The genetic landscape of the childhood cancer medulloblastoma.

in Science (New York, N.Y.) by D Williams Parsons, Meng Li, Xiaosong Zhang, Siân Jones, Rebecca J Leary, Jimmy Cheng-Ho Lin, Simina M Boca, Hannah Carter, Josue Samayoa, Chetan Bettegowda, Gary L Gallia, George I Jallo, Zev A Binder, Yuri Nikolsky, James Hartigan, Doug R Smith, Daniela S Gerhard, Daniel W Fults, Scott VandenBerg, Mitchel S Berger, Suely Kazue Nagahashi Marie, Sueli Mieko Oba Shinjo, Carlos Clara, Peter C Phillips, Jane E Minturn, Jaclyn A Biegel, Alexander R Judkins, Adam C Resnick, Phillip B Storm, Tom Curran, Yiping He, B Ahmed Rasheed, Henry S Friedman, Stephen T Keir, Roger McLendon, Paul A Northcott, Michael D Taylor, Peter C Burger, Gregory J Riggins, Rachel Karchin, Giovanni Parmigiani, Darell D Bigner, Hai Yan, Nick Papadopoulos, Bert Vogelstein, Kenneth W Kinzler, Victor E Velculescu

TLDR

  • The study looked at the genetic changes in a type of brain tumor called medulloblastoma (MB) in children. They used a special tool called a microarray to find out how many changes each tumor had and then used another tool called Sanger sequencing to look at the specific genes that were changed. They found that on average, each tumor had 11 changes, and they also found a specific type of change in some of the genes that could be important for understanding how tumors develop.

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

Overview

  • The study aimed to identify genetic alterations in medulloblastoma (MB), the most common malignant brain tumor of children, using high-density microarrays and Sanger sequencing in a set of 22 MBs. The hypothesis being tested was that the genetic landscape of MBs differs from that of adult solid tumors. The methodology used for the experiment included searching for copy number alterations using high-density microarrays and sequencing all known protein-coding genes and microRNA genes using Sanger sequencing. The primary objective of the study was to identify key differences between the genetic landscapes of adult and childhood cancers and to explore the role of developmental pathways in MBs.

Comparative Analysis & Findings

  • The study found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, the analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they highlight the importance of understanding the unique genetic landscape of childhood cancers. The identification of specific genetic alterations in MBs could lead to the development of targeted therapies for this tumor type. However, the study also has limitations, such as the small sample size and the need for further validation of the findings. Future research directions could include expanding the sample size, investigating the role of other developmental pathways in MBs, and exploring the potential of epigenetic therapies for this tumor type.
Read Full Article