Combination of high-resolution magic angle spinning proton magnetic resonance spectroscopy and microscale genomics to type brain tumor biopsies.
Advancements in the diagnosis and prognosis of brain tumor patients, and thus in their survival and quality of life, can be achieved using biomarkers that facilitate improved tumor typing. We introduce and implement a combinatorial metabolic and molecular approach that applies state-of-the-art, high-resolution magic angle spinning (HRMAS) proton (1H) MRS and gene transcriptome profiling to intact brain tumor biopsies, to identify unique biomarker profiles of brain tumors. Our results show that samples as small as 2 mg can be successfully processed, the HRMAS 1H MRS procedure does not result in mRNA degradation, and minute mRNA amounts yield high-quality genomic data. The MRS and genomic analyses demonstrate that CNS tumors have altered levels of specific 1H MRS metabolites that directly correspond to altered expression of Kennedy pathway genes; and exhibit rapid phospholipid turnover, which coincides with upregulation of cell proliferation genes. The data also suggest Sonic Hedgehog pathway (SHH) dysregulation may play a role in anaplastic ganglioglioma pathogenesis. That a strong correlation is seen between the HRMAS 1H MRS and genomic data cross-validates and further demonstrates the biological relevance of the MRS results. Our combined metabolic/molecular MRS/genomic approach provides insights into the biology of anaplastic ganglioglioma and a new potential tumor typing methodology that could aid neurologists and neurosurgeons to improve the diagnosis, treatment, and ongoing evaluation of brain tumor patients.
Tzika
A Aria
AA
NMR Surgical Laboratory, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. atzika@hms.harvard.edu
Astrakas
Loukas
L
Cao
Haihui
H
Mintzopoulos
Dionyssios
D
Andronesi
Ovidiu C
OC
Mindrinos
Michael
M
Zhang
Jiangwen
J
Rahme
Laurence G
LG
Blekas
Konstantinos D
KD
Likas
Aristidis C
AC
Galatsanos
Nikolas P
NP
Carroll
Rona S
RS
Black
Peter M
PM
D000328:Adult; D001706:Biopsy; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D016000:Cluster Analysis; D005240:Feasibility Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D006801:Humans; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008875:Middle Aged; D008954:Models, Biological; D009367:Neoplasm Staging / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results