Subgroup-Specific Prognostic Implications of TP53 Mutation in Medulloblastoma

• Authors: ZHUKOVA Nataliya; RAMASWAMY Vijay; REMKE Mark; PFAFF Elke; SHIH David J.H.; MARTIN Dianna C.; CASTELO-BRANCO Pedro; BASKIN Berivan; RAY Peter N.; BOUFFET Eric; BUEREN André O. von; JONES David T. W.; NORTHCOTT Paul A.; KOOL Marcel; STURM Dominik; PUGH Trevon J.; POMEROY Scott L.; CHO Yoon-Jae; PIETSCH Torsten; GESSI Marco; RUTKOWSKI Stefan; BOGNAR Laszlo; KLEKNER Almos; CHO Byung-Kyu; KIM Seung-Ki; WANG Kyu-Chang; EBERHART Charles G.; FEVRE-MONTANGE Michelle; FOULADI Maryam; FRENCH Pim J.; KROS Max; GRAJKOWSKA Wieslawa A.; GUPTA Nalin; WEISS William A.; HAUSER Peter; JABADO Nada; JOUVET Anne; JUNG Shin; KUMABE Toshihiro; LACH Boleslaw; LEONARD Jeffrey R.; RUBIN Joshua B.; LIAU Linda M.; MASSIMI Luca; POLLACK Ian F.; RA Young Shin; MEIR Erwin G. Van; ZITTERBART Karel; SCHÜLLER Ulrich; HILL Rebecca M.; LINDSEY Janet C.; SCHWALBE Ed C.; BAILEY Simon; ELLISON David W.; HAWKINS Cynthia; MALKIN David; CLIFFORD Steven C.; KORSHUNOV Andrey; PFISTER Stefan; TAYLOR Michael D.; TABORI Uri
• Year of publication: 2013
• Type: Article in Periodical
• Magazine / Source: Journal of Clinical Oncology
• MU Faculty or unit: Faculty of Medicine
• Doi: http://dx.doi.org/10.1200/JCO.2012.48.5052
• Field: Oncology and hematology
• Keywords: LI-FRAUMENI-SYNDROME; CRANIOSPINAL RADIOTHERAPY; CHILDREN; EXPRESSION; SURVIVAL; TUMORS; P53; CHROMOTHRIPSIS; CHEMOTHERAPY; MODEL
• Description: Purpose Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles. Patients and Methods We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas. Results TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/7P53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/7P53 mutant tumors. Five-year overall survival (OS;+/- SE) was 41 % +/- 9% and 81 % +/- 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P <.001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% +/- 9% and 97% +/- 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors. Conclusion Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.