title: Clonal mutations in primary human glial tumors: evidence in support of the mutator hypothesis.
abstract: BACKGROUND
  A verifiable consequence of the mutator hypothesis is that even low grade neoplasms would accumulate a large number of mutations that do not influence the tumor phenotype (clonal mutations). In this study, we have attempted to quantify the number of clonal mutations in primary human gliomas of astrocytic cell origin. These alterations were identified in tumor tissue, microscopically confirmed to have over 70% neoplastic cells.
  
  
  METHODS
  Random Amplified Polymorphic DNA (RAPD) analysis was performed using a set of fifteen 10-mer primers of arbitrary but definite sequences in 17 WHO grade II astrocytomas (low grade diffuse astrocytoma or DA) and 16 WHO grade IV astrocytomas (Glioblastoma Multiforme or GBM). The RAPD profile of the tumor tissue was compared with that of the leucocyte DNA of the same patient and alteration(s) scored. A quantitative estimate of the overall genomic changes in these tumors was obtained by 2 different modes of calculation.
  
  
  RESULTS
  The overall change in the tumors was estimated to be 4.24% in DA and 2.29% in GBM by one method and 11.96% and 6.03% in DA and GBM respectively by the other. The difference between high and lower grade tumors was statistically significant by both methods.
  
  
  CONCLUSIONS
  This study demonstrates the presence of extensive clonal mutations in gliomas, more in lower grade. This is consistent with our earlier work demonstrating that technique like RAPD analysis, unbiased for locus, is able to demonstrate more intra-tumor genetic heterogeneity in lower grade gliomas compared to higher grade. The results support the mutator hypothesis proposed by Loeb.
authors.affiliation: Dept. of Biochemistry, All India Institute of Medical Sciences, New Delhi, India. anjan.misra@chw.edu
authors.forename: Anjan
authors.initials: A
authors.lastname: Misra
authors.forename: Parthaprasad
authors.initials: P
authors.lastname: Chattopadhyay
authors.forename: Kunzang
authors.initials: K
authors.lastname: Chosdol
authors.forename: Chitra
authors.initials: C
authors.lastname: Sarkar
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Mahapatra
authors.forename: Subrata
authors.initials: S
authors.lastname: Sinha
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D003627:Data Interpretation, Statistical; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008957:Models, Genetic; D008962:Models, Theoretical; D009154:Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D015203:Reproducibility of Results
chemical_list: D017931:DNA Primers; D004247:DNA