Diagnostic Application of Genetically Distinct Medulloblastomas
Hye Sook Min, Seung- Ki Kim, Ji Yeoun Lee, Sung Hye Park. Seoul National University College of Medicine, Seoul, Korea
Background: Recent analysis on genetic features of medulloblastoma (MB) could classify it into 3 to 4 subgroups according to the gene expression profiles, including the Wingless signaling pathway-activated group (WNT), the Sonic Hedgehog signaling pathway-activated group (SHH) and the group showing neural/photoreceptor differentiation (non-WNT/SHH). These molecular features reflect the distinct developmental origin of MB and correlate with some clinicopathologic traits. To apply this to the practical diagnosis and to contribute the risk stratification, the present study analyzed 75 MBs subjected to immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), in addition to the array-based comparative genomic hybridization (array CGH).
Design: Clinicopathologic review of 75 MBs from the archive of Seoul National University Hospital (1999∼2009) was carried out. IHC was done in all cases for β–catenin, YAP1, GAP, filamin A, SFRP1, Eomes. Array CGH were performed in 36 cases by GenomArray (Macrogen Inc, Korea). FISH analysis was performed using commercially available digoxigenin-labeled cosmid probes for MYC (8q24.12-q24.13), MYCN (2p24), CEP2 (2p11.1- q11.1), CEP8 (8p11.1-q11.1), LIS1 (17p13.3), and RARA (17q21) from Vysis and MYB (6q23, Abott).
Results: The median age of patients was 13 years old (range: 1-30 yrs) and M:F ratio was 2.9:1 with 32% (24/75) mortality. Both filamin A and YAP1 were expressed in 6 cases, suggested as WNT group (8%). It included 5 classic and 1 desmoplastic/nodular (D/N) MB. 13 cases (17.4%) were suggested as SHH group showing positivity of filamin A, YAP1 and GAB, which included 8 D/N and 3 classic type. Two cases of large cell/anaplastic (LC/A) MB also showed positivity for these 3 markers. The non-WNT/SHH 56 cases (75%) comprised 40 classic, 9 D/N and 6 LC/A subtype. In array-CGH, 17/36 (47.2%) cases showed chr.17 aberrations (mostly i17q), 82.4% of which revealed chr. 7 gain and/or 8 loss. Chr.17 aberrations were observed in 17 cases correspondingly by FISH, and MYC/MYCN amplification were found in 1 and 3 cases, respectively. SHH subgroups showed the better survival than non-WNT/SHH subgroup (p=0.006), and i17q, 7 gain and/or 8 loss were significantly associated with poor clinical outcome (p<0.02, p<0.001).
Conclusions: From our study, we suggest that IHC for filamin A, YAP1 and GAB can be applied for the subgrouping of MB, but it can be supplemented by monosomy 6 using FISH and β-catenin or PTCH1 mutation study. Chr.7 gain and/or 8 loss are suggested as strong indicators of poor clinical outcome.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 261, Tuesday Afternoon