- Email: [email protected]
The Evolving Genomic Landscape of Recurrent Gliomas
World Neurosurgery News
Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH: NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 48: 2192-2202, 2012.
20. Sonnenschein C, Soto AM: The Society of Cells: Cancer and Control of Cell Proliferation. New York, NY: Springer Verlag; 1999. 21. Sonnenschein C, Soto AM: Somatic mutation theory of carcinogenesis: why it should be dropped and replaced. Mol Carcinog 29:205-211, 2000. 22. Soto AM, Sonnenschein C: Emergentism as a default: cancer as a problem of tissue organization. J Biosci 30:103-118, 2005. 23. Soto AM, Sonnenschein C: The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. Bioessays 33: 332-340, 2011.
26. Vaux DL: In defense of the somatic mutation theory of cancer. Bioessays 33:341-343, 2012.
24. Soto AM, Sonnenschein C: Paradoxes in carcinogenesis: there is light at the end of that tunnel! Disrupt Sci Technol 1:154-156, 2013.
27. Villano JL, Williams LE, Watson KS, Ignatius N, Wilson MT, Valyi-Nagy T, Michals EA, Engelhard HH: Delayed response and survival from NovoTTF-100A in recurrent GBM. Med Oncol 30:338, 2013.
25. Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbalý V, Ram Z, Villano JL,
28. Wang, R: The Blind Man and the Elephant. Available at: http://www.cs.princeton.edu/wrywang/ berkeley/258/parable.html. Accessed April 4, 2014.
29. Wick W, Weller M, van den Bent M, Sanson M, Weiler M, von Deimling A, Plass C, Hegi M, Platten M, Reifenberger G: MGMT testing-the challenges for biomarker-based glioma treatment. Nat Rev Neurol 10:372-385, 2014. 30. Wong ET, Lok E, Swanson KD, Gautam S, Engelhard HH, Lieberman F, Taillibert S, Ram Z, Villano JL: Response assessment of NovoTTF100A versus best physician’s choice chemotherapy in recurrent glioblastoma. Cancer Med 3: 592-602, 2014.
Department of Neurosurgery, Invision Health/Brain & Spine Center, Buffalo, New York, USA 1878-8750/$ - see front matter ª 2015 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.wneu.2015.03.003
The Evolving Genomic Landscape of Recurrent Gliomas Leonel Ampie1, Yael Kusne2, Nader Sanai3
Despite diagnostic and therapeutic advancements within the field of neurosurgical oncology, the recurrence of high-grade glioma is relatively common and results in a poor prognosis. A subset of glioma cells manage to evade surgery, radiation, and chemotherapy, leading to recurrent lesions and aggressive disease. In a study published in Science earlier this year, investigators from University of California, San Francisco, along with collaborating institutions, investigated the genomic landscape alterations between initial gliomas and their recurrence (1). The exomes of 23 World Health Organization grade II gliomas were sequenced at initial diagnosis and on recurrence (up to 11 years later); 33 somatic coding mutations were detected in the initial tumor, and an average of 54% of these mutations also were found in recurring lesions. These mutations were classified as shared because of their constancy and most were in IDH1, TP53, and ATRX genes. Conversely, private mutations, which were identified either at initial examination or in recurrence but were not constant, were presumed to have occurred at a later stage of glioma evolution. Initial and recurrent tumors displayed varying levels of genetic similarity, ranging from 75% mutation similarity to 25%. Recurrent tumors with 75% mutation similarity were described as displaying a pattern of linear clonal evolution, whereas those with 25% were classified as demonstrating a branched clonal evolution (Figure 1). The mutation that was observed and shared in all tumors was allocated within the IDH1 gene, which has been well established to be the initial genetic aberration detected in low-grade gliomagenesis. Because the IDH1 mutation was noted in all initial and recurrent tumors, this finding further strengthened the proposal
722
www.SCIENCEDIRECT.com
that recurrent lesions emerged from an earlier stage in the evolutionary pathway. Recurrent tumors also were more likely to harbor mutations in genes that conferred a proliferative advantage, such as in genes TP53 and ATRX. Initial and recurrent lesions shared somatic noncoding mutations, which implies a shared distant relationship and makes
Figure 1. Linear (left) versus branched clonal (right) evolution.
