Genome Analysis of Osteosarcoma Progression Samples Identifies FGFR1 Overexpression as a Potential Treatment Target and CHM as a Candidate Tumor Suppressor Gene.
Osteosarcoma (OS) is the most common primary malignant tumor of bone, showing complex chromosomal rearrangements but with few known consistent changes. Deeper biological understanding is crucial to find new therapies to improve patient survival. We have sequenced the whole exome of two primary tumors (before and after chemotherapy), one metastatic tumor and a matched normal sample from two OS patients, to identify mutations involved in cancer biology. The metastatic samples were also RNA sequenced. By RNA sequencing we identified dysregulated expression levels of drug resistance- and apoptosis-related genes. Two fusion transcripts were identified in one patient (OS111); the first resulted in p53 inactivation by fusing the first exon of TP53 to the fifth exon of FAM45A. The second fusion joined the two first exons of FGFR1 to the second exon of ZNF343. Furthermore, FGFR1 was amplified and highly expressed, representing a potential treatment target in this patient. Whole exome sequencing revealed large intertumor heterogeneity, with surprisingly few shared mutations. Careful evaluation and validation of the data sets revealed a number of artefacts, but one recurrent mutation was validated, a nonsense mutation in CHM (patient OS106), which also was the mutation with the highest expression frequency (53%). The second patient (OS111) had wild-type CHM, but a downregulated expression level. In a panel of 71 clinical samples, we confirmed significant low expression of CHM compared to the controls (p = 0.003). Furthermore, by analyzing public datasets, we identified a significant association between low expression and poor survival in two other cancer types. Together, these results suggest CHM as a candidate tumor suppressor gene that warrants further investigation.
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, NO-0310 Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Tale
T
Barøy
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, NO-0310 Oslo, Norway.|Norwegian Cancer Genomics Consortium, Oslo, Norway.
Chandra S R
CS
Chilamakuri
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, NO-0310 Oslo, Norway.|Norwegian Cancer Genomics Consortium, Oslo, Norway.
Susanne
S
Lorenz
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, NO-0310 Oslo, Norway.|Norwegian Cancer Genomics Consortium, Oslo, Norway.
Jinchang
J
Sun
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, NO-0310 Oslo, Norway.
Øyvind S
ØS
Bruland
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, NO-0310 Oslo, Norway.|Norwegian Cancer Genomics Consortium, Oslo, Norway.
Ola
O
Myklebost
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, NO-0310 Oslo, Norway.|Norwegian Cancer Genomics Consortium, Oslo, Norway.|Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, NO-0310 Oslo, Norway.
Leonardo A
LA
Meza-Zepeda
J Cell Biochem. 2003 Apr 15;88(6):1273-91
12647309
Clin Orthop Relat Res. 2000 Apr;(373):11-7
10810457
Br J Cancer. 2013 Oct 15;109 (8):2248-58
