Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation of OBFC1.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
21 03 2022
21 03 2022
Historique:
received:
28
07
2021
revised:
07
09
2021
accepted:
29
09
2021
pubmed:
5
10
2021
medline:
28
4
2022
entrez:
4
10
2021
Statut:
ppublish
Résumé
The 10q24.33 locus is known to be associated with susceptibility to cutaneous malignant melanoma (CMM), but the mechanisms underlying this association have been not extensively investigated. We carried out an integrative genomic analysis of 10q24.33 using epigenomic annotations and in vitro reporter gene assays to identify regulatory variants. We found two putative functional single nucleotide polymorphisms (SNPs) in an enhancer and in the promoter of OBFC1, respectively, in neural crest and CMM cells, one, rs2995264, altering enhancer activity. The minor allele G of rs2995264 correlated with lower OBFC1 expression in 470 CMM tumors and was confirmed to increase the CMM risk in a cohort of 484 CMM cases and 1801 controls of Italian origin. Hi-C and chromosome conformation capture (3C) experiments showed the interaction between the enhancer-SNP region and the promoter of OBFC1 and an isogenic model characterized by CRISPR-Cas9 deletion of the enhancer-SNP region confirmed the potential regulatory effect of rs2995264 on OBFC1 transcription. Moreover, the presence of G-rs2995264 risk allele reduced the binding affinity of the transcription factor MEOX2. Biologic investigations showed significant cell viability upon depletion of OBFC1, specifically in CMM cells that were homozygous for the protective allele. Clinically, high levels of OBFC1 expression associated with histologically favorable CMM tumors. Finally, preliminary results suggested the potential effect of decreased OBFC1 expression on telomerase activity in tumorigenic conditions. Our results support the hypothesis that reduced expression of OBFC1 gene through functional heritable DNA variation can contribute to malignant transformation of normal melanocytes.
Identifiants
pubmed: 34605909
pii: 6380790
doi: 10.1093/hmg/ddab293
pmc: PMC9077268
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
863-874Informations de copyright
© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Références
Med Oncol. 2012 Dec;29(5):3063-9
pubmed: 22644917
Nat Genet. 2017 May;49(5):680-691
pubmed: 28346442
RNA Biol. 2012 Sep;9(9):1139-43
pubmed: 22951592
PLoS Genet. 2012 Sep;8(9):e1002982
pubmed: 23028375
Nature. 2007 Feb 1;445(7127):506-10
pubmed: 17237768
Nat Commun. 2017 Feb 14;8:14418
pubmed: 28195176
Nat Genet. 2020 May;52(5):494-504
pubmed: 32341527
Nat Rev Cancer. 2017 Nov;17(11):692-704
pubmed: 29026206
Nucleic Acids Res. 2014 Jan;42(Database issue):D1001-6
pubmed: 24316577
Genet Med. 2021 Nov;23(11):2087-2095
pubmed: 34262154
Nat Genet. 1996 Jan;12(1):97-9
pubmed: 8528263
J Cancer Res Clin Oncol. 2009 Dec;135(12):1799-807
pubmed: 19557432
Nature. 2012 Aug 23;488(7412):540-4
pubmed: 22763445
J Biol Chem. 2009 Feb 27;284(9):5807-18
pubmed: 19119139
Nat Genet. 2012 Mar 18;44(4):369-75, S1-3
pubmed: 22426310
Bioinformatics. 2016 Dec 1;32(23):3543-3551
pubmed: 27515742
Expert Rev Mol Diagn. 2020 May;20(5):523-531
pubmed: 32124637
Biochimie. 2002 Jan;84(1):67-74
pubmed: 11900878
Nat Rev Genet. 2013 Jul;14(7):483-95
pubmed: 23752797
Nat Commun. 2018 Nov 14;9(1):4774
pubmed: 30429480
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Cancer Res. 2007 Jul 1;67(13):6113-20
pubmed: 17616667
Proteomics. 2016 Feb;16(3):417-26
pubmed: 26553150
Nucleic Acids Res. 2018 Jul 2;46(W1):W242-W245
pubmed: 29762716
Genome Res. 2014 Jun;24(6):999-1011
pubmed: 24501021
J Biol Chem. 2007 Jan 5;282(1):507-17
pubmed: 17074759
Cell Mol Life Sci. 2002 Aug;59(8):1317-26
pubmed: 12363035
J Invest Dermatol. 2015 Apr;135(4):1074-1079
pubmed: 25407435
Nucleic Acids Res. 2016 Jul 8;44(W1):W272-6
pubmed: 27185894
Nat Genet. 2013 Apr;45(4):422-7, 427e1-2
pubmed: 23535734
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Nat Struct Mol Biol. 2015 Nov;22(11):848-52
pubmed: 26581518
Neoplasma. 2018 Sep 19;65(5):745-752
pubmed: 29940775
J Proteome Res. 2015 Feb 6;14(2):1315-29
pubmed: 25546135
J Cell Sci. 2015 Aug 15;128(16):3106-16
pubmed: 26116569
Nat Genet. 2017 Sep;49(9):1326-1335
pubmed: 28759004
Nat Genet. 2015 Sep;47(9):987-995
pubmed: 26237428
Carcinogenesis. 2016 Jun;37(6):576-582
pubmed: 27207662
Carcinogenesis. 2020 May 14;41(3):284-295
pubmed: 31605138
Genes Dev. 2016 Jul 1;30(13):1483-91
pubmed: 27401551
J Vis Exp. 2015 Jan 03;(95):e52118
pubmed: 25549070
Bioinformatics. 2010 Sep 15;26(18):2336-7
pubmed: 20634204
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
J Biol Chem. 2009 Sep 25;284(39):26725-31
pubmed: 19648609
Genes Chromosomes Cancer. 2009 Dec;48(12):1037-50
pubmed: 19760604
Nat Rev Genet. 2019 Aug;20(8):467-484
pubmed: 31068683
Nat Protoc. 2007;2(7):1722-33
pubmed: 17641637