Longitudinal molecular trajectories of diffuse glioma in adults
GLASS Consortium [Collaborative Organization]; Barthel, Floris P.; Johnson, Kevin C.; Varn, Frederick S.; Moskalik, Anzhela D.; Tanner, Georgette; Kocakavuk, Emre; Anderson, Kevin J.; Abiola, Olajide; Aldape, Kenneth; Alfaro, Kristin D.; Alpar, Donat [Alpár, Donát (Molekuláris patho...), author] I. Department of Pathology
and experimental Can... (SU / FM / I); Amin, Samirkumar B.; Ashley, David M.; Bandopadhayay, Pratiti; Barnholtz-Sloan, Jill S.; Beroukhim, Rameen; Bock, Christoph; Brastianos, Priscilla K.; Brat, Daniel J.; Brodbelt, Andrew R.; Bruns, Alexander F.; Bulsara, Ketan R.; Chakrabarty, Aruna; Chakravarti, Arnab; Chuang, Jeffrey H.; Claus, Elizabeth B.; Cochran, Elizabeth J.; Connelly, Jennifer; Costello, Joseph F.; Finocchiaro, Gaetano; Fletcher, Michael N.; French, Pim J.; Gan, Hui K.; Gilbert, Mark R.; Gould, Peter V.; Grimmer, Matthew R.; Iavarone, Antonio; Ismail, Azzam; Jenkinson, Michael D.; Khasraw, Mustafa; Kim, Hoon; Kouwenhoven, Mathilde C. M.; LaViolette, Peter S.; Li, Meihong; Lichter, Peter; Ligon, Keith L.; Lowman, Allison K.; Malta, Tathiane M.; Mazor, Tali; McDonald, Kerrie L.; Molinaro, Annette M.; Do-Hyun, Nam; Nayyar, Naema; Ng, Ho Keung; Ngan, Chew Yee; Niclou, Simone P.; Niers, Johanna M.; Noushmehr, Houtan; Noorbakhsh, Javad; Ormond, D. Ryan; Park, Chul-Kee; Poisson, Laila M.; Rabadan, Raul; Radlwimmer, Bernhard; Rao, Ganesh; Reifenberger, Guido; Sa, Jason K.; Schuster, Michael; Shaw, Brian L.; Short, Susan C.; Smitt, Peter A. Sillevis; Sloan, Andrew E.; Smits, Marion; Suzuki, Hiromichi; Tabatabai, Ghazaleh; Van, Meir Erwin G.; Watts, Colin; Weller, Michael; Wesseling, Pieter; Westerman, Bart A.; Widhalm, Georg; Woehrer, Adelheid; Yung, W. K. Alfred; Zadeh, Gelareh; Huse, Jason T.; De, Groot John F.; Stead, Lucy F.; Verhaak, Roel G. W.** ✉; Barthel, FP [Collaborator]; Johnson, KC [Collaborator]; Varn, FS [Collaborator]; Moskalik, AD [Collaborator]; Tanner, G [Collaborator]; Kocakavuk, E [Collaborator]; Anderson, KJ [Collaborator]; Aldape, K [Collaborator]; Alfaro, KD [Collaborator]; Amin, SB [Collaborator]; Ashley, DM [Collaborator]; Bandopadhayay, P [Collaborator]; Barnholtz-Sloan, JS [Collaborator]; Beroukhim, R [Collaborator]; Bock, C [Collaborator]; Brastianos, PK [Collaborator]; Brat, DJ [Collaborator]; Brodbelt, AR [Collaborator]; Bulsara, KR [Collaborator]; Chakrabarty, A [Collaborator]; Chuang, JH [Collaborator]; Claus, EB [Collaborator]; Cochran, EJ [Collaborator]; Connelly, J [Collaborator]; Costello, JF [Collaborator]; Finocchiaro, G [Collaborator]; Fletcher, MN [Collaborator]; French, PJ [Collaborator]; Gan, HK [Collaborator]; Gilbert, MR [Collaborator]; Gould, PV [Collaborator]; Iavarone, A [Collaborator]; Ismail, A [Collaborator]; Jenkinson, MD [Collaborator]; Khasraw, M [Collaborator]; Kim, H [Collaborator]; Kouwenhoven, MCM [Collaborator]; LaViolette, PS [Collaborator]; Lichter, P [Collaborator]; Ligon, KL [Collaborator]; Lowman, AK [Collaborator]; Malta, TM [Collaborator]; McDonald, KL [Collaborator]; Molinaro, AM [Collaborator]; Nam, DH [Collaborator]; Ng, HK [Collaborator]; Niclou, SP [Collaborator]; Niers, JM [Collaborator]; Noushmehr, H [Collaborator]; Ormond, DR [Collaborator]; Park, CK [Collaborator]; Poisson, LM [Collaborator]; Rabadan, R [Collaborator]; Radlwimmer, B [Collaborator]; Rao, G [Collaborator]; Reifenberger, G [Collaborator]; Sa, JK [Collaborator]; Short, SC [Collaborator]; Smitt, PAS [Collaborator]; Sloan, AE [Collaborator]; Smits, M [Collaborator]; Suzuki, H [Collaborator]; Tabatabai, G [Collaborator]; Van, Meir EG [Collaborator]; Watts, C [Collaborator]; Weller, M [Collaborator]; Wesseling, P [Collaborator]; Westerman, BA [Collaborator]; Woehrer, A [Collaborator]; Yung, WKA [Collaborator]; Zadeh, G [Collaborator]; Huse, JT [Collaborator]; De Groot, JF [Collaborator]; Stead, LF [Collaborator]; Verhaak, RGW [Collaborator]
The evolutionary processes that drive universal therapeutic resistance in adult patients
with diffuse glioma remain unclear(12). Here we analysed temporally separated DNA-sequencing
data and matched clinical annotation from 222 adult patients with glioma. By analysing
mutations and copy numbers across the three major subtypes of diffuse glioma, we found
that driver genes detected at the initial stage of disease were retained at recurrence,
where as there was little evidence of recurrence-specific gene alterations. Treatment
with alkylating agents resulted in a hypermutator phenotype at different rates across
the glioma subtypes, and hypermutation was not associated with differences in overall
survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was
characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and
further converged with acquired alterations in the cell cycle and poor outcomes. The
clonal architecture of each tumour remained similar overtime, but the presence of
subclonal selection was associated with decreased survival. Finally, there were no
differences in the levels of immunoediting between initial and recurrentgliomas. Collectively,
our results suggest that the strongest selective pressures occur during earlyglioma
development and that current therapies shape this evolution in a largely stochastic
manner.
