Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma
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1 Recurrent somatic alterations of FGFR1 and NRK2 in pilocytic astrocytoma David.W. Jones*, Barbara Hutter*, Natalie Jäger*, ndrey Korshunov, Marcel Kool, Hans Jörg Warnatz, homas Zichner, Sally R. Lambert, Marina Ryzhova, Dong nh Khuong Quang, dam M. Fontebasso, drian M. Stütz, Sonja Hutter, Marc Zuckermann, Dominik Sturm, Jan Gronych, Bärbel Lasitschka, Sabine Schmidt, Huriye Şeker-Cin, Hendrik Witt, Marc Sultan, Meryem Ralser, Paul. Northcott, Volker Hovestadt, Sebastian Bender, Elke Pfaff, Sebastian Stark, Damien Faury, Jeremy Schwartzentruber, Jacek Majewski, Ursula D. Weber, Marc Zapatka, Benjamin Raeder, Matthias Schlesner, Catherine L. Worth, Cynthia C. Bartholomae, Christof von Kalle, Charles D. Imbusch, Sylwester Radomski, Chris Lawerenz, Peter van Sluis, Jan Koster, Richard Volckmann, Rogier Versteeg, Hans Lehrach, Camelia Monoranu, Beate Winkler, ndreas Unterberg, Christel Herold-Mende, ill Milde, ndreas E. Kulozik, Martin Ebinger, Martin U. Schuhmann, Yoon-Jae Cho, Scott L. Pomeroy, ndreas von Deimling, Olaf Witt, Michael D. aylor, Stephan Wolf, Matthias. Karajannis, Charles G. Eberhart, Wolfram Scheurlen, Martin Hasselblatt, Keith L. Ligon, Mark W. Kieran, Jan O. Korbel, Marie-Laure Yaspo, Benedikt Brors, Jörg Felsberg, Guido Reifenberger, V. Peter Collins, Nada Jabado, Roland Eils#, Peter Lichter# and Stefan M. Pfister# on behalf of the ICGC PedBrain umor Project Supplementary Figures (7) Supplementary Figure 1 halamus Hemisphere 4 th Ventricle Cerebellum 3 rd Ventricle Hypothalamus/ Optic Pathway Brainstem Supplementary Figure 1 Location distribution of the tumor cohort Summary of the distribution of tumor locations across our whole-genome sequencing cohort (n=96).
2 Supplementary Figure 2 a Somatic Genomewide SNVs P = e 05 r = 0.42 b Five prime base G C Mutation type > C > G > C > C > G C > trinucleotide normalized mutation count (log 10 ) ge at Diagnosis (Years) CG CG CG CG CG CG hree prime base Cerebellar Non cerebellar Supplementary Figure 2 Somatic genome-wide mutations a, Correlation between increasing patient age at diagnosis and somatic mutation burden, colored according to tumor location groups. b, Mutation context heatmap showing that the majority of somatic mutations are cytosine to thymine transitions in a CpG context, which is the most common background mutation type (caused by deamination of methylated cytosines). his, together with the extremely low overall mutation rate (0.064/Mb) suggests that many of the mutations present in pilocytic astrocytoma may be the result of background mutational processes in the cell of origin prior to initiation of tumorigenesis. Values relate to the frequency of each of the 96 possible trinucleotide changes, normalized for the frequency of this trinucleotide in the genome, on a log 10 scale.
