Longitudinal molecular trajectories of diffuse glioma in adults

Longitudinal molecular trajectories of diffuse glioma in adults. Barthel, F. P, Johnson, K. C, Varn, F. S, Moskalik, A. D, Tanner, G., Kocakavuk, E., Anderson, K. J, Abiola, O., Aldape, K., Alfaro, K. D, Alpar, D., Amin, S. B, Ashley, D. M, Bandopadhayay, P., Barnholtz-Sloan, J. S, Beroukhim, R., Bock, C., Brastianos, P. K, Brat, D. J, Brodbelt, A. R, Bruns, A. F, Bulsara, K. R, Chakrabarty, A., Chakravarti, A., Chuang, J. H, Claus, E. B, Cochran, E. J, Connelly, J., Costello, J. F, Finocchiaro, G., Fletcher, M. N, French, P. J, Gan, H. K, Gilbert, M. R, Gould, P. V, Grimmer, M. R, Iavarone, A., Ismail, A., Jenkinson, M. D, Khasraw, M., Kim, H., Kouwenhoven, M. C M, LaViolette, P. S, Li, M., Lichter, P., Ligon, K. L, Lowman, A. K, Malta, T. M, Mazor, T., McDonald, K. L, Molinaro, A. M, Nam, D., Nayyar, N., Ng, H. K., Ngan, C. Y., Niclou, S. P, Niers, J. M, Noushmehr, H., Noorbakhsh, J., Ormond, D R., Park, C., Poisson, L. M, Rabadan, R., Radlwimmer, B., Rao, G., Reifenberger, G., Sa, J. K, Schuster, M., Shaw, B. L, Short, S. C, Smitt, P. A S., Sloan, A. E, Smits, M., Suzuki, H., Tabatabai, G., Van Meir, E. G, Watts, C., Weller, M., Wesseling, P., Westerman, B. A, Widhalm, G., Woehrer, A., Yung, W K A., Zadeh, G., Huse, J. T, De Groot, J. F, Stead, L. F, Verhaak, R. G W, Barthel, F. P, Johnson, K. C, Varn, F. S, Moskalik, A. D, Tanner, G., Kocakavuk, E., Anderson, K. J, Aldape, K., Alfaro, K. D, Amin, S. B, Ashley, D. M, Bandopadhayay, P., Barnholtz-Sloan, J. S, Beroukhim, R., Bock, C., Brastianos, P. K, Brat, D. J, Brodbelt, A. R, Bulsara, K. R, Chakrabarty, A., Chuang, J. H, Claus, E. B, Cochran, E. J, Connelly, J., Costello, J. F, Finocchiaro, G., Fletcher, M. N, French, P. J, Gan, H. K, Gilbert, M. R, Gould, P. V, Iavarone, A., Ismail, A., Jenkinson, M. D, Khasraw, M., Kim, H., Kouwenhoven, M. C M, LaViolette, P. S, Lichter, P., Ligon, K. L, Lowman, A. K, Malta, T. M, McDonald, K. L, Molinaro, A. M, Nam, D., Ng, H. K., Niclou, S. P, Niers, J. M, Noushmehr, H., Ormond, D R., Park, C., Poisson, L. M, Rabadan, R., Radlwimmer, B., Rao, G., Reifenberger, G., Sa, J. K, Short, S. C, Smitt, P. A S., Sloan, A. E, Smits, M., Suzuki, H., Tabatabai, G., Van Meir, E. G, Watts, C., Weller, M., Wesseling, P., Westerman, B. A, Woehrer, A., Yung, W K A., Zadeh, G., Huse, J. T, De Groot, J. F, Stead, L. F, Verhaak, R. G W, & The GLASS Consortium Nature, November, 2019.

Paper doi abstract bibtex 1 download

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. 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, whereas 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 over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