24045665
Oncogene. 2016 Jun 2;35(22):2852-61
26387545
Int J Radiat Oncol Biol Phys. 2007;69(2 Suppl):S106-8
17848273
Cancer Med. 2014 Aug;3(4):980-7
24861215
Cancer Res. 2008 Aug 15;68(16):6661-8
18701490
PLoS One. 2011;6(10 ):e26091
22016816
J Clin Oncol. 2007 May 20;25(15):2057-62
17513810
Cancer. 1995 Jan 1;75(1 Suppl):203-10
8000997
Asian Pac J Cancer Prev. 2013;14(2):929-34
23621263
Oncotarget. 2015 Apr 10;6(10):7727-40
25762628
PLoS One. 2009 Dec 22;4(12):e8402
20027300
Cancer Discov. 2012 Dec;2(12):1118-33
23002168
J Clin Oncol. 2002 Feb 1;20(3):776-90
11821461
Int J Cancer. 2012 Jun 15;130(12):2824-34
21780101
Genome Biol. 2010;11(10):R106
20979621
BMC Med Genomics. 2011 Sep 20;4:66
21933437
Nature. 2012 Jan 18;481(7381):306-13
22258609
Int J Cancer. 1994 Jul 1;58(1):95-101
7912235
Nat Commun. 2015 Dec 09;6:10001
26647970
Genome Res. 2012 Mar;22(3):568-76
22300766
Genome Res. 2010 Sep;20(9):1297-303
20644199
Anal Cell Pathol (Amst). 2011;34(3):131-45
21673434
Curr Opin Oncol. 2000 Jul;12(4):330-6
10888418
N Engl J Med. 2012 Mar 8;366(10):883-92
22397650
Breast Cancer Res. 2011;13(6):R130
22171747
Cancer Metastasis Rev. 2007 Mar;26(1):153-81
17333344
Acta Oncol. 2015 Jan;54(1):25-33
24957555
Nature. 2012 Jan 11;481(7382):506-10
22237025
PLoS One. 2012;7(10):e48086
23133552
Cancer Cell. 2002 Sep;2(3):175-8
12242149
Science. 1991 Feb 8;251(4994):665-8
1846977
Genome Res. 2014 Oct;24(10):1624-36
25030888
Cancer Res. 2001 Oct 1;61(19):7225-32
11585759
Clin Cancer Res. 2011 Apr 15;17(8):2110-9
21372215
Anticancer Drugs. 2006 Nov;17 (10 ):1171-7
17075316
Cancer Res. 2002 Jun 1;62(11):3144-50
12036927
Expert Rev Anticancer Ther. 2006 Jul;6(7):1075-85
16831079
Biochem Soc Trans. 2011 Oct;39(5):1202-6
21936789
J Clin Oncol. 2003 May 15;21(10):2011-8
12743156
N Engl J Med. 1996 Oct 3;335(14):1041-8
8793930
Cancer. 2003 Aug 1;98(3):581-9
12879476
Neoplasma. 1998;45(4):223-30
9890665
Nat Rev Cancer. 2003 Sep;3(9):685-94
12951587
Oncotarget. 2016 Feb 2;7(5):5273-88
26672768
Nat Rev Cancer. 2010 Feb;10(2):116-29
20094046
J Biol Chem. 1994 Jan 21;269(3):2111-7
8294464
Ann Oncol. 2014 Mar;25(3):552-63
24265351
BMC Genomics. 2014 Jun 09;15:449
24912484
J Nucleic Acids. 2012;2012:950508
22203889
J Clin Oncol. 2013 Jun 10;31(17):2167-72
23630207
EMBO Mol Med. 2014 Apr;6(4):467-81
24503018
Apoptosis. 2009 Jan;14(1):124-33
19052873
Int J Cancer. 2013 Dec 1;133(11):2512-21
23436697
Teratog Carcinog Mutagen. 2001;21(4):275-82
11406833
J Natl Cancer Inst. 1997 Nov 19;89(22):1706-15
9390540
Genomics. 2014 Oct;104(4):234-41
25066378
Cell Death Dis. 2014 Feb 06;5:e1051
24503543
Clin Cancer Res. 1999 Mar;5(3):621-7
10100715
Ann Oncol. 2015 Feb;26(2):407-14
25421877
J Bioenerg Biomembr. 2001 Dec;33(6):493-501
11804191
J Cell Biol. 2012 Jun 11;197(6):801-17
22665522
Cell Rep. 2014 Apr 10;7(1):104-12
24703847
Sarcoma. 2015;2015:516843
25784831
Cell Mol Life Sci. 2005 Aug;62(15):1657-70
15924270
BMC Cancer. 2013 Mar 22;13:146
23522120
Sarcoma. 2012;2012:627254
22685381
Nat Biotechnol. 2013 Mar;31(3):213-9
23396013
EMBO J. 1994 Nov 15;13(22):5262-73
7957092
J Clin Oncol. 2003 Feb 1;21(3):536-42
12560446