Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy.
Cancer
Oncology
Urology
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
30 05 2019
30 05 2019
Historique:
entrez:
31
5
2019
pubmed:
31
5
2019
medline:
15
9
2020
Statut:
epublish
Résumé
Little is known about the genomic differences between metastatic urothelial carcinoma (LTUC) and upper tract urothelial carcinoma (UTUC). We compare genomic features of primary and metastatic UTUC and LTUC tumors in a cohort of patients with end stage disease. We performed whole exome sequencing on matched primary and metastatic tumor samples (N=37) from 7 patients with metastatic UC collected via rapid autopsy. Inter- and intra-patient mutational burden, mutational signatures, predicted deleterious mutations, and somatic copy alterations (sCNV) were analyzed. We investigated 3 patients with UTUC (3 primary samples, 13 metastases) and 4 patients with LTUC (4 primary samples, 17 metastases). We found that sSNV burden was higher in metastatic LTUC compared to UTUC. Moreover, the APOBEC mutational signature was pervasive in metastatic LTUC and less so in UTUC. Despite a lower overall sSNV burden, UTUC displayed greater inter- and intra-individual genomic distances at the copy number level between primary and metastatic tumors than LTUC. Our data also indicate that metastatic UTUC lesions can arise from small clonal populations present in the primary cancer. Importantly, putative druggable mutations were found across patients with the majority shared across all metastases within a patient. Metastatic UTUC demonstrated a lower overall mutational burden but greater structural variability compared to LTUC. Our findings suggest that metastatic UTUC displays a greater spectrum of copy number divergence from LTUC. Importantly, we identified druggable lesions shared across metastatic samples, which demonstrate a level of targetable homogeneity within individual patients.
Sections du résumé
BACKGROUND
Little is known about the genomic differences between metastatic urothelial carcinoma (LTUC) and upper tract urothelial carcinoma (UTUC). We compare genomic features of primary and metastatic UTUC and LTUC tumors in a cohort of patients with end stage disease.
METHODS
We performed whole exome sequencing on matched primary and metastatic tumor samples (N=37) from 7 patients with metastatic UC collected via rapid autopsy. Inter- and intra-patient mutational burden, mutational signatures, predicted deleterious mutations, and somatic copy alterations (sCNV) were analyzed.
RESULTS
We investigated 3 patients with UTUC (3 primary samples, 13 metastases) and 4 patients with LTUC (4 primary samples, 17 metastases). We found that sSNV burden was higher in metastatic LTUC compared to UTUC. Moreover, the APOBEC mutational signature was pervasive in metastatic LTUC and less so in UTUC. Despite a lower overall sSNV burden, UTUC displayed greater inter- and intra-individual genomic distances at the copy number level between primary and metastatic tumors than LTUC. Our data also indicate that metastatic UTUC lesions can arise from small clonal populations present in the primary cancer. Importantly, putative druggable mutations were found across patients with the majority shared across all metastases within a patient.
CONCLUSIONS
Metastatic UTUC demonstrated a lower overall mutational burden but greater structural variability compared to LTUC. Our findings suggest that metastatic UTUC displays a greater spectrum of copy number divergence from LTUC. Importantly, we identified druggable lesions shared across metastatic samples, which demonstrate a level of targetable homogeneity within individual patients.