83 [5]: 715-723, MAY 2015 WORLD NEUROSURGERY
World Neurosurgery News
independent origins unlikely. To exclude for the confounding factor of intratumoral heterogeneity, investigators sampled distinct regions of glioma specimens. Exome sequencing of these regions demonstrated that intratumoral heterogeneity was not significant enough to provide a plausible explanation between the genetic variance of initial and recurrent gliomas. The authors also investigated the effect of temozolomide (TMZ; an alkylating agent used in glioma therapy) in the genetic landscape of recurrent gliomas because of its mutagenic effect. There is a current lack of conclusive clinical data associating TMZ therapy with an increase in overall patient survival for low-grade gliomas (3). A hypermutated state was noted in recurrent tumors that were exposed to TMZ; most recurrent tumors in the cohort had 0.2 4.5 mutations per megabase, whereas those exposed to TMZ had 31.9 90.9 mutations per megabase. The vast majority of mutations detected were C/T/G/A transitions occurring primarily at CpC and CpT dinucleotides; this is a signature of TMZ-induced mutagenesis. The proposed mechanism of the acquisition of resistance to TMZ is attributable to mutations in genes that govern the mismatch repair (MMR) pathway. Mutations that target these genes lead to the production of aberrant proteins that make the MMR pathway dysfunctional. MMR-associated gene mutations were not detected in initial glioma tumors. In addition, this hypermutated state that is induced by the mutational pressure
REFERENCES 1. Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, Fouse SD, Yamamoto S, Ueda H, Tatsuno K, Asthana S, Jalbert LE, Nelson SJ, Bollen AW, Gustafson WC, Charron E, Weiss WA, Smirnov IV, Song JS, Olshen AB, Cha S, Zhao Y, Moore RA, Mungall AJ, Jones SJ, Hirst M, Marra MA, Saito N, Aburatani H, Mukasa A, Berger MS, Chang SM, Taylor BS, Costello JF: Mutational
offered by TMZ may be a driver for further dedifferentiation of the glioma into a higher-grade tumor. Other genes afflicted by TMZ include those that play a role in retinoblastoma (RB)- and Akt-mammalian target of rapamycin (mTOR) signaling pathways. For instance, TMZ therapy was associated with a splice-site mutation that has been associated with germline mutations in patients with hereditary retinoblastoma. One mutation identified in the Akt-mTOR signaling pathway was a gain of function mutation, which may lead to the hyperactivation of Akt and the induction of mTORdependent oncogenic transformation (2). There was no evidence identified to show that the mutations acquired in the RB and Akt-mTOR signaling pathways occurred before TMZ therapy. In the cohort of glioblastomas that progressed from nonhypermutated gliomas, genetic aberrations were acquired in RB and Akt-mTOR pathways via different mechanisms. These data clearly illustrate the direct effect of TMZ on induction of driver mutations in oncogenic signaling that may ultimately lead to the progression to higher-grade glioma. The investigators suggest future studies that attempt to weigh the initial antineoplastic effect of this chemotherapeutic alkylating agent versus the potential induction of driver mutations that may lead to malignant progression.
analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343:189-193, 2014. 2. Kang S, Bader AG, Vogt PK: Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci U S A 102:802-807, 2005. 3. Sanai N, Chang S, Berger MS: Low-grade gliomas in adults. J Neurosurg 115:948-965, 2011.
From the 1Georgetown University School of Medicine, Washington, DC, USA; 2University of Arizona School of Medicine, Tucson, Arizona, USA; and 3Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA 1878-8750/$ - see front matter ª 2015 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.wneu.2015.03.004
Call for Neurosurgery and the Arts World Neurosurgery is changing the cover art and filler art motif. This motif involves the display of art by neurosurgeons. Hence, we are seeking art, in any visual form, for this endeavor on an ongoing basis. Such art might naturally include photography, photographs of sculptures or paintings, prose or poetry, etc. We ask Neurosurgeons to submit high resolution images of such art. These images will be considered for future World Neurosurgery journal covers and for filler art. When submitting your images, please include a brief description. These can be submitted directly to [email protected].
