 0.3

  10. Functionality of Reported Results Not included in any GWAS chip Have not been examined in any disease Can be imputed May yield stronger associations (higher OR) rs62445869 rs4506592 rs7087507 7.7 (freq=0.316) 15.2 (freq=0.346) 13.6 (freq=0.233)

  11. ARID5B and IKZF1 expression in ALL

  12. ARID5B rs7896246 as an meQTL

  13. 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

  14. ARID5B and the Environment

  15. ARID5B and the Environment

  16. ARID5B and the Environment

  17. ARID5B and the Environment

  18. IKZF1 and the Environment

  19. IKZF1 and the Environment

  20. GWAS for Sex-specific Risk Markers A case-only study (Baylor, n = 237) Top hit was RASSF2 rs4813720 (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 NFkB

  21. GWAS for Sex-specific Risk Markers rs4813720 is a strong meQTL for cg22485289 within RASSF2 (positive correlation)

  22. GWAS for Sex-specific Risk Markers cg22485289 is hypomethylated in ALL

  23. GWAS for Sex-specific Risk Markers rs4813720 correlates with RASSF2 expression levels rs4813720 also correlates with RASSF2 methylation levels The CpG site affected by rs4813720 is critical one in childhood ALL development RASSF2 has two binding sites for Y-linked transcription factor SRY RASSF2 is targeted by the oncomir-17-92 Oncomir-17-92 is induced by MYC, which is induced by oestrogen RASSF2 and MIR17HG levels show inverse correlation in all leukaemia subtypes (MILE study)

  24. RASSF2 rs4813720: Potential Mechanism mir-17-92 (+) MYC (-) (-) RASSF2 (+) NFkB (+) (+) Oestrogen Tumour suppressor rs4813720 SRY Positive eQTL and meQTL for RASSF2 (-) RAS Proto-oncogene

  25. CONCLUSION 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 rs4813720 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

More Related