Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 08 2022
02 08 2022
Historique:
received:
05
03
2021
accepted:
06
07
2022
entrez:
2
8
2022
pubmed:
3
8
2022
medline:
5
8
2022
Statut:
epublish
Résumé
The benefit of molecularly-informed therapies in cancer of unknown primary (CUP) is unclear. Here, we use comprehensive molecular characterization by whole genome/exome, transcriptome and methylome analysis in 70 CUP patients to reveal substantial mutational heterogeneity with TP53, MUC16, KRAS, LRP1B and CSMD3 being the most frequently mutated known cancer-related genes. The most common fusion partner is FGFR2, the most common focal homozygous deletion affects CDKN2A. 56/70 (80%) patients receive genomics-based treatment recommendations which are applied in 20/56 (36%) cases. Transcriptome and methylome data provide evidence for the underlying entity in 62/70 (89%) cases. Germline analysis reveals five (likely) pathogenic mutations in five patients. Recommended off-label therapies translate into a mean PFS ratio of 3.6 with a median PFS1 of 2.9 months (17 patients) and a median PFS2 of 7.8 months (20 patients). Our data emphasize the clinical value of molecular analysis and underline the need for innovative, mechanism-based clinical trials.
Identifiants
pubmed: 35918329
doi: 10.1038/s41467-022-31866-4
pii: 10.1038/s41467-022-31866-4
pmc: PMC9346116
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4485Informations de copyright
© 2022. The Author(s).
Références
Clin Cancer Res. 2014 Jun 15;20(12):3087-93
pubmed: 24727320
Cell Rep. 2017 Jun 27;19(13):2878-2880
pubmed: 28658632
Cold Spring Harb Mol Case Stud. 2016 Nov;2(6):a001180
pubmed: 27900363
Oncoscience. 2017 Jun 23;4(5-6):47-56
pubmed: 28781987
Cancer Discov. 2017 Jun;7(6):586-595
pubmed: 28365644
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
Am J Surg Pathol. 2018 May;42(5):636-645
pubmed: 29356724
Nat Commun. 2019 Apr 9;10(1):1635
pubmed: 30967556
Nature. 2013 Jul 11;499(7457):214-218
pubmed: 23770567
Nat Commun. 2018 Jun 30;9(1):2447
pubmed: 29961079
EBioMedicine. 2020 Nov;61:103030
pubmed: 33039710
J Biotechnol. 2017 Nov 10;261:53-62
pubmed: 28803971
Hepatology. 2014 Apr;59(4):1427-34
pubmed: 24122810
Bioinformatics. 2014 May 15;30(10):1363-9
pubmed: 24478339
Nat Commun. 2020 Nov 4;11(1):5584
pubmed: 33149131
Clin Cancer Res. 2012 Jul 15;18(14):3952-60
pubmed: 22648269
Nat Genet. 2020 Mar;52(3):320-330
pubmed: 32025001
Cancer Discov. 2021 Nov;11(11):2780-2795
pubmed: 34112699
Nat Rev Cancer. 2018 Nov;18(11):696-705
pubmed: 30293088
Cancer Res. 2012 Nov 1;72(21):5454-62
pubmed: 22933060
Genome Res. 2021 Mar;31(3):448-460
pubmed: 33441414
Nat Med. 2019 May;25(5):744-750
pubmed: 31011206
Nat Genet. 2013 Aug;45(8):927-32
pubmed: 23817572
Nat Genet. 2014 Aug;46(8):912-918
pubmed: 25017105
Nat Med. 2017 Jun;23(6):703-713
pubmed: 28481359
Br J Cancer. 2012 Nov 6;107(10):1776-82
pubmed: 23047548
Pathology. 2015 Jan;47(1):7-12
pubmed: 25485653
Bioinformatics. 2021 May 11;:
pubmed: 33973999
J Clin Oncol. 2013 Jan 10;31(2):217-23
pubmed: 23032625
Nature. 2012 Aug 2;488(7409):100-5
pubmed: 22832583
Nat Med. 2019 May;25(5):751-758
pubmed: 31011205
PLoS Comput Biol. 2016 Apr 21;12(4):e1004873
pubmed: 27100738
Oncotarget. 2016 Jul 12;7(28):44322-44329
pubmed: 27322425
J Clin Oncol. 2008 Sep 20;26(27):4435-41
pubmed: 18802156
Bioinformatics. 2016 Sep 15;32(18):2847-9
pubmed: 27207943
Int J Cancer. 2016 Feb 15;138(4):881-90
pubmed: 26314551
J Clin Oncol. 2019 Mar 1;37(7):570-579
pubmed: 30653423
Ann Oncol. 2017 Dec 01;28(12):3015-3021
pubmed: 29045506
Nature. 2019 Nov;575(7781):210-216
pubmed: 31645765
J Clin Oncol. 2009 May 20;27(15):2503-8
pubmed: 19332734
Genes Chromosomes Cancer. 2021 May;60(5):314-331
pubmed: 33222322
Oncotarget. 2016 Apr 19;7(16):22140-9
pubmed: 26959888
Ann Oncol. 2015 Sep;26 Suppl 5:v133-8
pubmed: 26314775
Br J Cancer. 2013 Sep 3;109(5):1318-24
pubmed: 23860528
Eur J Cancer. 2020 Mar;127:118-122
pubmed: 32007711
Eur J Cancer. 2003 Sep;39(14):1990-2005
pubmed: 12957453
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
JCO Precis Oncol. 2018 Nov;2:1-13
pubmed: 35135162
JAMA Netw Open. 2019 Apr 5;2(4):e192597
pubmed: 31026023
Nature. 2007 Aug 2;448(7153):561-6
pubmed: 17625570
Cell Rep. 2017 Mar 14;18(11):2780-2794
pubmed: 28297679
Int J Cancer. 2020 Jun 1;146(11):3053-3064
pubmed: 31970771
Nat Commun. 2017 Dec 19;8(1):2126
pubmed: 29259247
Cytokine Growth Factor Rev. 2020 Apr;52:56-67
pubmed: 31899106
Int J Cancer. 2019 Dec 1;145(11):2963-2973
pubmed: 30963573
NPJ Genom Med. 2019 Jun 21;4:13
pubmed: 31263571
Nat Methods. 2015 Feb;12(2):115-21
pubmed: 25633503
Cancer Discov. 2018 Sep;8(9):1087-1095
pubmed: 29802158
N Engl J Med. 2015 Oct 29;373(18):1697-708
pubmed: 26510020
Cell. 2011 May 13;145(4):571-83
pubmed: 21565614
Ann Oncol. 2012 Sep;23(9):2409-2414
pubmed: 22357254
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Genome Biol. 2019 Nov 28;20(1):257
pubmed: 31779668
Bioinformatics. 2014 Apr 1;30(7):1015-6
pubmed: 24371154
Clin Cancer Res. 2000 Sep;6(9):3522-9
pubmed: 10999739
Int J Cancer. 2017 Sep 1;141(5):877-886
pubmed: 28597939
Bioinformatics. 2015 Jun 15;31(12):2032-4
pubmed: 25697820
Int J Cancer. 2019 Dec 1;145(11):2996-3010
pubmed: 31008532
Lancet Oncol. 2016 Oct;17(10):1386-1395
pubmed: 27575023
Nat Med. 2017 Apr;23(4):517-525
pubmed: 28288110
ESMO Open. 2019 Nov 13;4(6):e000583
pubmed: 31798980