Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.
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Torchia Jonathon, Picard Daniel, Lafay-Cousin Lucie, Hawkins Cynthia E, Kim Seung-Ki, Letourneau Louis, Ra Young-Shin, Ho King Ching, Chan Tiffany Sin Yu, Sin-Chan Patrick, Dunham Christopher P, Yip Stephen, Ng Ho-Keung, Lu Jian-Qiang, Albrecht Steffen, Pimentel José, Chan Jennifer A, Somers Gino R, Zielenska Maria, Faria Claudia C, Roque Lucia, Baskin Berivan, Birks Diane, Foreman Nick, Strother Douglas, Klekner Almos, Garami Miklos, Hauser Peter, Hortobágyi Tibor, Bognár Laszló, Wilson Beverly, Hukin Juliette, Carret Anne-Sophie, Van Meter Timothy E, Nakamura Hideo, Toledano Helen, Fried Iris, Fults Daniel, Wataya Takafumi, Fryer Chris, Eisenstat David D, Scheineman Katrin, Johnston Donna, Michaud Jean, Zelcer Shayna, Hammond Robert, Ramsay David A, Fleming Adam J, Lulla Rishi R, Fangusaro Jason R, Sirachainan Nongnuch, Larbcharoensub Noppadol, Hongeng Suradej, Barakzai Muhammad Abrar, Montpetit Alexandre, Stephens Derek, Grundy Richard G, Schüller Ulrich, Nicolaides Theodore, Tihan Tarik, Phillips Joanna, Taylor Michael D, Rutka James T, Dirks Peter, Bader Gary D, Warmuth-Metz Monika, Rutkowski Stefan, Pietsch Torsten, Judkins Alexander R, Jabado Nada, Bouffet Eric, Huang Annie
Аннотация
METHODS: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling.
FINDINGS: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes.
INTERPRETATION: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours.
FUNDING: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.