Identifiants
pubmed: 31145100
pii: 128728
doi: 10.1172/jci.insight.128728
pmc: PMC6629128
doi:
pii:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : K08 CA175154
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015704
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA230617
Pays : United States
Organisme : NIH HHS
ID : S10 OD020069
Pays : United States
Références
Hum Pathol. 2003 Jul;34(7):646-53
pubmed: 12874759
N Engl J Med. 2003 Aug 28;349(9):859-66
pubmed: 12944571
Cancer. 2008 Nov 1;113(9):2471-7
pubmed: 18823036
Cancer. 2009 Apr 1;115(7):1435-47
pubmed: 19215030
Genome Biol. 2009;10(3):R25
pubmed: 19261174
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Lancet. 2009 Jul 18;374(9685):239-49
pubmed: 19520422
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Genome Res. 2010 Sep;20(9):1297-303
pubmed: 20644199
Urology. 2012 Feb;79(2):384-90
pubmed: 22196406
J Clin Oncol. 2012 Apr 1;30(10):1107-13
pubmed: 22370319
Clin Cancer Res. 2012 Jun 15;18(12):3377-86
pubmed: 22553347
Bioinformatics. 2012 Jul 15;28(14):1811-7
pubmed: 22581179
Science. 2012 Oct 12;338(6104):221
pubmed: 22923433
BMC Genomics. 2012;13 Suppl 6:S16
pubmed: 23134596
Nucleic Acids Res. 2013 Apr 1;41(6):e67
pubmed: 23303777
CA Cancer J Clin. 2013 Jan;63(1):11-30
pubmed: 23335087
Nature. 2013 Feb 21;494(7437):366-70
pubmed: 23389445
Nat Biotechnol. 2013 Mar;31(3):213-9
pubmed: 23396013
J Clin Invest. 2013 Nov;123(11):4918-22
pubmed: 24135135
Nat Commun. 2013;4:2578
pubmed: 24153426
Bioinformatics. 2014 Apr 1;30(7):1015-6
pubmed: 24371154
Adv Urol. 2013;2013:317190
pubmed: 24382958
Nature. 2014 Mar 20;507(7492):315-22
pubmed: 24476821
Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3110-5
pubmed: 24520177
Cancer Cell. 2014 Feb 10;25(2):152-65
pubmed: 24525232
J Clin Oncol. 2014 Jun 20;32(18):1895-901
pubmed: 24821881
Cancer Discov. 2014 Oct;4(10):1140-53
pubmed: 25096233
Eur Urol. 2015 Feb;67(2):241-9
pubmed: 25257030
Ann Oncol. 2015 Jan;26(1):64-70
pubmed: 25319062
Nat Commun. 2014 Nov 17;5:5496
pubmed: 25400221
Curr Protoc Bioinformatics. 2013;43:11.10.1-33
pubmed: 25431634
Hum Mutat. 2015 Apr;36(4):E2423-9
pubmed: 25703262
Cancer Genet. 2015 Sep;208(9):434-40
pubmed: 26235493
Eur Urol. 2015 Dec;68(6):970-7
pubmed: 26278805
J Urol. 2016 Jun;195(6):1684-1689
pubmed: 26778714
Eur Urol. 2016 Sep;70(3):e71
pubmed: 26852077
Genome Biol. 2016 Feb 22;17:31
pubmed: 26899170
Nat Med. 2016 Apr;22(4):369-78
pubmed: 26928463
Oncogene. 2017 Jan 5;36(1):35-46
pubmed: 27270441
Trends Biochem Sci. 2016 Jul;41(7):578-594
pubmed: 27283515
Nat Genet. 2016 Dec;48(12):1490-1499
pubmed: 27749842
Lancet. 2017 Jan 7;389(10064):67-76
pubmed: 27939400
Nat Genet. 2017 Feb;49(2):296-302
pubmed: 27941798
Cancer. 1989 Dec 15;64(12):2448-58
pubmed: 2819654
Eur Urol. 2017 Oct;72(4):544-554
pubmed: 28390739
Nat Med. 2017 Jun;23(6):703-713
pubmed: 28481359
Cell. 2017 Jun 1;169(6):1105-1118.e15
pubmed: 28575672
Eur Urol. 2017 Oct;72(4):641-649
pubmed: 28601352
Clin Cancer Res. 2017 Nov 1;23(21):6487-6497
pubmed: 28760909
JCO Precis Oncol. 2017 Jul;2017:
pubmed: 28890946
Lancet. 2017 Nov 18;390(10109):2266-2277
pubmed: 28916371
J Natl Compr Canc Netw. 2017 Oct;15(10):1240-1267
pubmed: 28982750
Cancer Cell. 2017 Nov 13;32(5):574-589.e6
pubmed: 29136504
Nucleic Acids Res. 2018 Jan 4;46(D1):D1068-D1073
pubmed: 29156001
Transl Oncol. 2018 Feb;11(1):37-42
pubmed: 29161613
Cancer. 2018 May 15;124(10):2115-2124
pubmed: 29517810
Clin Genitourin Cancer. 2018 Aug;16(4):e751-e760
pubmed: 29551583
Cell. 2018 Aug 9;174(4):1033
pubmed: 30096301
J Natl Compr Canc Netw. 2018 Sep;16(9):1041-1053
pubmed: 30181416
Clin Genitourin Cancer. 2018 Dec;16(6):e1237-e1242
pubmed: 30217764
J Cell Physiol. 2019 May;234(5):6976-6982
pubmed: 30317582
Clin Cancer Res. 2019 Feb 1;25(3):967-976
pubmed: 30352907
Urol Clin North Am. 1993 May;20(2):333-47
pubmed: 8388136