Unusual KRAS Missense Mutation (P.E63K) in Patient with Juvenile Pilocytic Astrocytoma of the Tectum Lianne Q Chau,1 Michael L Levy,2 John Ross Crawford3

Images in… BMJ Case Rep: first published as 10.1136/bcr-2018-228128 on 22 February 2019. Downloaded from Unusual KRAS missense mutation (p.E63K) in patient with juvenile pilocytic astrocytoma of the tectum Lianne Q Chau,1 Michael L Levy,2 John Ross Crawford3

1Tumor Initiation and Description in the cerebellum, brainstem, hypothalamus and Maintenance Program, Sanford A 24-year-old woman with a history of tectal optic tract and rarely become anaplastic or malig- Burnham Prebys Medical glioma initially diagnosed at 7 years of age nant.2 The majority of JPAs are associated with Discovery Institute, La Jolla, presented following cyst fenestration and increased activation of the mitogen-activated California, USA biopsy for progression on neuroimaging. protein kinase (MAPK) signalling pathway.1 2 The 2Neurosurgery, University of most common genetic alteration, found in over California San Diego, San Diego, Contrast enhanced MRI of the brain revealed a California, USA relatively well-defined mass with progression of 70% of cases, is the KIAA1549-BRAF fusion, 3Neurosciences and Pediatrics, solid and cystic components in the tectal region a 2 Mb tandem duplication of 7q34 that leads University of California San of the brainstem (figure 1). At initial presenta- to loss of the N-terminus regulatory domain of Diego, San Diego, California, tion at 7 years of age, the patient underwent BRAF and thus constitutive activation of MAPK.2 USA an endoscopic third ventriculostomy followed Several other gene fusions such as FAM131B- by ventriculoperitoneal shunt placement for BRAF, SRGAP3-RAFand FGFR1-TACC1 have Correspondence to treatment of persistent hydrocephalus. Due to also been reported, but are much less common.1 2 Dr John Ross Crawford, the location and slow growing nature of the These gene fusions are primarily found in cere- jrcrawford@ ucsd.edu tumour, the patient did not undergo surgical bellar JPAs and less frequently in non-cerebellar resection, radiation, or chemotherapy, but JPAs.1 2 Non-fusion mutations in genes along the Accepted 28 January 2019 was monitored with serial MRI. Histologi- MAPK pathway are found more frequently in cally, the tumour was classified as a juvenile non-cerebellar JPAs, and include somatic BRAF, pilocytic astrocytoma (JPA). A next generation KRAS, FGFR1, PTPN11 mutations as well as the sequencing panel consisting of 397 cancer-re- germline NF1 mutation.1 2 lated genes (table 1) performed on paraffin-em- KRAS is an oncogene that encodes for the bedded formalin fixed tumour of the previously KRAS protein, a GTPase involved in signal trans- untreated tumour revealed a clinically signifi- duction.3 KRAS is involved in several signalling cant KRAS missense mutation (c.187G>A p. cascades, including MAPK, PI3K/AKT, RAL-GDS, E63K). Variants in JAK1 (c.6+1G>T, splice JAK/STAT3 and NORE1/RASFF1 pathways and

site exon 2), RAF1 (c.1423T>C p.F475L) thus plays a role in a variety of cellular processes http://casereports.bmj.com/ and NOTCH3 (c.1505C>T p.S502F) were including cell proliferation, apoptosis, growth also detected. However, following review of arrest, differentiation, transcription and trans- Catalogue of Somatic Mutations in Cancer lation.3 Activating mutations in KRAS decrease (COSMIC) database (https://cancer.sanger.ac. GTP hydrolysis activity and most notably lead to uk/cosmic), these specific mutations have not increased cell proliferation through the MAPK and been reported and are considered variants of PI3K/AKT pathways.3 KRAS mutations have been unknown significance. implicated in numerous cancers and are associated JPAs are slow growing WHO grade I tumours with a less favourable outcome.3 They have the that account for approximately 20% of paedi- highest incidence rates in pancreatic, colon and 1 atric brain tumours. JPAs can arise sporadically, lung carcinomas, but are rare in JPAs, occurring in on September 30, 2021 by guest. Protected copyright. as with this particular patient, or in association 2% or less of cases.2 3 The KRAS p.E63K mutation with neurofibromatosis type 1 (NF1), a familial detected in our patient comprises approximately tumour syndrome that increases the risk of devel- 0.025% (11 of 43 817) of all KRAS mutations oping gliomas.1 2 These tumours often develop reported (COSMIC, October 2018), and has been

To cite: Chau LQ, Levy ML, Crawford JR. BMJ Case Rep 2019;12:e228128. doi:10.1136/bcr-2018- Figure 1 MRI demonstrates a cystic and solid hyperintense mass of the dorsal tectum (A) with associated minimal 228128 contrast enhancement and hydrocephalus (B).

