|
1
|
Wijetunga NA, Yahalom J, Imber BS. The art of war: using genetic insights to understand and harness radiation sensitivity in hematologic malignancies. Front Oncol 2025; 14:1478078. [PMID: 40191738 PMCID: PMC11968681 DOI: 10.3389/fonc.2024.1478078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 11/20/2024] [Indexed: 04/09/2025] Open
Abstract
It is well established that hematologic malignancies are often considerably radiosensitive, which enables usage of far lower doses of therapeutic radiotherapy. This review summarizes the currently known genomic landscape of hematologic malignancies, particularly as it relates to radiosensitivity and the field of radiation oncology. By tracing the historical development of the modern understanding of radiosensitivity, we focus on the discovery and implications of pivotal mutated genes in hematologic malignancies such as TP53, ATM, and other genes critical to DNA repair pathways. These genetic insights have contributed significantly to the advancement of personalized medicine, aiming to enhance treatment precision and outcomes, and there is an opportunity to extend these insights to personalized radiotherapy. We explore the transition from early discoveries to the current efforts in integrating comprehensive genomic data into clinical practice. Specific examples from Hodgkin lymphoma, non-Hodgkin lymphoma, and plasma cell neoplasms illustrate how genetic mutations could influence radiosensitivity and impact subsequent radiotherapeutic response. Despite the advancements, challenges remain in translating these genetic insights into routine clinical practice, particularly due to the heterogeneity of alterations and the complex interactions within cancer signaling pathways. We emphasize the potential of radiogenomics to address these challenges by identifying genetic markers that predict radiotherapy response and toxicity, thereby refining treatment strategies. The need for robust decision support systems, standardized protocols, and ongoing education for healthcare providers is critical to the successful integration of genomic data into radiation therapy. As research continues to validate genetic markers and explore novel therapeutic combinations, the promise of personalized radiotherapy becomes increasingly attainable, offering the potential to significantly improve outcomes for patients with hematologic malignancies.
Collapse
Affiliation(s)
- N. Ari Wijetunga
- Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, United States
| | - Joachim Yahalom
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Brandon S. Imber
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| |
Collapse
|
|
2
|
Santo G, di Santo G, Cicone F, Virgolini I. Peptide receptor radionuclide therapy with somatostatin analogs beyond gastroenteropancreatic neuroendocrine tumors. J Neuroendocrinol 2025; 37:e70013. [PMID: 40064181 PMCID: PMC11919479 DOI: 10.1111/jne.70013] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 02/07/2025] [Accepted: 02/18/2025] [Indexed: 03/20/2025]
Abstract
First isolated by Brazeau et al. in 1972, somatostatin (SST) is a neuropeptide known for regulating various signaling pathways through its specific cell surface receptors. Somatostatin receptors (SSTRs) comprise a family of five G protein-coupled receptors that are widely distributed across the human body and are expressed by various tumor types. The growing understanding of their clinical potential led to the introduction of both cold and radiolabeled somatostatin analogs (SSAs), which have revolutionized the management of several cancers, especially neuroendocrine tumors. As a direct consequence, advances in peptide receptor radionuclide therapy (PRRT) over the last 30 years led to the approval of 177Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors (GEPNETs). Theoretically, any cancer patients whose tumors express SSTR, as demonstrated in vivo through SSTR-based molecular imaging, could be candidates for PRRT, especially those with limited treatment options. However, evidence on the efficacy of PRRT in non-GEPNET SSTR-expressing tumors is limited, and mainly derived from small retrospective studies. Given the limited therapeutic options for advanced/metastatic patients, there is a clear need for randomized trials to formally approve PRRT with SSAs for patients who may benefit from this treatment, particularly in certain types of neuroendocrine neoplasms such as lung carcinoids, paragangliomas, and meningiomas, where high rates of disease control (up to 80%) can be achieved. In addition, emerging evidence supports the potential of combination therapies, alpha emitters, and non-SSTR-based radionuclide therapy in tumors beyond GEPNET. This review aims to provide a comprehensive overview of PRRT's role in cancers beyond GEPNET, exploring new possibilities and future directions for most SSTR highly expressing tumors.
