Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2

Thomas A. Buchholz, Xifeng Wu, Abu Hussain, Susan L. Tucker, Gordon B. Mills, Bruce Haffty, Sherry Bergh, Michael Story, Fady B. Geara, William A. Brock

Research output: Contribution to journalArticle

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Abstract

The BRCA1 and BRCA2 gene products are thought to play important roles in the processing of DNA damage. To assess whether heterozygous mutations in these genes are associated with cellular radiosensitivity, we performed an in vitro radiation clonogenic survival assay on dermal fibroblasts obtained from 8 sequence-proven BRCA heterozygotes (6 BRCA1, 2 BRCA2). These data were compared to results obtained from a previous set of 17 prospectively studied cancer patients who had a negligible risk for a BRCA mutation. In addition, results from radiation-induced chromatid break assay performed on lymphocytes obtained from 9 BRCA heterozygotes (8 BRCA1, 1 BRCA2) were compared to results from a control group of 18 women with no cancer history. Results from both assays suggested that cells containing a heterozygous mutation in BRCA1 or BRCA2 were more radiosensitive than controls. For the fibroblast studies, the mean surviving fraction at 2 Gy (SF2) for carriers was 0.279 vs. 0.348 for the control set (p = 0.007). For the lymphocyte studies, the mean number of chromatid breaks after 125 cGy of radiation was 0.79 breaks per cell for the carriers vs. 0.45 for the controls (p = 0.0005). There was no apparent difference in the radiosensitivity between cells with BRCA1 vs. BRCA2 mutations (p = 0.769), although the small sample size minimizes the certainty of this observation. These preliminary results are consistent with a relationship between a germline mutation in BRCA1 or BRCA2 and a hypersensitivity to radiation. This phenotype could possibly predispose to an increased risk of radiation-induced mutagenesis and carcinogenesis.

Original languageEnglish (US)
Pages (from-to)557-561
Number of pages5
JournalInternational Journal of Cancer
Volume97
Issue number5
DOIs
StatePublished - Feb 10 2002
Externally publishedYes

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Germ-Line Mutation
Haplotypes
Radiation
Mutation
Chromatids
Radiation Tolerance
Heterozygote
BRCA2 Protein
Fibroblasts
BRCA1 Protein
Lymphocytes
Mutagenesis
Sample Size
DNA Damage
Neoplasms
Hypersensitivity
Carcinogenesis
Phenotype
Control Groups
Skin

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Buchholz, Thomas A. ; Wu, Xifeng ; Hussain, Abu ; Tucker, Susan L. ; Mills, Gordon B. ; Haffty, Bruce ; Bergh, Sherry ; Story, Michael ; Geara, Fady B. ; Brock, William A. / Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2. In: International Journal of Cancer. 2002 ; Vol. 97, No. 5. pp. 557-561.
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Buchholz, TA, Wu, X, Hussain, A, Tucker, SL, Mills, GB, Haffty, B, Bergh, S, Story, M, Geara, FB & Brock, WA 2002, 'Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2', International Journal of Cancer, vol. 97, no. 5, pp. 557-561. https://doi.org/10.1002/ijc.10109

Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2. / Buchholz, Thomas A.; Wu, Xifeng; Hussain, Abu; Tucker, Susan L.; Mills, Gordon B.; Haffty, Bruce; Bergh, Sherry; Story, Michael; Geara, Fady B.; Brock, William A.

In: International Journal of Cancer, Vol. 97, No. 5, 10.02.2002, p. 557-561.

Research output: Contribution to journalArticle

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AU - Wu, Xifeng

AU - Hussain, Abu

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AU - Mills, Gordon B.

AU - Haffty, Bruce

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AU - Story, Michael

AU - Geara, Fady B.

AU - Brock, William A.

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