International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Oncology ScandMolecular Genotyping of Medulloblastoma: A New Treatment Era By Stephanie A. Terezakis, MD, Senior Editor, Iris C. Gibbs, MD, Daphne A. Haas-Kogan, MD, Associate Editors Medulloblastoma is the most common malignant central nervous system tumor of childhood. The current classification schemes are based primarily on histopathology, with treatment dependent upon risk stratification incorporating clinical factors of age, extent of surgical resection, and metastatic disease. For children more than 3 years of age, the current mainstay of treatment involves maximal surgical resection followed by adjuvant craniospinal irradiation (CSI) and boost, in combination with concurrent and maintenance chemotherapy. Although the poor prognostic impact of additional histopathological factors, such as large-cell variant and diffuse anaplasia, have been recognized, the incorporation of molecular genetic features into treatment strategies has previously been elusive. With advances in molecular genetics, it has now been recognized that medulloblastoma comprises a heterogeneous group of tumors with distinct genomic signatures and associated prognostic implications (1-5). Four principal transcriptional subgroups of medulloblastoma are recognized, which include: Wnt, Shh (sonic hedgehog), Group 3, and Group 4 (6). The Wnt and Shh groups are associated with biomarkers of aberrant signaling pathways that drive tumor initiation, whereas Group 3 and Group 4 are more vaguely defined as the underlying genetic alterations driving clinical outcomes that are less well understood. The identification of underlying biology as a clinical driver provides tremendous opportunities for better therapeutic targeting (eg, Shh inhibitors) and allows re-stratification of prognostic groups beyond the clinical markers in use today.
Northcott et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011. (1) Summary: Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. Northcott et al studied a large cohort of medulloblastomas to evaluate and to characterize the distinct subtypes of medulloblastoma. They determined gene expression profiles and DNA copy number aberrations for 103 medulloblastomas, and identified subgroups using bioinformatics. With these techniques, they identified 4 distinct, non-overlapping molecular variants: Wnt, Shh, Group C, and Group D. Each subgroup was identified as having specific demographics, histology, metastatic status, and Int J Radiation Oncol Biol Phys, Vol. 89, No. 2, pp. 229e231, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.12.021
DNA copy number aberrations. In addition, these groupings were significant, with Group C patients (NPR3-positive tumors identified by immunohistochemistry) demonstrating diminished progression-free and overall survival regardless of metastatic disease status. Therefore, the subclassification of medulloblastomas into 1 of the 4 distinct subgroups has both potential therapeutic and prognostic implications, leading to a number of different avenues for new research and changing the paradigm of medulloblastoma management. Comment: The authors have used an integrative genomics approach to define prognostically significant molecular subgroups that may help to identify appropriate targeted therapies against each individual biologically distinct subtype. It is possible that these molecular variants in fact represent 4 distinct diseases, and, furthermore, investigation into larger cohorts of medulloblastoma patients will likely identify subclusters within each subgroup. The authors identified different genetic aberrations, demographics, risk of metastases, and clinical outcomes for both Group C and Group D tumors. The most apparent differences were related to the expression of MYC in Group C and Wnt tumors and the high expression of MYCN in Shh tumors. Group D tumors neither expressed MYC nor MYCN, demonstrating a distinct, non-overlapping genetic profile. In addition, only 1 of 294 medulloblastomas demonstrated staining for both Group C and D signature genes. Therefore 2 non-Shh/Wnt subgroups were identified with support from the data presented (Group C, childhood tumors with high MYC expression and frequent leptomeningeal metastases, and Group D). The identification of biological correlates sheds light on traditional prognostic factors such as sex and age. For example, the St. Jude Medulloblastomae96 study demonstrated that highrisk medulloblastoma was significantly more prevalent in males than in females (7). Similarly, females have been shown to have better outcomes than males (8). This may in fact be due to the higher prevalence of Wnt tumors in females, particularly as improved survival has been demonstrated in older female patients, the age group in which Wnt tumors are also most prevalent. Similarly, prior and ongoing studies treat infants as a group with relatively uniform treatment recommendations (9). This study suggests departure from this one-size-fits-all approach, separating infants according to histologic subgroup, treating
230
Oncology Scan
poor-prognosis Group C and Group D tumors, and betterprognosis desmoplastic (likely Shh) tumors with distinct regimens. Key to this study is the finding that immunohistochemistry can reliably assign medulloblastomas to subgroups, rendering subclassification widely available and clinically practical. The interplay between the clinical and histopathologic factors historically used for prognostication, and new information on genetic subtyping, will allow us to advance rational therapeutics to biologically individualize therapy.