Collapse
Affiliation(s)
- Giulia Santo
- Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria
- Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy
| | - Gianpaolo di Santo
- Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Francesco Cicone
- Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy
| | - Irene Virgolini
- Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria
| |
Collapse
|
|
3
|
Ramezani F, Takhshid MA, Abuei H, Farhadi A, Mosleh-Shirazi MA, Ramezani P. Combined Effects of Annexin A5 Overexpression, 5-Fluorouracil Treatment, and Irradiation on Cell Viability of Caski Cervical Cancer Cell Line. Reprod Sci 2024; 31:2654-2666. [PMID: 38811453 DOI: 10.1007/s43032-024-01575-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/22/2024] [Indexed: 05/31/2024]
Abstract
Cervical cancer is the fourth leading cause of cancer deaths in women globally. Combining gene therapy with chemo- and radiotherapy may improve cervical cancer treatment outcomes. This study evaluated the effects of Annexin A5(ANXA5) overexpression alongside 5-fluorouracil (5-FU) and irradiation on the viability of CaSki cervical squamous cell carcinoma (SCC) cells. pAdenoVator-CMV-ANXA5-IRES-GFP-plasmid and mock plasmid were transfected into CaSki cells using calcium-phosphate. Seventy-two hours post-transfection, GFP expression was quantified by fluorescence microscopy and flow cytometry to evaluate transfection efficiency. ANXA5 overexpression was confirmed via qPCR. Twenty-four hours post-transfection, cells received a single dose of 8 Gy and were treated with 1 and 2 µg/ml of 5-FU (IC50 = 2.783 µg/ml). Cell viability, apoptosis, cell cycle stage, and Bcl-2 and Bax gene expression were assessed via MTT, annexin V/7-AAD, PI staining, and qPCR assays, respectively. ANXA5 was overexpressed 31.5-fold compared to control (p < 0.0001). MTT assays showed ANXA5 overexpression dose-dependently reduced CaSki cell viability (p < 0.001). IC50 of 5-FU was reduced from 2.783 μg/mL to 1.794 μg/mL when combined with ANXA5 overexpression. Additive effects on cell death were observed for ANXA5 plus 5-FU or irradiation versus ANXA5 alone. Apoptosis assays indicated combinatorial treatment increased CaSki cell apoptosis over ANXA5 alone. Cell cycle analysis revealed ANXA5 arrested cell cycle at G1/S phases; the percentage of cells in the S phase further rose with combination treatment. Finally, combination therapy significantly decreased Bcl-2 expression and increased Bax versus control (p < 0.001). Altogether, ANXA5 overexpression alongside 5-FU and irradiation may improve cervical squamous cell carcinoma (SCC) treatment efficacy. Further, in vivo investigations are warranted to confirm these in vitro results.
Collapse
Affiliation(s)
- Faezeh Ramezani
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Ali Takhshid
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.
- School of Paramedical Sciences, Diagnostic Laboratory Sciences and Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Haniyeh Abuei
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Farhadi
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
- School of Paramedical Sciences, Diagnostic Laboratory Sciences and Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Amin Mosleh-Shirazi
- Ionizing and Non-Ionizing Radiation Protection Research Center (INIRPRC), School of Paramedical Sciences, Shiraz University of Medical Sciences, Meshkinfam St, Shiraz, Iran
- Physics Unit, Department of Radio-Oncology, School of Medicine, Shiraz University of Medical Sciences, Namazi Teaching Hospital, Namazi Square, Shiraz, Iran
| | - Pouya Ramezani
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|
|
4
|
Zhang X, Huang X, Cao Y, Mao Y, Zhu Y, Zhang Q, Zhang T, Chang L, Wang C. Dynamic analysis of predictive biomarkers for radiation therapy efficacy in non-small cell lung cancer patients by next-generation sequencing based on blood specimens. Pathol Res Pract 2024; 253:154972. [PMID: 38064866 DOI: 10.1016/j.prp.2023.154972] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 01/24/2024]
Abstract
PURPOSE Radiotherapy plays an important role in the treatment of non-small cell lung cancer, and the aim of this study was to explore the potential association of single gene mutation or pathway mutations with radiotherapy response using targeted next-generation sequencing (NGS) testing of peripheral blood specimens. MATERIAL AND METHODS We performed NGS containing 425 genes on peripheral blood specimens from 13 NSCLC patients pre- and post-radiotherapy or post-radiotherapy. Patients whose tumors were in complete response or partial response within 1 month after radiotherapy were classified as a radiotherapy-sensitive group; otherwise, they were categorized as a radiotherapy-resistant group. The relationship between single gene mutations, signaling pathway mutations, dynamic fluctuations in circulating tumor DNA （ctDNA）, and radiotherapy response was investigated. RESULTS Of these 13 patients，6 patients were categorized as a radiotherapy-sensitive group (46.2%), and 7 patients were categorized as a radiotherapy-resistant group (53.8%). No correlation between single gene mutations and response to radiotherapy. Mutations in the SWI/SNF complex were more likely to occur in the radiotherapy-sensitive group than in the other group (p = 0.07). Among all patients，9 patients underwent NGS tests pre- and post-radiotherapy. Dynamic analysis based on ctDNA before and after treatment revealed that a decrease in ctDNA abundance was observed in all patients in the radiotherapy-sensitive group. CONCLUSIONS SWI/SNF complex mutations may be potential predictive biomarkers of radiotherapy response. Decreased ctDNA abundance after radiotherapy correlates with better efficacy of radiotherapy.
