To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21 bp short allele), a single copy knock-in of the 47 bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.
Nature communications. 2023 Aug 23*** epublish ***
Sandor Spisak, Viktoria Tisza, Pier Vitale Nuzzo, Ji-Heui Seo, Balint Pataki, Dezso Ribli, Zsofia Sztupinszki, Connor Bell, Mersedeh Rohanizadegan, David R Stillman, Sarah Abou Alaiwi, Alan B Bartels, Marton Papp, Anamay Shetty, Forough Abbasi, Xianzhi Lin, Kate Lawrenson, Simon A Gayther, Mark Pomerantz, Sylvan Baca, Norbert Solymosi, Istvan Csabai, Zoltan Szallasi, Alexander Gusev, Matthew L Freedman
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA., Department of Physics of Complex Systems, ELTE Eötvös Loránd University, Pázmány P. s. 1A, Budapest, 1117, Hungary., Computational Health Informatics Program (CHIP) Boston Children's Hospital Harvard Medical School, Boston, MA, 02215, USA., Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary., Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA., Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. .