title: Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules.
abstract: Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient.
authors: Institute of Pathology, University of Würzburg, Würzburg, Germany.
authors: E
authors: E
authors: Leich
authors: S
authors: S
authors: Weißbach
authors: H-U
authors: HU
authors: Klein
authors: T
authors: T
authors: Grieb
authors: J
authors: J
authors: Pischimarov
authors: T
authors: T
authors: Stühmer
authors: M
authors: M
authors: Chatterjee
authors: T
authors: T
authors: Steinbrunn
authors: C
authors: C
authors: Langer
authors: M
authors: M
authors: Eilers
authors: S
authors: S
authors: Knop
authors: H
authors: H
authors: Einsele
authors: R
authors: R
authors: Bargou
authors: A
authors: A
authors: Rosenwald
references: Blood. 2004 Dec 1;104(12):3712-21
references: 15297310
references: Hematology Am Soc Hematol Educ Program. 2011;2011:344-53
references: 22160056
references: Blood. 2011 Feb 10;117(6):1998-2004
references: 21149634
references: J Clin Oncol. 2011 Aug 1;29(22):3030-6
references: 21709195
references: Blood. 2012 Aug 2;120(5):1060-6
references: 22529291
references: Eur J Cancer. 2006 Jul;42(11):1574-80
references: 16797970
references: Leukemia. 2004 Nov;18(11):1883-90
references: 15356648
references: N Engl J Med. 2011 Jun 16;364(24):2305-15
references: 21663470
references: Blood. 2010 Oct 7;116(14):2403-4
references: 20930078
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D561-8
references: 21045058
references: Nature. 2011 Mar 24;471(7339):467-72
references: 21430775
references: Oncol Rep. 2012 Jan;27(1):3-9
references: 21971890
references: Cancer Res. 2003 Sep 15;63(18):5850-8
references: 14522909
references: Leukemia. 2009 Nov;23(11):1941-56
references: 19657360
references: N Engl J Med. 2011 Mar 17;364(11):1046-60
references: 21410373
references: Br J Haematol. 2008 Mar;140(6):625-34
references: 18302711
references: J Clin Oncol. 2011 Dec 1;29(34):4574-80
references: 22025157
references: J Clin Oncol. 2005 Sep 10;23(26):6333-8
references: 16155016
references: Br J Haematol. 2010 May;149(4):529-36
references: 20331455
references: Int J Hematol. 2003 Aug;78(2):106-13
references: 12953803
references: Cancer Treat Rev. 2012 Aug;38(5):494-504
references: 22305205
references: Blood. 2012 Aug 2;120(5):1077-86
references: 22573403
references: J Clin Oncol. 2011 Dec 1;29(34):4534-40
references: 22025154
references: Blood. 2004 Aug 1;104(3):607-18
references: 15090448
references: Blood. 2008 Oct 15;112(8):3403-11
references: 18635812
references: J Clin Oncol. 2011 Dec 1;29(34):4541-7
references: 22025149
references: J Clin Oncol. 2010 Nov 20;28(33):4985-95
references: 20975071
references: Eur J Cancer. 2006 Jul;42(11):1520-9
references: 16781866
references: Haematologica. 2012 Aug;97(8):1272-7
references: 22371180
references: N Engl J Med. 2011 Mar 24;364(12):1144-53
references: 21428770
references: Lancet Oncol. 2008 Dec;9(12):1157-65
references: 19038762
references: Nat Genet. 2011 May;43(5):491-8
references: 21478889
references: Cancer Res. 2004 Mar 15;64(6):2016-23
references: 15026338
references: Mayo Clin Proc. 2009 Dec;84(12):1095-110
references: 19955246
references: Semin Cancer Biol. 2010 Dec;20(6):424-30
references: 20883788
references: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references: 16199517