A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus

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 H. 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 and Matthew L. Freedman ()
Additional contact information
Sandor Spisak: Dana-Farber Cancer Institute
Viktoria Tisza: Dana-Farber Cancer Institute
Pier Vitale Nuzzo: Dana-Farber Cancer Institute
Ji-Heui Seo: Dana-Farber Cancer Institute
Balint Pataki: ELTE Eötvös Loránd University, Pázmány P. s. 1A
Dezso Ribli: ELTE Eötvös Loránd University, Pázmány P. s. 1A
Zsofia Sztupinszki: Computational Health Informatics Program (CHIP) Boston Children’s Hospital Harvard Medical School
Connor Bell: Dana-Farber Cancer Institute
Mersedeh Rohanizadegan: Dana-Farber Cancer Institute
David R. Stillman: Dana-Farber Cancer Institute
Sarah Abou Alaiwi: Dana-Farber Cancer Institute
Alan H. Bartels: Dana-Farber Cancer Institute
Marton Papp: Research Centre for Natural Sciences
Anamay Shetty: Dana-Farber Cancer Institute
Forough Abbasi: Cedars-Sinai Medical Center
Xianzhi Lin: Cedars-Sinai Medical Center
Kate Lawrenson: Cedars-Sinai Medical Center
Simon A. Gayther: Cedars-Sinai Medical Center
Mark Pomerantz: Dana-Farber Cancer Institute
Sylvan Baca: Dana-Farber Cancer Institute
Norbert Solymosi: ELTE Eötvös Loránd University, Pázmány P. s. 1A
Istvan Csabai: ELTE Eötvös Loránd University, Pázmány P. s. 1A
Zoltan Szallasi: Computational Health Informatics Program (CHIP) Boston Children’s Hospital Harvard Medical School
Alexander Gusev: Dana-Farber Cancer Institute
Matthew L. Freedman: Dana-Farber Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40616-z

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