Collapse
Affiliation(s)
- Xuemei Zhang
- Thoracic Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xu Huang
- Thoracic Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yang Cao
- Thoracic Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuxin Mao
- Thoracic Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yingying Zhu
- Thoracic Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qian Zhang
- Thoracic Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Tao Zhang
- Thoracic Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Lele Chang
- Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chunbo Wang
- Thoracic Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China.
| |
Collapse
|
|
5
|
Butkiewicz D, Krześniak M, Gdowicz-Kłosok A, Składowski K, Rutkowski T. DNA Double-Strand Break Response and Repair Gene Polymorphisms May Influence Therapy Results and Prognosis in Head and Neck Cancer Patients. Cancers (Basel) 2023; 15:4972. [PMID: 37894339 PMCID: PMC10605140 DOI: 10.3390/cancers15204972] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/05/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Radiotherapy and cisplatin-based chemotherapy belong to the main treatment modalities for head and neck squamous cell carcinoma (HNSCC) and induce cancer cell death by generating DNA damage, including the most severe double-strand breaks (DSBs). Alterations in DSB response and repair genes may affect individual DNA repair capacity and treatment sensitivity, contributing to the therapy resistance and poor prognosis often observed in HNSCC. In this study, we investigated the association of a panel of single-nucleotide polymorphisms (SNPs) in 20 DSB signaling and repair genes with therapy results and prognosis in 505 HNSCC patients treated non-surgically with DNA damage-inducing therapies. In the multivariate analysis, there were a total of 14 variants associated with overall, locoregional recurrence-free or metastasis-free survival. Moreover, we identified 10 of these SNPs as independent predictors of therapy failure and unfavorable prognosis in the whole group or in two treatment subgroups. These were MRE11 rs2155209, XRCC5 rs828907, RAD51 rs1801321, rs12593359, LIG4 rs1805388, CHEK1 rs558351, TP53 rs1042522, ATM rs1801516, XRCC6 rs2267437 and NBN rs2735383. Only CHEK1 rs558351 remained statistically significant after correcting for multiple testing. These results suggest that specific germline variants related to DSB response and repair may be potential genetic modifiers of therapy effects and disease progression in HNSCC treated with radiotherapy and cisplatin-based chemoradiation.
Collapse
Affiliation(s)
- Dorota Butkiewicz
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Małgorzata Krześniak
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Agnieszka Gdowicz-Kłosok
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Krzysztof Składowski
- I Radiation and Clinical Oncology Department, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Tomasz Rutkowski
- I Radiation and Clinical Oncology Department, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
- Radiotherapy Department, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| |
Collapse
|
|
6
|
Wang H, Xie H, Wang S, Zhao J, Gao Y, Chen J, Zhao Y, Guo G. PARP-1 genetic polymorphism associated with radiation sensitivity of non-small cell lung cancer. Pathol Oncol Res 2022; 28:1610751. [PMID: 36590386 PMCID: PMC9795517 DOI: 10.3389/pore.2022.1610751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 11/23/2022] [Indexed: 12/15/2022]
Abstract
About 70% of non-small cell lung cancer (NSCLC) patients require radiotherapy. However, due to the difference in radiation sensitivity, the treatment outcome may differ for the same pathology and choice of treatment. Poly (ADP-ribose) polymerase 1 (PARP-1) is a key gene responsible for DNA repair and is involved in base excision repair as well as repair of single strand break induced by ionizing radiation and oxidative damage. In order to investigate the relationship between PARP-1 gene polymorphism and radiation sensitivity in NSCLC, we collected 141 primary NSCLC patients undergoing three-dimensional conformal radiotherapy. For each case, the gross tumor volumes (GTV) before radiation and that after 40 Gy radiation were measured to calculate the tumor regression rate. TaqMan real-time polymerase chain reaction was performed to genotype the single-nucleotide polymorphisms (SNPs). Genotype frequencies for PARP-1 genotypes were 14.2% for C/C, 44.7% for C/G and 41.1% for G/G. The average tumor regression rate after 40 Gy radiation therapy was 35.1% ± 0.192. Tumor regression rate of mid-term RT of C/C genotype was 44.6% ± 0.170, which was higher than that of genotype C/G and G/G (32.4% ± 0.196 and 34.8% ± 0.188, respectively) with statistical significance (F = 3.169 p = 0.045). The higher tumor regression rate in patients with C/C genotype suggested that G allele was a protective factor against radiation therapy. Using the median tumor regression rate of 34%, we divided the entire cohort into two groups, and found that the frequency distribution of PARP-1 gene rs3219073 had significant difference between these two groups (p < 0.05). These results showed that PARP-1 gene polymorphism may affect patient radiation sensitivity and predict the efficacy of radiotherapy. It therefore presents an opportunity for developing new therapeutic targets to improve radiotherapy outcome.
