Molecular profiling and analysis of genetic aberrations aimed at identifying potential therapeutic targets in fibrolamellar carcinoma of the liver.
DNAJ homolog
Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)
TERT
catalytic subunit of protein kinase A (PRKACA)
fibrolamellar carcinoma (FLC)
member 1 (DNAJB1)
subfamily B
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
15 09 2020
15 09 2020
Historique:
received:
16
02
2020
revised:
23
03
2020
accepted:
13
04
2020
pubmed:
15
7
2020
medline:
16
6
2021
entrez:
15
7
2020
Statut:
ppublish
Résumé
Fibrolamellar carcinoma (FLC) is a rare primary liver cancer of young adults. A functional chimeric transcript resulting from the in-frame fusion of the DNAJ homolog, subfamily B, member 1 (DNAJB1), and the catalytic subunit of protein kinase A (PRKACA) genes on chromosome 19 is believed to be unique in FLC, with a possible role in pathogenesis, yet with no established therapeutic value. The objective of the current study was to understand the molecular landscape of FLC and to identify potential novel therapeutic targets. Archival fresh, formalin-fixed, paraffin-embedded samples from patients with FLC who prospectively consented to an institutional review board-approved protocol were analyzed using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a next-generation sequencing assay encompassing up to 468 key cancer genes. Custom targeted RNA-Seq was performed in selected patients. Demographics, treatment, and outcome data were collected prospectively. Survival outcomes were estimated and correlated with mutation and/or copy number alterations. A total of 33 tumor samples from 31 patients with FLC were analyzed. The median age of the patients at the time of diagnosis was 18 years and approximately 53% were women. The DNAJB1-PRKACA fusion transcript was detected in 100% of patients. In 10 of 31 patients in which MSK-IMPACT did not detect the fusion, its presence was confirmed by targeted RNA-Seq. TERT promoter mutation was the second most common, and was detected in 7 patients. The median follow up was 30 months (range, 6-153 months). The 3-year overall survival rate was 84% (95% CI, 61%-93%). The DNAJB1-PRKACA fusion transcript is nonspecific and nonsensitive to FLC. Its potential therapeutic value currently is under evaluation. Opportunities currently are under development for therapy that may be driven or related to the DNAJB1-PRKACA fusion transcript or any therapeutic target identified from next-generation sequencing in patients with FLC.
Sections du résumé
BACKGROUND
Fibrolamellar carcinoma (FLC) is a rare primary liver cancer of young adults. A functional chimeric transcript resulting from the in-frame fusion of the DNAJ homolog, subfamily B, member 1 (DNAJB1), and the catalytic subunit of protein kinase A (PRKACA) genes on chromosome 19 is believed to be unique in FLC, with a possible role in pathogenesis, yet with no established therapeutic value. The objective of the current study was to understand the molecular landscape of FLC and to identify potential novel therapeutic targets.
METHODS
Archival fresh, formalin-fixed, paraffin-embedded samples from patients with FLC who prospectively consented to an institutional review board-approved protocol were analyzed using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a next-generation sequencing assay encompassing up to 468 key cancer genes. Custom targeted RNA-Seq was performed in selected patients. Demographics, treatment, and outcome data were collected prospectively. Survival outcomes were estimated and correlated with mutation and/or copy number alterations.
RESULTS
A total of 33 tumor samples from 31 patients with FLC were analyzed. The median age of the patients at the time of diagnosis was 18 years and approximately 53% were women. The DNAJB1-PRKACA fusion transcript was detected in 100% of patients. In 10 of 31 patients in which MSK-IMPACT did not detect the fusion, its presence was confirmed by targeted RNA-Seq. TERT promoter mutation was the second most common, and was detected in 7 patients. The median follow up was 30 months (range, 6-153 months). The 3-year overall survival rate was 84% (95% CI, 61%-93%).
CONCLUSIONS
The DNAJB1-PRKACA fusion transcript is nonspecific and nonsensitive to FLC. Its potential therapeutic value currently is under evaluation. Opportunities currently are under development for therapy that may be driven or related to the DNAJB1-PRKACA fusion transcript or any therapeutic target identified from next-generation sequencing in patients with FLC.
Identifiants
pubmed: 32663328
doi: 10.1002/cncr.32960
pmc: PMC8224539
mid: NIHMS1712870
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4126-4135Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : National Cancer Institute Cancer Center
ID : P30-CA008748
Organisme : Josée and Henry R. Kravis Center for Molecular Oncology
Informations de copyright
© 2020 American Cancer Society.
Références
Oncologist. 2020 Dec;25(12):e1837-e1845
pubmed: 32154962
JCO Precis Oncol. 2017 Jul;2017:
pubmed: 28890946
Nat Med. 2017 Jun;23(6):703-713
pubmed: 28481359
Chang Gung Med J. 2009 May-Jun;32(3):336-9
pubmed: 19527614
Mod Pathol. 2015 Jan;28(1):103-10
pubmed: 24925055
Genes (Basel). 2016 May 26;7(6):
pubmed: 27240403
Hepatology. 1997 Oct;26(4):877-83
pubmed: 9328308
Histopathology. 2016 Apr;68(5):686-92
pubmed: 26259677
Hepatology. 2014 Jun;59(6):2228-37
pubmed: 24443104
BMC Cancer. 2005 Oct 31;5:142
pubmed: 16259635
Mod Pathol. 2005 Nov;18(11):1417-23
pubmed: 15920538
Am J Clin Oncol. 1999 Feb;22(1):22-8
pubmed: 10025374
Sci Rep. 2017 Mar 17;7:44653
pubmed: 28304380
Oncologist. 2020 Nov;25(11):925-e1603
pubmed: 32400000
Asian Pac J Cancer Prev. 2003 Aug-Dec;4(4):302-6
pubmed: 14728587
Gastrointest Cancer Res. 2013 Jan;6(1):3-9
pubmed: 23505572
Hepatology. 2004 Mar;39(3):798-803
pubmed: 14999699
Oncotarget. 2015 Jan 20;6(2):755-70
pubmed: 25605237
Proc Natl Acad Sci U S A. 2015 Nov 3;112(44):E5916-25
pubmed: 26489647
Mod Pathol. 2010 Sep;23(9):1180-90
pubmed: 20495535
Mol Cancer Ther. 2011 Jan;10(1):126-37
pubmed: 21177375
Science. 2014 Feb 28;343(6174):1010-4
pubmed: 24578576
Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):13076-13084
pubmed: 29162699
Mod Pathol. 2020 Apr;33(4):648-656
pubmed: 31676785
Semin Liver Dis. 2011 Feb;31(1):61-70
pubmed: 21344351
Clin Cancer Res. 2019 Aug 1;25(15):4712-4722
pubmed: 31028088
J Gastroenterol Hepatol. 2002 Apr;17(4):401-5
pubmed: 11982719
Cancer Immunol Res. 2019 May;7(5):805-812
pubmed: 30902819
Cancer. 1980 Jul 15;46(2):372-9
pubmed: 6248194
Mod Pathol. 2015 Jun;28(6):822-9
pubmed: 25698061
J Mol Diagn. 2015 May;17(3):251-64
pubmed: 25801821