Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism
Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% des...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Nature Publishing Group
2017
|
| Online Access: | http://hdl.handle.net/1721.1/108203 https://orcid.org/0000-0001-8855-8647 |
| _version_ | 1826200369980506112 |
|---|---|
| author | Oldridge, Derek A. Wood, Andrew C. Weichert-Leahey, Nina Crimmins, Ian Sussman, Robyn Winter, Cynthia McDaniel, Lee D. Diamond, Maura Hart, Lori S. Zhu, Shizhen Durbin, Adam D. Anders, Lars Tian, Lifeng Zhang, Shile Wei, Jun S. Khan, Javed Bramlett, Kelli Rahman, Nazneen Capasso, Mario Iolascon, Achille Gerhard, Daniela S. Guidry Auvil, Jaime M. Hakonarson, Hakon Diskin, Sharon J. Thomas Look, A. Maris, John M. Abraham, Brian Joseph Young, Richard A. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Oldridge, Derek A. Wood, Andrew C. Weichert-Leahey, Nina Crimmins, Ian Sussman, Robyn Winter, Cynthia McDaniel, Lee D. Diamond, Maura Hart, Lori S. Zhu, Shizhen Durbin, Adam D. Anders, Lars Tian, Lifeng Zhang, Shile Wei, Jun S. Khan, Javed Bramlett, Kelli Rahman, Nazneen Capasso, Mario Iolascon, Achille Gerhard, Daniela S. Guidry Auvil, Jaime M. Hakonarson, Hakon Diskin, Sharon J. Thomas Look, A. Maris, John M. Abraham, Brian Joseph Young, Richard A. |
| author_sort | Oldridge, Derek A. |
| collection | MIT |
| description | Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells. Here we investigate the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation and transcription factor binding sites. We show that SNP rs2168101 G>T is the most highly associated variant (combined P = 7.47 × 10[superscript −29], odds ratio 0.65, 95% confidence interval 0.60–0.70), and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumour formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P = 0.028) in neuroblastoma primary tumours, and ablates GATA3 binding (P < 0.0001). We demonstrate allelic imbalance favouring the G-containing strand in tumours heterozygous for this SNP, as demonstrated both by RNA sequencing (P < 0.0001) and reporter assays (P = 0.002). These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumour cells. |
| first_indexed | 2024-09-23T11:35:21Z |
| format | Article |
| id | mit-1721.1/108203 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:35:21Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1082032022-10-01T04:37:19Z Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism Oldridge, Derek A. Wood, Andrew C. Weichert-Leahey, Nina Crimmins, Ian Sussman, Robyn Winter, Cynthia McDaniel, Lee D. Diamond, Maura Hart, Lori S. Zhu, Shizhen Durbin, Adam D. Anders, Lars Tian, Lifeng Zhang, Shile Wei, Jun S. Khan, Javed Bramlett, Kelli Rahman, Nazneen Capasso, Mario Iolascon, Achille Gerhard, Daniela S. Guidry Auvil, Jaime M. Hakonarson, Hakon Diskin, Sharon J. Thomas Look, A. Maris, John M. Abraham, Brian Joseph Young, Richard A. Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Abraham, Brian Joseph Young, Richard A Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells. Here we investigate the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation and transcription factor binding sites. We show that SNP rs2168101 G>T is the most highly associated variant (combined P = 7.47 × 10[superscript −29], odds ratio 0.65, 95% confidence interval 0.60–0.70), and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumour formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P = 0.028) in neuroblastoma primary tumours, and ablates GATA3 binding (P < 0.0001). We demonstrate allelic imbalance favouring the G-containing strand in tumours heterozygous for this SNP, as demonstrated both by RNA sequencing (P < 0.0001) and reporter assays (P = 0.002). These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumour cells. National Institutes of Health (U.S.) (R01-CA109901) 2017-04-18T13:12:44Z 2017-04-18T13:12:44Z 2015-11 2015-02 Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/108203 Oldridge, Derek A.; Wood, Andrew C.; Weichert-Leahey, Nina; Crimmins, Ian; Sussman, Robyn; Winter, Cynthia; McDaniel, Lee D. et al. “Genetic Predisposition to Neuroblastoma Mediated by a LMO1 Super-Enhancer Polymorphism.” Nature 528, no. 7582 (November 11, 2015): 418–421. © 2015 Macmillan Publishers Limited, part of Springer Nature https://orcid.org/0000-0001-8855-8647 en_US http://dx.doi.org/10.1038/nature15540 Nature Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Oldridge, Derek A. Wood, Andrew C. Weichert-Leahey, Nina Crimmins, Ian Sussman, Robyn Winter, Cynthia McDaniel, Lee D. Diamond, Maura Hart, Lori S. Zhu, Shizhen Durbin, Adam D. Anders, Lars Tian, Lifeng Zhang, Shile Wei, Jun S. Khan, Javed Bramlett, Kelli Rahman, Nazneen Capasso, Mario Iolascon, Achille Gerhard, Daniela S. Guidry Auvil, Jaime M. Hakonarson, Hakon Diskin, Sharon J. Thomas Look, A. Maris, John M. Abraham, Brian Joseph Young, Richard A. Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism |
| title | Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism |
| title_full | Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism |
| title_fullStr | Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism |
| title_full_unstemmed | Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism |
| title_short | Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism |
| title_sort | genetic predisposition to neuroblastoma mediated by a lmo1 super enhancer polymorphism |
| url | http://hdl.handle.net/1721.1/108203 https://orcid.org/0000-0001-8855-8647 |
| work_keys_str_mv | AT oldridgedereka geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT woodandrewc geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT weichertleaheynina geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT crimminsian geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT sussmanrobyn geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT wintercynthia geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT mcdanielleed geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT diamondmaura geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT hartloris geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT zhushizhen geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT durbinadamd geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT anderslars geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT tianlifeng geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT zhangshile geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT weijuns geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT khanjaved geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT bramlettkelli geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT rahmannazneen geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT capassomario geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT iolasconachille geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT gerharddanielas geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT guidryauviljaimem geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT hakonarsonhakon geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT diskinsharonj geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT thomaslooka geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT marisjohnm geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT abrahambrianjoseph geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism AT youngricharda geneticpredispositiontoneuroblastomamediatedbyalmo1superenhancerpolymorphism |