Chau LQ, et al. BMJ Case Rep 2019;12:e228128. doi:10.1136/bcr-2018-228128 1 Images in… BMJ Case Rep: first published as 10.1136/bcr-2018-228128 on 22 February 2019. Downloaded from ZNF521 U2AF1 TNFRSF14 SUFU SOX9 SLC34A2 RNF43 RAD21 PRDM16 PIK3CB PARK2 NR4A3 NCOA1 MRE11A MDM2 LMO1 KDM6A IRF2 HRAS GNA11 FRS2 FGFR2 FAS ETV6 ERBB2 DICER1 CRKL CDKN2A CD274 C11orf30 BCL6 ATRX ARAF RAF1 FGFR1 ZNF384 TSHR TNFAIP3 STK11 SOX2 SF3B1 RICTOR RAC1 PRDM1 PIK3CA PALB2 NPM1 MYH9 MPL MCL1 LIFR KDM5C INPP4B HNF1A GMPS FOXP1 FGFR1 FANCL ETV5 EPHB1 DDR2 CREBBP CDKN1B CCNE1 BTK BCL2L2 ATR AR PPARG EWSR1 ZNF217 TSC2 TMPRSS2 STAT5B SOX10 SETD2 RET QKI PPP2R1A PIK3C2B PAK3 NOTCH3 MYH11 MN1 MAP3K1 LCP1 KDM5A INHBA HIP1 GLI1 FOXO1 FGF6 FANCG ETV4 EPHA7 DDIT3 COL1A1 CDKN1A CCND3 BTG1 BCL2L1 ATP2B3 APC PDGFRA ETV6 ZMYM2 TSC1 THRAP3 STAT4 SOCS1 SETBP1 RBM10 PTPRC PPARG PDK1 NUP98 NOTCH2 MYD88 MLLT4 MAP2K4 KRAS KAT6B IL7R HGF GID4 FOXL2 FGF4 FANCF ETV1 EPHA5 DAXX CLTCL1 CDK8 CCND2 BRIP1 BCL2 ATP1A1 AMER1 NTRK2 ETV5 ZBTB2 TRRAP TGFBR2 STAT3 SNCAIP SDHD RB1 PTPN11 POLE PDGFRB NUP93 NOTCH1 MYCN MLLT3 MAP2K2 KMT2D KAT6A IKZF1 H3F3A GATA6 FOXA1 FGF3 FANCE ESR1 EPHA3 CYLD CIC CDK6 CCND1 BRD4 BCL11B ATM ALK NTRK1 ETV4 XPO1 TRIP11 TET2 STAG2 SMO SDHC RARA PTEN POLD1 NUP214 NKX2-1 MYCL MLH1 MAP2K1 KMT2A JUN IKBKE GSK3B GATA4 FLT4 FGF23 FANCD2 ERRFI1 EP300 CUL3 CHEK2 CDK4 CBLB BRCA2 BCL11A ATF6 AKT3 NR4A3 ETV1 http://casereports.bmj.com/ WT1 TRIM33 TERT SS18 SMARCB1 SDHB RANBP2 PTCH1 PMS2 PDCD1LG2 PDGFRA NUMA1 NIN MYC MITF MAML2 KLHL6 JAK3 IGF2 GRM3 GATA3 FLT3 FGF19 FANCC ERG EIF1AX CTNNB1 CHEK1 CDK12 CBL BRCA1 BARD1 ASXL1 AKT2 NOTCH2 EGFR WRN TRIM24 TERC SRGAP3 SMARCA4 SDHA RANBP17 PRSS8 PMS1 PCM1 NTRK3 NFKBIA MYB MET MAGI2 KIT JAK2 IGF1R GRIN2A GATA2 FLT1 FGF14 FANCA ERCC5 EGFR CTNNA1 CHD4 CDH11 CBFB BRAF BAP1 ASPSCR1 AKT1 MYB DDIT3 on September 30, 2021 by guest. Protected copyright. WISP3 TPR TCF7L2 SRC SMAD4 RUNX1T1 RALGDS PRKDC PLCG2 PBRM1 NTRK2 NFE2L2 MUTYH MEN1 LZTR1 KIF5B JAK1 IDH2 GPR124 GATA1 FLCN FGF10 FAM46C ERCC4 EBF1 CTCF CHD2 CDH1 CASP8 BMPR1A AXL ARID2 AKAP9 TMPRSS2 FUS BRD4 XO1 WHSC1 TP53 TBX3 SPTA1 SMAD3 RUNX1 RAF1 PRKCI PIK3R2 PAX7 NTRK1 NF2 MTOR MEF2B LYN KEL ITK GNAS GABRA6 FH FBXW7 EZH2 ERCC3 DOT1L CSF3R CEBPA CDC73 CARD11 BLM AXIN1 ARID1B ACVR1B SS18 FO BRAF VHL TOP2A TAF1 SPOP SMAD2 RPTOR RAD51 PRKAR1A PIK3R1 PAX5 NSD1 NF1 MSH6 MED12 LRP1B KEAP1 IRS2 HSP90AA1 IDH1 GNAQ FUS FGFR4 FBXO11 EXT1 ERBB4 DNMT3A CSF1R CDKN2C CD79B CAMTA1 BCORL1 AURKB ARID1A ABL2 ASPSCR1 ROS1 FGFR3 Next generation cancer gene panel

