Making Sense of Intratumor Genetic Heterogeneity: Altered Frequency of Androgen Receptor CAG Repeat Length Variants in Breast Cancer Tissues

Authors

  • Bruce Gottlieb,

    Corresponding author
    1. Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada
    2. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    • Lady Davis Institute for Medical Research, Montreal, Quebec, Canada
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  • Carlos Alvarado,

    1. Lady Davis Institute for Medical Research, Montreal, Quebec, Canada
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  • Chunlin Wang,

    1. Stanford Genome Technology Center, Stanford University, Palo Alto, California
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  • Baback Gharizadeh,

    1. Stanford Genome Technology Center, Stanford University, Palo Alto, California
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  • Farbod Babrzadeh,

    1. Stanford Genome Technology Center, Stanford University, Palo Alto, California
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  • Brent Richards,

    1. Lady Davis Institute for Medical Research, Montreal, Quebec, Canada
    2. Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada
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  • Gerald Batist,

    1. Lady Davis Institute for Medical Research, Montreal, Quebec, Canada
    2. Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada
    3. Department of Medicine, McGill University, Montreal, Quebec, Canada
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  • Mark Basik,

    1. Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada
    2. Department of Medicine, McGill University, Montreal, Quebec, Canada
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  • Lenore K. Beitel,

    1. Lady Davis Institute for Medical Research, Montreal, Quebec, Canada
    2. Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada
    3. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    4. Department of Medicine, McGill University, Montreal, Quebec, Canada
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  • Mark Trifiro

    1. Lady Davis Institute for Medical Research, Montreal, Quebec, Canada
    2. Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada
    3. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    4. Department of Medicine, McGill University, Montreal, Quebec, Canada
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  • Additional Supporting Information may be found in the online version of this article.

  • Communicated by Stephen J. Chanock

  • Contract grant sponsor: The Weekend to End Breast Cancer Fund of the Segal Cancer Centre of the Jewish General Hospital.

Correspondence to: Bruce Gottlieb, Lady Davis Institute for Medical Research, 3755 Côte Ste Catherine Road, Montreal, Quebec, Canada, H3T 1E2. E-mail: bruce.gottlieb@mcgill.ca

ABSTRACT

To examine the significance of intratumor genetic heterogeneity (ITGH) of the androgen receptor (AR) gene in breast cancer, patient-matched samples of laser capture microdissected breast tumor cells, adjacent normal breast epithelia cells, and peripheral blood leukocytes were sequenced using a novel next generation sequencing protocol. This protocol measured the frequency of distribution of a variable AR CAG repeat length, a functional polymorphism associated with breast cancer risk. All samples exhibited some degree of ITGH with up to 30 CAG repeat length variants identified. Each type of tissue exhibited a different distribution profile of CAG repeat lengths with substantial differences in the frequencies of zero and 18–25 CAG AR variants. Tissue differences in the frequency of ARs with each of these CAG repeat lengths were significant as measured by paired, twin t-tests. These results suggest that preferential selection of 18–25 CAG repeat length variants in breast tumors may be associated with breast cancer, and support the observation that shorter CAG repeats may protect against breast cancer. They also suggest that merely identifying variant genes will be insufficient to determine the critical mutational events of oncogenesis, which will require measuring the frequency of distribution of mutations within cancerous and matching normal tissues.

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