Collapse
Affiliation(s)
- Hetong Wang
- Department of Radiation Oncology, The Tenth People’s Hospital of Shenyang, Shenyang, China,Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Haitao Xie
- Department of Radiation Oncology, Liaoning Cancer Hospital, Shenyang, China
| | | | - Jiaying Zhao
- Department of Radiation Oncology, Qingdao United Family Healthcare, Qingdao, China
| | - Ya Gao
- Department of Oncology, Kailuan Hospital, Tangshan, Hebei, China
| | - Jun Chen
- Department of Radiation Oncology, The Tenth People’s Hospital of Shenyang, Shenyang, China
| | - Yuxia Zhao
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Genyan Guo
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China,*Correspondence: Genyan Guo,
| |
Collapse
|
|
7
|
Li D, Ding J, Liu TL, Wang F, Meng XX, Liu S, Yang Z, Zhu H. SARS-CoV-2 receptor binding domain radio-probe: a non-invasive approach for angiotensin-converting enzyme 2 mapping in mice. Acta Pharmacol Sin 2022; 43:1749-1757. [PMID: 34815544 PMCID: PMC8609177 DOI: 10.1038/s41401-021-00809-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 10/28/2021] [Indexed: 12/11/2022]
Abstract
The spike protein of SARS-CoV-2 interacts with angiotensin-converting enzyme 2 (ACE2) of human respiratory epithelial cells, which leads to infection. Furthermore, low-dose radiation has been found to reduce inflammation and aid the curing of COVID-19. The receptor binding domain (RBD), a recombinant spike protein with a His tag at the C-terminus, binds to ACE2 in human body. We thus constructed a radioiodinated RBD as a molecule-targeted probe to non-invasively explore ACE2 expression in vivo, and to investigate radiotherapy pathway for inhibiting ACE2. RBD was labeled with [124I]NaI using an N-bromosuccinimide (NBS)-mediated method, and 124I-RBD was obtained after purification with a specific activity of 28.9 GBq/nmol. Its radiochemical purity was (RCP) over 90% in saline for 5 days. The dissociation constant of 124I-RBD binding to hACE2 was 75.7 nM. The uptake of 124I-RBD by HeLaACE+ cells at 2 h was 2.96% ± 0.35%, which could be substantially blocked by an excessive amount of RBD, and drop to 1.71% ± 0.23%. In BALB/c mice, the biodistribution of 124I-RBD after intravenous injection showed a moderate metabolism rate, and its 24 h-post injection (p.i.) organ distribution was similar to the expression profile in body. Micro-PET imaging of mice after intrapulmonary injection showed high uptake of lung at 1, 4, 24 h p.i.. In conclusion, the experimental results demonstrate the potential of 124I-RBD as a novel targeted molecular probe for COVID-19. This probe may be used for non-invasive ACE2 mapping in mammals.