WORLD NEUROSURGERY 83 [5]: 715-723, MAY 2015
www.WORLDNEUROSURGERY.org
723
Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH: NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 48: 2192-2202, 2012.
20. Sonnenschein C, Soto AM: The Society of Cells: Cancer and Control of Cell Proliferation. New York, NY: Springer Verlag; 1999. 21. Sonnenschein C, Soto AM: Somatic mutation theory of carcinogenesis: why it should be dropped and replaced. Mol Carcinog 29:205-211, 2000. 22. Soto AM, Sonnenschein C: Emergentism as a default: cancer as a problem of tissue organization. J Biosci 30:103-118, 2005. 23. Soto AM, Sonnenschein C: The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. Bioessays 33: 332-340, 2011.
26. Vaux DL: In defense of the somatic mutation theory of cancer. Bioessays 33:341-343, 2012.
24. Soto AM, Sonnenschein C: Paradoxes in carcinogenesis: there is light at the end of that tunnel! Disrupt Sci Technol 1:154-156, 2013.
27. Villano JL, Williams LE, Watson KS, Ignatius N, Wilson MT, Valyi-Nagy T, Michals EA, Engelhard HH: Delayed response and survival from NovoTTF-100A in recurrent GBM. Med Oncol 30:338, 2013.
25. Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbalý V, Ram Z, Villano JL,
28. Wang, R: The Blind Man and the Elephant. Available at: http://www.cs.princeton.edu/wrywang/ berkeley/258/parable.html. Accessed April 4, 2014.
29. Wick W, Weller M, van den Bent M, Sanson M, Weiler M, von Deimling A, Plass C, Hegi M, Platten M, Reifenberger G: MGMT testing-the challenges for biomarker-based glioma treatment. Nat Rev Neurol 10:372-385, 2014. 30. Wong ET, Lok E, Swanson KD, Gautam S, Engelhard HH, Lieberman F, Taillibert S, Ram Z, Villano JL: Response assessment of NovoTTF100A versus best physician’s choice chemotherapy in recurrent glioblastoma. Cancer Med 3: 592-602, 2014.
Department of Neurosurgery, Invision Health/Brain & Spine Center, Buffalo, New York, USA 1878-8750/$ - see front matter ª 2015 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.wneu.2015.03.003
The Evolving Genomic Landscape of Recurrent Gliomas Leonel Ampie1, Yael Kusne2, Nader Sanai3
Despite diagnostic and therapeutic advancements within the field of neurosurgical oncology, the recurrence of high-grade glioma is relatively common and results in a poor prognosis. A subset of glioma cells manage to evade surgery, radiation, and chemotherapy, leading to recurrent lesions and aggressive disease. In a study published in Science earlier this year, investigators from University of California, San Francisco, along with collaborating institutions, investigated the genomic landscape alterations between initial gliomas and their recurrence (1). The exomes of 23 World Health Organization grade II gliomas were sequenced at initial diagnosis and on recurrence (up to 11 years later); 33 somatic coding mutations were detected in the initial tumor, and an average of 54% of these mutations also were found in recurring lesions. These mutations were classified as shared because of their constancy and most were in IDH1, TP53, and ATRX genes. Conversely, private mutations, which were identified either at initial examination or in recurrence but were not constant, were presumed to have occurred at a later stage of glioma evolution. Initial and recurrent tumors displayed varying levels of genetic similarity, ranging from 75% mutation similarity to 25%. Recurrent tumors with 75% mutation similarity were described as displaying a pattern of linear clonal evolution, whereas those with 25% were classified as demonstrating a branched clonal evolution (Figure 1). The mutation that was observed and shared in all tumors was allocated within the IDH1 gene, which has been well established to be the initial genetic aberration detected in low-grade gliomagenesis. Because the IDH1 mutation was noted in all initial and recurrent tumors, this finding further strengthened the proposal
722
www.SCIENCEDIRECT.com
that recurrent lesions emerged from an earlier stage in the evolutionary pathway. Recurrent tumors also were more likely to harbor mutations in genes that conferred a proliferative advantage, such as in genes TP53 and ATRX. Initial and recurrent lesions shared somatic noncoding mutations, which implies a shared distant relationship and makes
Figure 1. Linear (left) versus branched clonal (right) evolution.
