Ex Vivo Chromosomal Radiosensitivity Testing in Patients with Pathological Germline Variants in Breast Cancer High-Susceptibility Genes and .

Background: Individual radiosensitivity is an important factor in the occurrence of undesirable consequences of radiotherapy. The potential for increased radiosensitivity has been linked to highly penetrant heterozygous mutations in DNA repair genes such as and . By studying the chromosomal radiosensitivity of mutation carriers compared to the general population, we study whether increased chromosomal radiation sensitivity is observed in patients with variants.

Methods: Three-color-fluorescence in situ hybridization was performed on ex vivo-irradiated peripheral blood lymphocytes from 64 female patients with a heterozygous germline or mutation. Aberrations in chromosomes #1, #2 and #4 were analyzed. Mean breaks per metaphase (B/M) served as the parameter for chromosomal radiosensitivity. The results were compared with chromosomal radiosensitivity in a cohort of generally healthy individuals and patients with rectal cancer or breast cancer.

Results: Patients with mutations ( = 64; B/M 0.47) overall showed a significantly higher chromosomal radiosensitivity than general healthy individuals ( = 211; B/M 0.41) and patients with rectal cancer ( = 379; B/M 0.44) and breast cancer ( = 147; B/M 0.45) without proven germline mutations. Chromosomal radiosensitivity varied depending on the locus of the mutation.

Conclusions: mutations result in slightly increased chromosomal sensitivity to radiation. A few individual patients have a marked increase in radiation sensitivity. Therefore, these patients are at a higher risk for adverse therapeutic consequences.