@ARTICLE{Barthel2019-kv,
  title    = "Longitudinal molecular trajectories of diffuse glioma in adults",
  author   = "Barthel, Floris P and Johnson, Kevin C and Varn, Frederick S and
              Moskalik, Anzhela D and Tanner, Georgette and Kocakavuk, Emre and
              Anderson, Kevin J and Abiola, Olajide and Aldape, Kenneth and
              Alfaro, Kristin D and Alpar, Donat and Amin, Samirkumar B and
              Ashley, David M and Bandopadhayay, Pratiti and Barnholtz-Sloan,
              Jill S and Beroukhim, Rameen and Bock, Christoph and Brastianos,
              Priscilla K and Brat, Daniel J and Brodbelt, Andrew R and Bruns,
              Alexander F and Bulsara, Ketan R and Chakrabarty, Aruna and
              Chakravarti, Arnab and Chuang, Jeffrey H and Claus, Elizabeth B
              and Cochran, Elizabeth J and Connelly, Jennifer and Costello,
              Joseph F and Finocchiaro, Gaetano and Fletcher, Michael N and
              French, Pim J and Gan, Hui K and Gilbert, Mark R and Gould, Peter
              V and Grimmer, Matthew R and Iavarone, Antonio and Ismail, Azzam
              and Jenkinson, Michael D and Khasraw, Mustafa and Kim, Hoon and
              Kouwenhoven, Mathilde C M and LaViolette, Peter S and Li, Meihong
              and Lichter, Peter and Ligon, Keith L and Lowman, Allison K and
              Malta, Tathiane M and Mazor, Tali and McDonald, Kerrie L and
              Molinaro, Annette M and Nam, Do-Hyun and Nayyar, Naema and Ng, Ho
              Keung and Ngan, Chew Yee and Niclou, Simone P and Niers, Johanna
              M and Noushmehr, Houtan and Noorbakhsh, Javad and Ormond, D Ryan
              and Park, Chul-Kee and Poisson, Laila M and Rabadan, Raul and
              Radlwimmer, Bernhard and Rao, Ganesh and Reifenberger, Guido and
              Sa, Jason K and Schuster, Michael and Shaw, Brian L and Short,
              Susan C and Smitt, Peter A Sillevis and Sloan, Andrew E and
              Smits, Marion and Suzuki, Hiromichi and Tabatabai, Ghazaleh and
              Van Meir, Erwin G and Watts, Colin and Weller, Michael and
              Wesseling, Pieter and Westerman, Bart A and Widhalm, Georg and
              Woehrer, Adelheid and Yung, W K Alfred and Zadeh, Gelareh and
              Huse, Jason T and De Groot, John F and Stead, Lucy F and Verhaak,
              Roel G W and Barthel, Floris P and Johnson, Kevin C and Varn,
              Frederick S and Moskalik, Anzhela D and Tanner, Georgette and
              Kocakavuk, Emre and Anderson, Kevin J and Aldape, Kenneth and
              Alfaro, Kristin D and Amin, Samirkumar B and Ashley, David M and
              Bandopadhayay, Pratiti and Barnholtz-Sloan, Jill S and Beroukhim,
              Rameen and Bock, Christoph and Brastianos, Priscilla K and Brat,
              Daniel J and Brodbelt, Andrew R and Bulsara, Ketan R and
              Chakrabarty, Aruna and Chuang, Jeffrey H and Claus, Elizabeth B
              and Cochran, Elizabeth J and Connelly, Jennifer and Costello,
              Joseph F and Finocchiaro, Gaetano and Fletcher, Michael N and
              French, Pim J and Gan, Hui K and Gilbert, Mark R and Gould, Peter
              V and Iavarone, Antonio and Ismail, Azzam and Jenkinson, Michael
              D and Khasraw, Mustafa and Kim, Hoon and Kouwenhoven, Mathilde C
              M and LaViolette, Peter S and Lichter, Peter and Ligon, Keith L
              and Lowman, Allison K and Malta, Tathiane M and McDonald, Kerrie
              L and Molinaro, Annette M and Nam, Do-Hyun and Ng, Ho Keung and
              Niclou, Simone P and Niers, Johanna M and Noushmehr, Houtan and
              Ormond, D Ryan and Park, Chul-Kee and Poisson, Laila M and
              Rabadan, Raul and Radlwimmer, Bernhard and Rao, Ganesh and
              Reifenberger, Guido and Sa, Jason K and Short, Susan C and Smitt,
              Peter A Sillevis and Sloan, Andrew E and Smits, Marion and
              Suzuki, Hiromichi and Tabatabai, Ghazaleh and Van Meir, Erwin G
              and Watts, Colin and Weller, Michael and Wesseling, Pieter and
              Westerman, Bart A and Woehrer, Adelheid and Yung, W K Alfred and
              Zadeh, Gelareh and Huse, Jason T and De Groot, John F and Stead,
              Lucy F and Verhaak, Roel G W and {The GLASS Consortium}",
  abstract = "The evolutionary processes that drive universal therapeutic
              resistance in adult patients with diffuse glioma remain
              unclear1,2. 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, whereas 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 over time, but the presence of subclonal
              selection was associated with decreased survival. Finally, there
              were no differences in the levels of immunoediting between
              initial and recurrent gliomas. Collectively, our results suggest
              that the strongest selective pressures occur during early glioma
              development and that current therapies shape this evolution in a
              largely stochastic manner.",
  journal  = "Nature",
  month    =  nov,
  year     =  2019,
  url      = "https://doi.org/10.1038/s41586-019-1775-1",
  issn     = "0028-0836, 1476-4687",
  doi      = "10.1038/s41586-019-1775-1",
  pmid     = "31748746",
  authorclass = {coauthor},
  contribution = {data\_analysis},
  affiliation = {JAX}
}

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