83 [5]: 715-723, MAY 2015 WORLD NEUROSURGERY
World Neurosurgery News
independent origins unlikely. To exclude for the confounding factor of intratumoral heterogeneity, investigators sampled distinct regions of glioma specimens. Exome sequencing of these regions demonstrated that intratumoral heterogeneity was not significant enough to provide a plausible explanation between the genetic variance of initial and recurrent gliomas. The authors also investigated the effect of temozolomide (TMZ; an alkylating agent used in glioma therapy) in the genetic landscape of recurrent gliomas because of its mutagenic effect. There is a current lack of conclusive clinical data associating TMZ therapy with an increase in overall patient survival for low-grade gliomas (3). A hypermutated state was noted in recurrent tumors that were exposed to TMZ; most recurrent tumors in the cohort had 0.2 4.5 mutations per megabase, whereas those exposed to TMZ had 31.9 90.9 mutations per megabase. The vast majority of mutations detected were C/T/G/A transitions occurring primarily at CpC and CpT dinucleotides; this is a signature of TMZ-induced mutagenesis. The proposed mechanism of the acquisition of resistance to TMZ is attributable to mutations in genes that govern the mismatch repair (MMR) pathway. Mutations that target these genes lead to the production of aberrant proteins that make the MMR pathway dysfunctional. MMR-associated gene mutations were not detected in initial glioma tumors. In addition, this hypermutated state that is induced by the mutational pressure
REFERENCES 1. Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, Fouse SD, Yamamoto S, Ueda H, Tatsuno K, Asthana S, Jalbert LE, Nelson SJ, Bollen AW, Gustafson WC, Charron E, Weiss WA, Smirnov IV, Song JS, Olshen AB, Cha S, Zhao Y, Moore RA, Mungall AJ, Jones SJ, Hirst M, Marra MA, Saito N, Aburatani H, Mukasa A, Berger MS, Chang SM, Taylor BS, Costello JF: Mutational
offered by TMZ may be a driver for further dedifferentiation of the glioma into a higher-grade tumor. Other genes afflicted by TMZ include those that play a role in retinoblastoma (RB)- and Akt-mammalian target of rapamycin (mTOR) signaling pathways. For instance, TMZ therapy was associated with a splice-site mutation that has been associated with germline mutations in patients with hereditary retinoblastoma. One mutation identified in the Akt-mTOR signaling pathway was a gain of function mutation, which may lead to the hyperactivation of Akt and the induction of mTORdependent oncogenic transformation (2). There was no evidence identified to show that the mutations acquired in the RB and Akt-mTOR signaling pathways occurred before TMZ therapy. In the cohort of glioblastomas that progressed from nonhypermutated gliomas, genetic aberrations were acquired in RB and Akt-mTOR pathways via different mechanisms. These data clearly illustrate the direct effect of TMZ on induction of driver mutations in oncogenic signaling that may ultimately lead to the progression to higher-grade glioma. The investigators suggest future studies that attempt to weigh the initial antineoplastic effect of this chemotherapeutic alkylating agent versus the potential induction of driver mutations that may lead to malignant progression.
analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343:189-193, 2014. 2. Kang S, Bader AG, Vogt PK: Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci U S A 102:802-807, 2005. 3. Sanai N, Chang S, Berger MS: Low-grade gliomas in adults. J Neurosurg 115:948-965, 2011.
From the 1Georgetown University School of Medicine, Washington, DC, USA; 2University of Arizona School of Medicine, Tucson, Arizona, USA; and 3Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA 1878-8750/$ - see front matter ª 2015 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.wneu.2015.03.004
Call for Neurosurgery and the Arts World Neurosurgery is changing the cover art and filler art motif. This motif involves the display of art by neurosurgeons. Hence, we are seeking art, in any visual form, for this endeavor on an ongoing basis. Such art might naturally include photography, photographs of sculptures or paintings, prose or poetry, etc. We ask Neurosurgeons to submit high resolution images of such art. These images will be considered for future World Neurosurgery journal covers and for filler art. When submitting your images, please include a brief description. These can be submitted directly to [email protected].
WORLD NEUROSURGERY 83 [5]: 715-723, MAY 2015
www.WORLDNEUROSURGERY.org
723