MB-04: A NOVEL GERMLINE MUTATION IN ALK GENE (M1199L) IDENTYFIED IN THE WNT TYPE OF MEDULLOBLASTOMA

OBJECTIVE: Rearrangements involving ALK gene were identified in different cancers, including neuroblastoma. Microarrays data indicate that ALK is expressed in a subset of medulloblastoma tumours. Therefore we investigated if ALK gene is also mutated in this disease and simultaneously we characterised molecular profile of tumours. METHODS: Tumours from 64 medulloblastoma patients were studied for detection of ALK mutations in exons 23 and 25 using Sanger method. The molecular subtypes of tumours were identified by application of NanoString technology, detection of monosomy 6, mutations in CTNNB1 gene and by immunohistochemistry using a panel of representative antibodies. RESULTS: Three ALK variants were detected and two resulted in intron variant (rs3738867, rs113866835). The third one was heterozygous mutation c.3595A > T in exon 23 (M1199L) in the ALK kinase domain which was identified in the WNT tumour. Results of three in silico algorithms confirmed the pathogenicity of this novel mutation. Presence of ALK expression was confirmed by immunohistochemistry. DNA testing of probands’ mother points to inherited character of mutation. Tumour with ALK mutation was diagnosed as classic medulloblastoma, however with visible focal anaplastic features. Patient is disease free 6 years since diagnosis. CONCLUSION: This is the first evidence of inherited ALK mutation in the WNT type of medulloblastoma, what altogether with presence of ALK expression supports possible involvement of ALK gene in development of this type of tumours. The study was funded by the NCN, Grants No 2011/01/B/NZ4/01066 and 6917/B/P01/2011/40 and by Internal Funding from the IPCZD, Grant no S124/2012 and 233/15, Poland.