ubset of genes (28) for which potential rearrangements are evaluated are ubset of genes (28) for which potential rearrangements VEGFA TOP1 SYK SPEN SLIT2 ROS1 RAD50 PREX2 PIK3CG PAX3 NRAS NCOA2 MSH2 MDM4 LRIG3 KDR IRF4 HSD3B1 GNA13 FUBP1 FGFR3 FAT1 EWSR1 ERBB3 DNM2 CRLF2 CDKN2B CD79A CACNA1D BCOR AURKA ARFRP1 Genes for which entire coding panel is interrogated coding panel is interrogated Genes for which entire ABL1 S ALK Table 1 Table RET FGFR2

2 Chau LQ, et al. BMJ Case Rep 2019;12:e228128. doi:10.1136/bcr-2018-228128 Images in… BMJ Case Rep: first published as 10.1136/bcr-2018-228128 on 22 February 2019. Downloaded from reported once in a patient with a cerebellar JPA.1 Our finding understand the functional consequences of previously unchar- represents the first reported case of KRAS p.E63K mutation acterised novel gene mutations in low grade glioma. in a non-cerebellar JPA of the tectum. It is unclear what role if any the KRAS mutation or the unreported variants of JAK1, Contributors Dr JRC was responsible for the design and creation of the case report RAF1 and NOTCH3 may play in tumour growth. Further and approve of its contents. Dr MLL was responsible for the design and creation of the case report and approve of its contents. LC was responsible for the design and studies on phenotype/genotype correlations are required to creation of the case report and approve of its contents. The authors have nothing to disclose. Funding The authors have not declared a specific grant for this research from any Learning points funding agency in the public, commercial or not-for-profit sectors. Competing interests None declared. ►► Juvenile pilocytic astrocytomas (JPAs) are relatively common Patient consent for publication Obtained. low grade gliomas that are associated with mutations in Provenance and peer review Not commissioned; externally peer reviewed. genes that encode for proteins in the MAPK pathway. ►► KRAS mutations are rare in JPAs and have been found in 2% References or less of cases. 1 Cin H, Meyer C, Herr R, et al. Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic ►► The KRAS p.E63K missense mutation comprises about astrocytoma. Acta Neuropathol 2011;121:763–74. 0.025% of all reported KRAS mutations. We report the first 2 Collins VP, Jones DT, Giannini C. Pilocytic astrocytoma: pathology, molecular case of this mutation in non-cerebellar pilocytic astrocytoma mechanisms and markers. Acta Neuropathol 2015;129:775–88. of the tectum. 3 Jancík S, Drábek J, Radzioch D, et al. Clinical relevance of KRAS in human cancers. J Biomed Biotechnol 2010;2010:1–13.

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Chau LQ, et al. BMJ Case Rep 2019;12:e228128. doi:10.1136/bcr-2018-228128 3