Ellison et al. Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J Clin Oncol 2011. (2) Summary: This study validated independent prognostic biomarkers in a cohort of 207 non-infant medulloblastoma patients, ages 3 to 16 years, treated on the International Society of Pediatric Oncology CNS9102 (PNET3) trial. The authors used immunohistochemistry, fluorescent in situ hybridization (FISH), and direct sequencing to identify tumors with genetic aberrations in the Wnt pathway and tumors with copy number abnormalities (CNAs) of potential prognostic significance (MYC/MYCN amplification, CNAs of chromosomes 6 and 17). Molecular variables, including nuclear immunoreactivity for b-catenin, CTNNB1 mutation, and monosomy 6 were found to be favorable prognostic factors, whereas MYC amplification was associated with poor outcomes. Clinicopathologic variables including metastatic disease and large-cell/anaplastic (LC/A) phenotype were associated with poor progression-free survival. Taking into account these observations, the authors developed a clinical stratification model based on validated biomarkers and clinicopathologic factors, resulting in 3 prognostically distinct groups (eg, low-risk, standard-risk, and high-risk) that demonstrated statistically different progression-free survival (P
Radiation Oncology biology
physics
www.redjournal.org
Oncology ScandMolecular Genotyping of Medulloblastoma: A New Treatment Era By Stephanie A. Terezakis, MD, Senior Editor, Iris C. Gibbs, MD, Daphne A. Haas-Kogan, MD, Associate Editors Medulloblastoma is the most common malignant central nervous system tumor of childhood. The current classification schemes are based primarily on histopathology, with treatment dependent upon risk stratification incorporating clinical factors of age, extent of surgical resection, and metastatic disease. For children more than 3 years of age, the current mainstay of treatment involves maximal surgical resection followed by adjuvant craniospinal irradiation (CSI) and boost, in combination with concurrent and maintenance chemotherapy. Although the poor prognostic impact of additional histopathological factors, such as large-cell variant and diffuse anaplasia, have been recognized, the incorporation of molecular genetic features into treatment strategies has previously been elusive. With advances in molecular genetics, it has now been recognized that medulloblastoma comprises a heterogeneous group of tumors with distinct genomic signatures and associated prognostic implications (1-5). Four principal transcriptional subgroups of medulloblastoma are recognized, which include: Wnt, Shh (sonic hedgehog), Group 3, and Group 4 (6). The Wnt and Shh groups are associated with biomarkers of aberrant signaling pathways that drive tumor initiation, whereas Group 3 and Group 4 are more vaguely defined as the underlying genetic alterations driving clinical outcomes that are less well understood. The identification of underlying biology as a clinical driver provides tremendous opportunities for better therapeutic targeting (eg, Shh inhibitors) and allows re-stratification of prognostic groups beyond the clinical markers in use today.
Northcott et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011. (1) Summary: Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. Northcott et al studied a large cohort of medulloblastomas to evaluate and to characterize the distinct subtypes of medulloblastoma. They determined gene expression profiles and DNA copy number aberrations for 103 medulloblastomas, and identified subgroups using bioinformatics. With these techniques, they identified 4 distinct, non-overlapping molecular variants: Wnt, Shh, Group C, and Group D. Each subgroup was identified as having specific demographics, histology, metastatic status, and Int J Radiation Oncol Biol Phys, Vol. 89, No. 2, pp. 229e231, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.12.021
DNA copy number aberrations. In addition, these groupings were significant, with Group C patients (NPR3-positive tumors identified by immunohistochemistry) demonstrating diminished progression-free and overall survival regardless of metastatic disease status. Therefore, the subclassification of medulloblastomas into 1 of the 4 distinct subgroups has both potential therapeutic and prognostic implications, leading to a number of different avenues for new research and changing the paradigm of medulloblastoma management. Comment: The authors have used an integrative genomics approach to define prognostically significant molecular subgroups that may help to identify appropriate targeted therapies against each individual biologically distinct subtype. It is possible that these molecular variants in fact represent 4 distinct diseases, and, furthermore, investigation into larger cohorts of medulloblastoma patients will likely identify subclusters within each subgroup. The authors identified different genetic aberrations, demographics, risk of metastases, and clinical outcomes for both Group C and Group D tumors. The most apparent differences were related to the expression of MYC in Group C and Wnt tumors and the high expression of MYCN in Shh tumors. Group D tumors neither expressed MYC nor MYCN, demonstrating a distinct, non-overlapping genetic profile. In addition, only 1 of 294 medulloblastomas demonstrated staining for both Group C and D signature genes. Therefore 2 non-Shh/Wnt subgroups were identified with support from the data presented (Group C, childhood tumors with high MYC expression and frequent leptomeningeal metastases, and Group D). The identification of biological correlates sheds light on traditional prognostic factors such as sex and age. For example, the St. Jude Medulloblastomae96 study demonstrated that highrisk medulloblastoma was significantly more prevalent in males than in females (7). Similarly, females have been shown to have better outcomes than males (8). This may in fact be due to the higher prevalence of Wnt tumors in females, particularly as improved survival has been demonstrated in older female patients, the age group in which Wnt tumors are also most prevalent. Similarly, prior and ongoing studies treat infants as a group with relatively uniform treatment recommendations (9). This study suggests departure from this one-size-fits-all approach, separating infants according to histologic subgroup, treating
230
Oncology Scan
poor-prognosis Group C and Group D tumors, and betterprognosis desmoplastic (likely Shh) tumors with distinct regimens. Key to this study is the finding that immunohistochemistry can reliably assign medulloblastomas to subgroups, rendering subclassification widely available and clinically practical. The interplay between the clinical and histopathologic factors historically used for prognostication, and new information on genetic subtyping, will allow us to advance rational therapeutics to biologically individualize therapy.
Ellison et al. Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J Clin Oncol 2011. (2) Summary: This study validated independent prognostic biomarkers in a cohort of 207 non-infant medulloblastoma patients, ages 3 to 16 years, treated on the International Society of Pediatric Oncology CNS9102 (PNET3) trial. The authors used immunohistochemistry, fluorescent in situ hybridization (FISH), and direct sequencing to identify tumors with genetic aberrations in the Wnt pathway and tumors with copy number abnormalities (CNAs) of potential prognostic significance (MYC/MYCN amplification, CNAs of chromosomes 6 and 17). Molecular variables, including nuclear immunoreactivity for b-catenin, CTNNB1 mutation, and monosomy 6 were found to be favorable prognostic factors, whereas MYC amplification was associated with poor outcomes. Clinicopathologic variables including metastatic disease and large-cell/anaplastic (LC/A) phenotype were associated with poor progression-free survival. Taking into account these observations, the authors developed a clinical stratification model based on validated biomarkers and clinicopathologic factors, resulting in 3 prognostically distinct groups (eg, low-risk, standard-risk, and high-risk) that demonstrated statistically different progression-free survival (P
