Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2.
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.
Buchholz
Thomas A
TA
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. tbuchhol@notes.mdacc.tmc.edu
Wu
Xifeng
X
Hussain
Abu
A
Tucker
Susan L
SL
Mills
Gordon B
GB
Haffty
Bruce
B
Bergh
Sherry
S
Story
Michael
M
Geara
Fady B
FB
Brock
William A
WA
D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D002842:Chromatids / Q000528:radiation effects; D019457:Chromosome Breakage; D003114:Colony-Forming Units Assay; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D018095:Germ-Line Mutation / Q000235:genetics*; D006239:Haplotypes; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D010051:Ovarian Neoplasms / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics
D019313:BRCA1 Protein; D024682:BRCA2 Protein