Germline MBD4 Mutations and Predisposition to Uveal Melanoma.
Journal
Journal of the National Cancer Institute
ISSN: 1460-2105
Titre abrégé: J Natl Cancer Inst
Pays: United States
ID NLM: 7503089
Informations de publication
Date de publication:
04 01 2021
04 01 2021
Historique:
received:
20
12
2019
revised:
19
03
2020
accepted:
26
03
2020
pubmed:
3
4
2020
medline:
22
6
2021
entrez:
3
4
2020
Statut:
ppublish
Résumé
Uveal melanoma (UM) arises from malignant transformation of melanocytes in the uveal tract of the eye. This rare tumor has a poor outcome with frequent chemo-resistant liver metastases. BAP1 is the only known predisposing gene for UM. UMs are generally characterized by low tumor mutation burden, but some UMs display a high level of CpG>TpG mutations associated with MBD4 inactivation. Here, we explored the incidence of germline MBD4 variants in a consecutive series of 1093 primary UM case patients and a series of 192 UM tumors with monosomy 3 (M3). We performed MBD4 targeted sequencing on pooled germline (n = 1093) and tumor (n = 192) DNA samples of UM patients. MBD4 variants (n = 28) were validated by Sanger sequencing. We performed whole-exome sequencing on available tumor samples harboring MBD4 variants (n = 9). Variants of unknown pathogenicity were further functionally assessed. We identified 8 deleterious MBD4 mutations in the consecutive UM series, a 9.15-fold (95% confidence interval = 4.24-fold to 19.73-fold) increased incidence compared with the general population (Fisher exact test, P = 2.00 × 10-5, 2-sided), and 4 additional deleterious MBD4 mutations in the M3 cohort, including 3 germline and 1 somatic mutations. Tumors carrying deleterious MBD4 mutations were all associated with high tumor mutation burden and a CpG>TpG hypermutator phenotype. We demonstrate that MBD4 is a new predisposing gene for UM associated with hypermutated M3 tumors. The tumor spectrum of this predisposing condition will likely expand with the addition of MBD4 to diagnostic panels. Tumors arising in such a context should be recognized because they may respond to immunotherapy.
Sections du résumé
BACKGROUND
Uveal melanoma (UM) arises from malignant transformation of melanocytes in the uveal tract of the eye. This rare tumor has a poor outcome with frequent chemo-resistant liver metastases. BAP1 is the only known predisposing gene for UM. UMs are generally characterized by low tumor mutation burden, but some UMs display a high level of CpG>TpG mutations associated with MBD4 inactivation. Here, we explored the incidence of germline MBD4 variants in a consecutive series of 1093 primary UM case patients and a series of 192 UM tumors with monosomy 3 (M3).
METHODS
We performed MBD4 targeted sequencing on pooled germline (n = 1093) and tumor (n = 192) DNA samples of UM patients. MBD4 variants (n = 28) were validated by Sanger sequencing. We performed whole-exome sequencing on available tumor samples harboring MBD4 variants (n = 9). Variants of unknown pathogenicity were further functionally assessed.
RESULTS
We identified 8 deleterious MBD4 mutations in the consecutive UM series, a 9.15-fold (95% confidence interval = 4.24-fold to 19.73-fold) increased incidence compared with the general population (Fisher exact test, P = 2.00 × 10-5, 2-sided), and 4 additional deleterious MBD4 mutations in the M3 cohort, including 3 germline and 1 somatic mutations. Tumors carrying deleterious MBD4 mutations were all associated with high tumor mutation burden and a CpG>TpG hypermutator phenotype.
CONCLUSIONS
We demonstrate that MBD4 is a new predisposing gene for UM associated with hypermutated M3 tumors. The tumor spectrum of this predisposing condition will likely expand with the addition of MBD4 to diagnostic panels. Tumors arising in such a context should be recognized because they may respond to immunotherapy.
Identifiants
pubmed: 32239153
pii: 5814932
doi: 10.1093/jnci/djaa047
pmc: PMC7781447
doi:
Substances chimiques
Endodeoxyribonucleases
EC 3.1.-
MBD4 protein, human
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
80-87Informations de copyright
© The Author(s) 2020. Published by Oxford University Press.
Références
Lancet. 1996 May 4;347(9010):1222-5
pubmed: 8622452
Ocul Oncol Pathol. 2018 Apr;4(3):145-151
pubmed: 29765944
Cancer Cell. 2017 Aug 14;32(2):204-220.e15
pubmed: 28810145
Oncotarget. 2016 Jan 26;7(4):4624-31
pubmed: 26683228
Am J Surg Pathol. 2012 Jun;36(6):818-30
pubmed: 22367297
Nucleic Acids Res. 2012 Oct;40(19):9917-26
pubmed: 22848106
Nature. 2020 Feb;578(7793):94-101
pubmed: 32025018
Nucleic Acids Res. 2003 Sep 15;31(18):5399-404
pubmed: 12954776
Nucleic Acids Res. 2012 Jun;40(11):4841-9
pubmed: 22362737
JAMA Ophthalmol. 2015 Aug;133(8):881-7
pubmed: 25974357
Nat Genet. 2016 Jun;48(6):675-80
pubmed: 27089179
Cancer Discov. 2013 Oct;3(10):1122-1129
pubmed: 23861464
N Engl J Med. 2010 Dec 2;363(23):2191-9
pubmed: 21083380
Immunogenetics. 2019 May;71(5-6):433-436
pubmed: 30714079
Clin Cancer Res. 2019 Sep 15;25(18):5513-5524
pubmed: 31227496
Nature. 2009 Jan 29;457(7229):599-602
pubmed: 19078957
Oncol Rep. 2019 Sep;42(3):1133-1140
pubmed: 31322271
NPJ Genom Med. 2017;2:
pubmed: 28781888
Ann Oncol. 2019 Aug 1;30(8):1370-1380
pubmed: 31150059
J Natl Cancer Inst. 2018 Dec 1;110(12):1328-1341
pubmed: 30517737
Nature. 1999 Sep 16;401(6750):301-4
pubmed: 10499592
Nat Commun. 2018 May 14;9(1):1866
pubmed: 29760383
Nat Commun. 2018 Jan 9;9(1):116
pubmed: 29317634
Science. 2010 Dec 3;330(6009):1410-3
pubmed: 21051595
Ophthalmology. 1998 Jan;105(1):195-8
pubmed: 9442799
Br J Ophthalmol. 2017 Jan;101(1):38-44
pubmed: 27574175
Blood. 2018 Oct 4;132(14):1526-1534
pubmed: 30049810