Erratum to non-homologous end-joining protein expression screen from radiosensitive cancer patients yields a novel DNA double strand break repair phenotype.

[This corrects the article DOI: 10.21037/atm.2017.03.04.].

A radiation-induced and radiation-sensitive, delayed onset angiosarcoma arising in a precursor lymphangioendothelioma.

An 83-year-old female was treated with mastectomy and postoperative radiotherapy for breast cancer 30 years prior to developing a new small patch of thickening and scaliness on her left upper back, within the previous radiotherapy field. Serial excision biopsies revealed this to be a lymphangioendothelioma with no suggestion of malignancy. In early 2006 the lesion began to enlarge and take on a more erythematous plaque-like appearance. She was reviewed by a specialist dermatologist and an excision biopsy revealed a low-grade cutaneous angiosarcoma; this was approximately 38 years after radiotherapy to this region, the longest reported period between irradiation and in-field angiosarcoma development (the previous being 16 years). To our knowledge, this is the first case of post-radiotherapy angiosarcoma with a diagnosed precursor lesion. The lesion was treated with surgical excision and adjuvant radiotherapy. After further in- and out of- field recurrences, low dose radiotherapy elicited a surprisingly rapid and complete response within the treated areas; this was unusual in that these tumours are characteristically radiation-resistant. The radiosensitive case we report here raises the possibility that radiation should be more widely considered in the therapy of this disease. Methods of treatment of this rare malignancy are discussed.

In vitro prediction of breast cancer therapy toxicity.

BACKGROUND: Understanding the basis of clinical radiosensitivity is a key goal of radiation research. In this study, we used the limiting dilution assay (LDA) to analyze in vitro radiosensitivity of cell lines from individuals with breast and other cancers, who had been treated with ionizing radiation, and who either had a non-radiosensitive (RS) radiation response or who were clinically RS. METHODS: Lymphoblastoid cell lines (LCLs) were created from 29 cancer patients including 19 RS patients, 10 controls who had not developed severe normal tissue reactions, and 1 ataxia telangiectasia RS control cell line. The clinically RS patients had grade 3 or grade 4 reactions; one had a grade 2 reaction. All cells were exposed to graded doses of gamma-radiation in vitro and cell survival assessed via LDA. Cell survival was expressed on non-linear regression analysis-fitted survival curves and also as the surviving fraction at 2 Gray (Gy) (SF2). RESULTS: Our LDA analysis yielded two notable positive results. Firstly, it could distinguish control cells from cells from pooled breast cancer cases with severe reactions of all types (acute reactors, consequential late reactors and late reactors). Secondly, two radiosensitivity outliers were detected on the fitted curves, corresponding clinically to grade 3 and 4 late radiation reactions in breast and head and neck cancer cases respectively. The assay showed considerable cell survival heterogeneity. CONCLUSIONS: The LDA as used here may provide unique clinical utility in detecting potential RS breast cancer patients prior to radiotherapy (RT), a form of personalized medicine. The assay may be especially useful in situations where its results can be temporally available prior to therapy initiation (e.g., those patients not undergoing RT until some months after surgery, typically those having adjuvant chemotherapy prior to RT). Two LCLs from RS outliers could potentially yield insight into the cellular and/or genetic basis of radiosensitivity, for example by undertaking genomic analyses on these cell lines.

Non-homologous end-joining protein expression screen from radiosensitive cancer patients yields a novel DNA double strand break repair phenotype.

BACKGROUND: Clinical radiosensitivity is a significant impediment to tumour control and cure, in that it restricts the total doses which can safely be delivered to the whole radiotherapy population, within the tissue tolerance of potentially radiosensitive (RS) individuals. Understanding its causes could lead to personalization of radiotherapy. METHODS: We screened tissues from a unique bank of RS cancer patients for expression defects in major DNA double-strand break repair proteins, using Western blot analysis and subsequently reverse-transcriptase polymerase chain reaction and pulsed-field gel electrophoresis. RESULTS: We hypothesized that abnormalities in expression of these proteins may explain the radiosensitivity of some of our cancer patients. The cells from one patient showed a reproducibly consistent expression reduction in two complex-forming DNA double-strand break repair protein components (DNA Ligase IV and XRCC4). We also showed a corresponding reduction in both gene products at the mRNA level. Additionally, the mRNA inducibility by ionizing radiation was increased for one of the proteins in the patient's cells. We confirmed the likely functional significance of the non-homologous end-joining (NHEJ) expression abnormalities with a DNA double strand break (DNA DSB) repair assay. CONCLUSIONS: We have identified a novel biological phenotype linked to clinical radiosensitivity. This is important in that very few molecular defects are known in human radiotherapy subjects. Such knowledge may contribute to the understanding of radiation response mechanisms in cancer patients and to personalization of radiotherapy.