3 Supplementary Figure 3 a MKRN1:BRF fusion dup(7) (P58) b CLCN6:BRF fusion (P144) BRF MKRN1 der. chr7 der. chr1 der. chr7 BRF CLCN6 t(1;7) MKRN1 expression CLCN6 expression BRF expression BRF expression...ggcgcgcc CCGGGCGGG... MKRN1 exons 1-4 BRF exons N- KD -C...CCGGGCGG CCGGGCGGG... CLCN6 exons 1-2 BRF exons N- KD -C c GNI1:BRF fusion inv(7) (P30) d NCC2:NRK2 fusion inv(9) (P134) der. chr7 der. chr9 GNI1 BRF NRK2 NCC2 GNI1 gene NCC2 expression BRF gene NRK2 expression...ggcgcgcgcgccg GCCCCGGGC... GNI1 exon 1 BRF exons GGCCGCGCGG GGCGCGCG... NCC2 exons 1-4 NRK2 exons N- KD -C N- BB KD -C Supplementary Figure 3 Novel fusion gene variants in pilocytic astrocytoma a, MKRN1:BRF fusion in ICGC_P58 resulting from a short tandem duplication at 7q34. b, CLCN6:BRF fusion in ICGC_P144 resulting from a t(1;7) translocation. c, GNI1:BRF fusion in ICGC_P30 resulting from an inv(7)(q21:q34). d, NCC2:NRK2 fusion in ICGC_P134 resulting from a complex inversion on chromosome 9. In each case, the cdn sequence at the fusion breakpoint and resulting exon and protein structures are indicated. KD, kinase domain; BB, BB dimerization domain.
4 Supplementary Figure 4 a KRS b Chromosome 12 PL SW SW L19F Q22K (P142) umor DN G G N E63K R73M (P117) Blood DN HVD umor RN G C C C C C C C G C C C G C G G C C C C G C C G C C C C G C C G C F G E G R M Y Q D R M S Y E E Q G KRS Supplementary Figure 4 Double mutations on a single KRS allele a, Schematic of the protein domain structure of KRS, with the mutations identified in ICGC_P117 (red) and ICGC_P142 (purple) annotated. PL, P loop; SW, switch domain; HVD, hypervariable domain. b, IGV screenshot of ICGC_P117 indicating that both mutations occur on one allele of KRS. Sequencing reads are displayed as grey bars, with single reads harboring both mutations indicated in darker grey. partial cdn and protein sequence of KRS are displayed below.
5 Supplementary Figure 5 a, ICGC_P69, pfgfr positive b, ICGC_P69, perk positive c, ICGC_P62, pfgfr negative d, ICGC_P62, perk positive Supplementary Figure 5 Immunopositivity for phospho-fgfr in an FGFR1-mutant pilocytic astrocytoma a, Immunohistochemical staining showing clear positivity for phospho-fgfr in ICGC_P69, which has an N546K mutation in FGFR1. b, IHC staining showing clear positivity for phospho-erk1/2 in the same case. c, IHC for phospho-fgfr is negative in ICGC_P62, which is FGFR1 wild-type but carries a KI1549:BRF fusion. d, IHC staining for phospho-erk1/2 in ICGC_P62, however, shows that it also has clear MPK pathway activation due to the BRF fusion.
6 Supplementary Figure 6 Empty Vector PPN11 W -H PPN11 E69K -H PPN11 E76 -H FGFR1 W -U1 FGFR1 N546K -U1 FGFR1 K656E -U1 PPN11 E69K -H + FGFR1 N546K -U1 PPN11 E76 -H + FGFR1 K656E -U1 α-u1 α-h α-perk1/2 α-erk1/2 Supplementary Figure 6 In vitro assessment of FGFR1 and PPN11 mutants Western blot analysis of NIH33 cells transfected with empty pcdn3.1 vector (EV), PPN11 W, PPN11 E69K, PPN11 E76, FGFR1 W, FGFR1 N546K, FGFR1 K656E, PPN11 E69K + FGFR1 N546K or PPN11 E76 + FGFR1 K656E. PPN11 variants are tagged with the H epitope, and FGFR1 variants with the U1 epitope. Cells were serum-starved 24hrs after transient transfection, and harvested after a further 24hrs. PPN11 mutants alone do not result in elevated phospho-erk1/2 (perk1/2), while the FGFR1 mutants, alone or in combination with PPN11 mutants, clearly showed increased ERK phosphorylation.
7 Supplementary Figure 7 Supplementary Figure 7 MPK pathway changes in pilocytic astrocytoma Summary of the major components in the FGFR/MPK signaling pathway that are deregulated in pilocytic astrocytoma tumorigenesis. Frequencies are estimated from previous literature reports together with novel findings from the present study. Yellow mutation indicators show genes that are known to be altered in pilocytic astrocytoma. Red indicators show genes for which germline alterations have also been linked to pilocytic astrocytoma development.
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