High frequency in vivo loss of heterozygosity is primarily a consequence of mitotic recombination

Pawan K. Gupta, Amrik Sahota, Simeon Boyd, Steven Bye, Changshun Shao, J. Patrick O'Neill, Timothy C. Hunter, Richard J. Albertini, Peter J. Stambrook, Jay A. Tischfieid

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114 Scopus citations


We have used the adenine phosphoribosyltransferase gene (APRT; 16q24) to investigate the mechanisms of loss of heterozygosity (LOH) in normal human somatic cells in vivo. APRT-deficient (APRT(-/-), APRT(-/0) T lymphocytes from the peripheral blood of four obligate APRT heterozygotes (APRT(+/-) with characterized germ-line mutations were selected in medium containing 100 μM 2,6-diaminopurine. A total of 80 2,6-diaminopurine-resistant T-cell clones from 2 of the heterozygotes were analyzed for this study. The presence or absence of LOH of proximal linked microsatellite repeat markers was used to divide the clones into two groups: (a) those in which LOH was likely due to localized changes in APRT (e.g., point mutations); and (b) those with LOH at additional loci. A total of 61 clones (76%) exhibited LOH of linked microsatellite repeat markers at different locations of 16q, which extended from the smallest measured region (<5.5 cM) to the entire 16q arm. The remaining 19 clones (24%) had point mutations in APRT or other relatively minor alterations. Ten clones with LOH encompassing different regions of 16q were examined by conventional cytogenetics and by fluorescence in situ hybridization using an APRT cosmid probe. All clones exhibited a normal diploid karyotype, and nine exhibited two copies of APRT. The one clone that was hemizygous for APRT had the smallest observed region of LOH in clones from that individual. These results indicate that mitotic recombination to a much lesser extent, deletion may be the primary mechanisms for the relatively high frequency of in vivo LOH observed in normal human T cells. Because LOH leads to the expression of recessive tumor suppressor genes in many cancers, these data have significant implications for the role of LOH in the early stages of tumor development, especially in breast cancer.

Original languageEnglish (US)
Pages (from-to)1188-1193
Number of pages6
JournalCancer Research
Issue number6
StatePublished - 1997
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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