Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients

Purpose: The dose intensity of radiotherapy (RT) used in cancer treatment i s limited in rare individuals who display severe normal tissue reactions af ter standard RT treatments. Novel predictive assays are required to identif y these individuals prior to treatment. The mechanisms responsible for such reactions are unknown, but may involve dysfunction of genes involved in th e sensing and response of cells to DNA damage. The breast cancer susceptibi lity genes BRCA1 and BRCA2 are implicated in DNA damage repair and the cont rol of genome stability, The purpose of this study was to determine if clin ical radiation hypersensitivity is related to mutations of the BRCA1 and BR CA2 genes. Such information is of potential use in the clinical management of BRCA mutation carriers and their families, Methods and Materials: Twenty-two cancer patients who developed severe norm al tissue reactions after RT were screened for mutations of BRCA1 and BRCA2 , using various methods including protein truncation testing, direct DNA se quencing, and a PCR-based BRCA1 exon 13 duplication test. Results: No mutations were detected in the 22 patients tested, despite scre ening for the majority of commonly described types of mutations of BRCA1 an d BRCA2. Conclusion: These early results suggest that genes other than BRCA1 and BRC A2 probably account for most cases of clinical radiation hypersensitivity, and that screening for mutations of BRCA1 and BRCA2 is unlikely to be usefu l in predicting response to radiotherapy. However, it has not been excluded that some BRCA1 or BRCA2 heterozygotes might experience unexpected RT toxi city; further BRCA mutation screening on radiation sensitive individuals is warranted, (C) 2000 Elsevier Science Inc.