NDA@SZTAKI

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis

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

SchĂĽller, 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

Elsevier

2015-05

RB Pathology / patolĂłgia, kĂłrtan

RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkolĂłgia

BACKGROUND:Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours.
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.

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Article

PeerReviewed

info:eu-repo/semantics/article

text

http://real.mtak.hu/40359/1/Molecular%20subgroups%20of%20at...

Torchia, Jonathon and Picard, Daniel and Lafay-Cousin, Lucie and Hawkins, Cynthia E and Kim, Seung-Ki and Letourneau, Louis and Ra, Young-Shin and Ho, King Ching and Chan, Tiffany Sin Yu and Sin-Chan, Patrick and Dunham, Christopher P and Yip, Stephen and Ng, Ho-keung and Lu, Jian-Qiang and Albrecht, Steffen and Pimentel, José and Chan, Jennifer A and Somers, Gino R and Zielenska, Maria and Faria, Claudia C and Roque, Lucia and Baskin, Berivan and Birks, Diane and Foreman, Nick and Strother, Douglas and Klekner, Almos and Garami, Miklos and Hauser, Peter and Hortobágyi, Tibor and Bognár, Laszló and Wilson, Beverly and Hukin, Juliette and Carret, Anne-Sophie and Van Meter, Timothy E and Nakamura, Hideo and Toledano, Helen and Fried, Iris and Fults, Daniel and Wataya, Takafumi and Fryer, Chris and Eisenstat, David D and Scheineman, Katrin and Johnston, Donna and Michaud, Jean and Zelcer, Shayna and Hammond, Robert and Ramsay, David A and Fleming, Adam J and Lulla, Rishi R and Fangusaro, Jason R and Sirachainan, Nongnuch and Larbcharoensub, Noppadol and Hongeng, Suradej and Barakzai, Muhammad Abrar and Montpetit, Alexandre and Stephens, Derek and Grundy, Richard G and Schüller, Ulrich and Nicolaides, Theodore and Tihan, Tarik and Phillips, Joanna and Taylor, Michael D and Rutka, James T and Dirks, Peter and Bader, Gary D and Warmuth-Metz, Monika and Rutkowski, Stefan and Pietsch, Torsten and Judkins, Alexander R and Jabado, Nada and Bouffet, Eric and Huang, Annie (2015) Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. The Lancet Oncology, 16 (5). pp. 569-582. ISSN 1470-2045

http://real.mtak.hu/40359/

http://dx.doi.org/10.1016/S1470-2045(15)70114-2

doi:10.1016/S1470-2045(15)70114-2