Designing and implementing quality control for multi-center screening of mutations in the ATM gene among women with breast cancer

Hum Mutat. 2003 May;21(5):542-50. doi: 10.1002/humu.10206.


Epidemiologic studies of breast and other cancers are increasingly turning toward large, multi-center designs in order to obtain adequate power to detect low-penetrance susceptibility alleles. The size of such studies often makes it necessary to distribute the genetic screening efforts to multiple sites. Careful standardization of screening methodology and quality control across sites is required for such multi-center screening designs to be efficient. In this report, we illustrate our approach to these challenges in the context of the WECARE (Women's Environment, Cancer and Radiation Epidemiology) Study, a multi-center population-based genetic epidemiologic study of women with unilateral and bilateral breast cancer. We provide optimized conditions for screening the ataxia-telangiectasia gene (ATM) for variation by denaturing high-performance liquid chromatography (DHPLC) and describe the results of two independent quality control studies at four international centers employing these conditions. Finally, we report novel mutations in the ATM gene identified both in patients with ataxia-telangiectasia and in patients with unilateral or bilateral breast cancer.

Publication types

  • Multicenter Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics*
  • Cell Cycle Proteins
  • Chromatography, High Pressure Liquid / methods
  • DNA / chemistry
  • DNA / genetics
  • DNA Mutational Analysis
  • DNA-Binding Proteins
  • Denmark / epidemiology
  • Female
  • Genetic Carrier Screening / methods
  • Genetic Testing / methods*
  • Genetic Testing / standards
  • Heterozygote
  • Humans
  • Mutation
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • Protein-Serine-Threonine Kinases / genetics*
  • Quality Control
  • Sensitivity and Specificity
  • Tumor Suppressor Proteins
  • United States / epidemiology


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • DNA
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases