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Compromized DNA repair as a basis for identification of cancer radiotherapy patients with extreme radiosensitivity.

ABSTRACT: A small percentage of cancer radiotherapy patients develop abnormally severe side effects as a consequence of intrinsic radiosensitivity. We analysed the ?-H2AX response to ex-vivo irradiation of peripheral blood lymphocytes (PBL) and plucked eyebrow hair follicles from 16 patients who developed severe late radiation toxicity following radiotherapy, and 12 matched control patients. Longer retention of the ?-H2AX signal and lower colocalization efficiency of repair factors in over-responding patients confirmed that DNA repair in these individuals was compromised. Five of the radiosensitive patients harboured LoF mutations in DNA repair genes. An extensive range of quantitative parameters of the ?-H2AX response were studied with the objective to establish a predictor for radiosensitivity status. The most powerful predictor was the combination of the fraction of the unrepairable component of ?-H2AX foci and repair rate in PBL, both derived from non-linear regression analysis of foci repair kinetics. We introduce a visual representation of radiosensitivity status that allocates a position for each patient on a two-dimensional "radiosensitivity map". This analytical approach provides the basis for larger prospective studies to further refine the algorithm, ultimately to triage capability.

SUBMITTER: Lobachevsky P

PROVIDER: S-EPMC5159273 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Compromized DNA repair as a basis for identification of cancer radiotherapy patients with extreme radiosensitivity.

Lobachevsky Pavel P Leong Trevor T Daly Patricia P Smith Jai J Best Nickala N Tomaszewski Jonathan J Thompson Ella R ER Li Na N Campbell Ian G IG Martin Roger F RF Martin Olga A OA

Cancer letters 20160928 2

A small percentage of cancer radiotherapy patients develop abnormally severe side effects as a consequence of intrinsic radiosensitivity. We analysed the γ-H2AX response to ex-vivo irradiation of peripheral blood lymphocytes (PBL) and plucked eyebrow hair follicles from 16 patients who developed severe late radiation toxicity following radiotherapy, and 12 matched control patients. Longer retention of the γ-H2AX signal and lower colocalization efficiency of repair factors in over-responding pati ...[more]

PMID: 27693457

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Project description:BackgroundUterine corpus endometrial cancer (UCEC) exhibit heterogeneity in their DNA repair capacity, which can impact their response to radiotherapy. Our study aimed to identify potential DNA repair-related biomarkers for predicting radiation response in UCEC.MethodsWe conducted a thorough analysis of 497 UCEC samples obtained from TCGA database. Using LASSO-COX regression analysis, we constructed a radiosensitivity signature and subsequently divided patients into the radiosensitive (RS) and the radioresistant (RR) groups based on their radiosensitivity index. The GSVA and GSEA were performed to explore functional annotations. The CIBERSORT and ESTIMATE algorithms were utilized to investigate the immune infiltration status of the two groups. Additionally, we utilized the Tumor Immune Dysfunction and Exclusion (TIDE), Immunophenotype Score (IPS), and pRRophetic algorithms to predict the effectiveness of different treatment modalities.ResultsWe constructed a radiosensitivity index consists of four DNA repair-related genes. Patients in the RS group demonstrated significantly improved prognosis compared to patients in the RR group when treated with radiotherapy. We observed that the RS group exhibited a higher proportion of the POLE ultra-mutated subtype, while the RR group had a higher proportion of the copy number high subtype. GSVA enrichment analysis revealed that the RS group exhibited enrichment in DNA damage repair pathways. Notably, the RS group demonstrated a higher proportion of naïve B cells and follicular helper T cells, while regulatory T cells (Tregs) and memory B cells were more abundant in the RR group. Furthermore, patients in the RS-PD-L1-high subgroup exhibited enrichment in immune-related pathways and increased sensitivity to immunotherapy, which is likely to contribute to their improved prognosis. Additionally, we conducted in vitro experiments to validate the expression of radiosensitivity genes in non-radioresistant (AN3CA) and radioresistant (AN3CA/IR) endometrial cancer cells.ConclusionsIn conclusion, our research successfully constructed a radiosensitivity signature with robust predictive capacity. These findings shed light on the association between immune activation, PD-L1 expression, and the response to immunotherapy in the context of radiotherapy.

Project description:Despite the frequent use of ionising radiation (IR) in therapy and diagnostics and the unavoidable exposure to external radiation sources, our knowledge regarding the radiosensitivity of human blood cell populations is limited and published data, obtained under different experimental conditions, are heterogeneous. To compare the radiosensitivity of different hematopoietic cell populations, we set out to determine the responses of cells obtained from peripheral blood of healthy volunteers under identical conditions (resting, non-stimulated cells). First, we measured the radiation response of T cells (Treg, Th, CTL), B cells, NK cells, CD34+ progenitor cells and monocytes obtained from peripheral blood and monocyte-derived macrophages (Mph) and immature dendritic cells (iDC) ex vivo and show that T and B cells are highly sensitive, starting to undergo apoptosis following IR with a dose as low as 0.125 Gy. Importantly, there was no clear threshold dose and cell death/apoptosis increased up to a saturation level with a dose of 2 Gy. The sensitivity decreased in the order of T cells > NK and B cells > monocytes > macrophages and iDC. The data confirm a previous report that Mph and iDC are radiation-resistant compared to their progenitor monocytes. Although non-stimulated T and B cells were highly radiation-sensitive compared to monocytes and macrophages, they were competent in the repair of DNA double-strand breaks, as shown by a decline in γH2AX foci in the post-exposure period. CD34+ cells obtained from peripheral blood also showed γH2AX decline post-exposure, indicating they are repair competent. Granulocytes (CD15+) did not display any γH2AX staining following IR. Although peripheral blood lymphocytes, the main fraction are T cells, were significantly more radiation-sensitive than monocytes, they displayed the expression of the repair proteins XRCC1, ligase III and PARP-1, which were nearly non-expressed in monocytes. To assess whether monocytes are depleted in vivo following IR, we measured the amount of T cells and monocytes in cancer patients who received total-body radiation (TBR, 6 × 2 Gy). We observed that the number of T cells in the peripheral blood significantly declined already after the first day of TBR and remained at a low level, which was accompanied by an increase in the number of γH2AX foci in the surviving CD3+ T cell fraction. In contrast, the number of monocytes did not decline extensively, reflecting their radiation resistance compared to T cells. Monocytes also showed an accumulation of γH2AX foci in vivo, but the levels were significantly lower than in T cells. CD56+ NK cells displayed a response similar to T cells. The data support the notion that unstimulated T cell subfractions are nearly equally radiation sensitive. There are, however, remarkable differences in the radiation sensitivity between the lymphoid and the myeloid lineage, with lymphoid cells being significantly more sensitive than cells of the myeloid lineage. In the myeloid lineage, macrophages and iDCs were the most radio-resistant cell types.

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Compromized DNA repair as a basis for identification of cancer radiotherapy patients with extreme radiosensitivity.

Publications

Compromized DNA repair as a basis for identification of cancer radiotherapy patients with extreme radiosensitivity.

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