Scientific presentations at conferences

References and more information related to presented posters or scientific talks.

Systematic characterisation of chromatin modifiers in endometrial cancer @ EACR Congress 2022

P1-227, presented on 21/06/2022 in Seville

Abstract

Systematic characterisation of chromatin modifiers in endometrial cancer

K. Z. Kedzierska1, M. W. Brown1, B. Kinnersley2, C. Arnedo-Pac3, A. J. Gruber4, D. C. Wedge5, D. J. Woodcock6, D. N. Church1
EC GeCIP Working Group 100 000 Genomes Project Genomics England

1Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK; 2Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK; 3Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, ES; 4Systems Biology & Biomedical Data Science Laboratory, University of Konstanz, Konstanz, DE; 5Manchester Cancer Research Centre, University of Manchester, Manchester, UK; 6Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

Introduction While chromatin remodelers are mutated in many cancer types, several lines of circumstantial evidence suggest they are particularly important in endometrial cancer (EC). ARID1A - a key component of the SWI/SNF remodelling complex, is one of the most frequently mutated EC drivers. Concurrent ARID1A and ARID1B loss is associated with dedifferentiated EC. Other chromatin remodelers, such as CHD4 and BCOR, have been identified as drivers in EC. However, systematic analysis of alterations of chromatin modifiers in EC beyond the SWI/SNF complex is still lacking. We sought to address this and define the associated changes in chromatin architecture.

Material and Methods We analysed whole genome sequence (WGS) data from the Genomics England 100,000 Genomes Project EC cohort (n=665) along with WES and RNA-seq from The Cancer Genome Atlas (TCGA) pan-cancer (n=10,295) and EC (UCEC and UCS, n=586) cohorts. We analysed chromatin accessibility profiling (ATAC-seq) data from the TCGA pan-cancer cohort (n=410) and a panel of EC cell lines (n=12).

Results and Discussions We identified 15 chromatin modifiers as EC drivers in the GEL cohort. These include known EC drivers such as ARID1A, ARID1B, ARID5B, CTCF and additional pan-cancer drivers CREBBP, SETD1B, SETDB1 and SMARCA4 new to EC. ARID1A mutations are highly over-represented in EC (TCGA EC vs pan-cancer cohort, Fisher’s Exact Test, Odds ratio = 10.53, p-value < 2.2e-16) with 40-53% of samples harbouring a mutation. The 1p36.11 region, which contains the ARID1A gene, is deleted in 66 samples in the GEL cohort.

BCOR, a member of the PRC1.1 complex, is mutated in 18% of all EC samples with a recurrent N1459S mutation in 9% of samples near-unique to EC. CDH4, a member of the NuRD complex, mutated in 20% of EC, has 2 missense hotspots in its functional domains. Conversely, alterations in CDH3 and HDAC2 consist in significant proportions of frameshift deletions. CTCF is mutated in half of the samples with mismatch repair deficiency subtype.

There are significant differences in the open chromatin regions in relation to SWI/SNF mutational status in EC and colorectal cancers, as well in EC derived cell lines.

Conclusion Alterations in chromatin remodelers are highly recurrent in EC, with approximately two-thirds of cases harbouring mutations in at least one gene. The mutational status of chromatin modifiers correlates with altered open chromatin profiles. Investigating perturbations of chromatin architecture is critical for understanding differentiation and disease progression in EC.

References

  1. Adapted from “Endometrial cancer” and “Chromatin organisation”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates\
  2. Makker, V., MacKay, H., Ray-Coquard, I. et al. Endometrial cancer. Nat Rev Dis Primers 7, 88 (2021). https://doi.org/10.1038/s41572-021-00324-8\
  3. “Womb Cancer | Cancer Research UK.” Womb Cancer | Cancer Research UK, www.cancerresearchuk.org, 23 Jan. 2022, https://www.cancerresearchuk.org/about-cancer/womb-cancer\
  4. Henley, S. J. et al. Annual report to the nation on the status of cancer, part I: national cancer statistics. Cancer 126, 2225–2249 (2020)\
  5. Astolfi A, Fiore M, Melchionda F, Indio V, Bertuccio SN, Pession A. BCOR involvement in cancer. Epigenomics. 2019 May;11(7):835-855. doi: 10.2217/epi-2018-0195
DPhil candidate in Genomic Medicine and Statistics

My research interests include tumor evolution, heterogeneity and epigenomics.