Collapse
Affiliation(s)
- Dan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jin Ding
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Te-Li Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Feng Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Xiang-Xi Meng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Song Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zhi Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Hua Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| |
Collapse
|
|
8
|
MicroRNA-29a Manifests Multifaceted Features to Intensify Radiosensitivity, Escalate Apoptosis, and Revoke Cell Migration for Palliating Radioresistance-Enhanced Cervical Cancer Progression. Int J Mol Sci 2022; 23:ijms23105524. [PMID: 35628336 PMCID: PMC9141925 DOI: 10.3390/ijms23105524] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/03/2022] [Accepted: 05/13/2022] [Indexed: 11/16/2022] Open
Abstract
Radioresistance remains a major clinical challenge in cervical cancer therapy and results in tumor relapse and metastasis. Nevertheless, the detailed mechanisms are still largely enigmatic. This study was conducted to elucidate the prospective impacts of microRNA-29a (miR-29a) on the modulation of radioresistance-associated cervical cancer progression. Herein, we established two pairs of parental wild-type (WT) and radioresistant (RR) cervical cancer cells (CaSki and C33A), and we found that constant suppressed miR-29a, but not miR-29b/c, was exhibited in RR-clones that underwent a dose of 6-Gy radiation treatment. Remarkably, radioresistant clones displayed low radiosensitivity, and the reduced apoptosis rate resulted in augmented surviving fractions, measured by the clonogenic survival curve assay and the Annexin V/Propidium Iodide apoptosis assay, respectively. Overexpression of miR-29a effectively intensified the radiosensitivity and triggered the cell apoptosis in RR-clones. In contrast, suppressed miR-29a modestly abridged the radiosensitivity and abolished the cell apoptosis in WT-clones. Hence, ectopically introduced miR-29a into RR-clones notably attenuated the wound-healing rate and cell migration, whereas reduced miR-29a aggravated cell mobilities of WT-clones estimated via the in vitro wound-healing assay and time-lapse recording assay. Notably, we further established the in vivo short-term lung locomotion metastasis model in BALB/c nude mice, and we found that increased lung localization was shown after tail-vein injection of RR-CaSki cells compared to those of WT-CaSki cells. Amplified miR-29a significantly eliminated the radioresistance-enhanced lung locomotion. Our data provide evidence suggesting that miR-29a is a promising microRNA signature in radioresistance of cervical cancer cells and displays multifaceted innovative roles involved in anti-radioresistance, escalated apoptosis, and anti-cell migration/metastasis. Amalgamation of a nucleoid-based strategy (miR-29a) together with conventional radiotherapy may be an innovative and eminent strategy to intensify the radiosensitivity and further protect against the subsequent radioresistance and the potential metastasis in cervical cancer treatment.
Collapse
|
|
9
|
Bodei L, Kidd M, Modlin IM. Clinical and scientific considerations of genomics and metabolomics in radionuclide therapy. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00198-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
|
|
10
|
Dose-response relationship after yttrium-90-radioembolization with glass microspheres in patients with neuroendocrine tumor liver metastases. Eur J Nucl Med Mol Imaging 2021; 49:1700-1710. [PMID: 34873638 DOI: 10.1007/s00259-021-05642-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 11/28/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND In radioembolization, response is achieved through the irradiation and damaging of tumor DNA. For hepatic metastases of neuroendocrine tumors, a dose-response relationship has not been established yet. This study assesses whether increasing tumor-absorbed doses lead to increased response rates. METHODS We included all patients who underwent yttrium-90 (90Y) glass microspheres radioembolization in our center if both pre- and post-treatment contrast-enhanced CT and post-injection PET/CT were available. Up to five hepatic tumors and the healthy hepatic tissue were delineated, and absorbed dose was quantified using post-injection PET/CT. Response was measured according to RECIST 1.1 on patient and tumor level. Linear mixed models were used to study the relationship between absorbed dose and response on tumor level. Logistic regression analysis was used on patient level to study dose-response and hepatic dose-toxicity relationships. RESULTS A total of 128 tumors in 26 patients (31 procedures) were included in the response analysis. While correcting for confounding by tumor volume, a significant effect of response on dose was found (p = 0.0465). Geometric mean of absorbed dose for responding tumors was 170 Gy, for stable disease 101 Gy, and for progressive disease 67 Gy. No significant dose-toxicity relationship could be identified. CONCLUSION In patients with neuroendocrine tumor liver metastases, treated with 90Y-radioembolization, a clear dose-response relationship was found. We propose to perform 90Y-radioembolization with an absolute minimum planned tumor-absorbed dose of 150 Gy.
Collapse
|
|
11
|
Developing ZNF Gene Signatures Predicting Radiosensitivity of Patients with Breast Cancer. JOURNAL OF ONCOLOGY 2021; 2021:9255494. [PMID: 34504527 PMCID: PMC8423582 DOI: 10.1155/2021/9255494] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/22/2021] [Accepted: 08/16/2021] [Indexed: 12/13/2022]
Abstract
Adjuvant radiotherapy is one of the main treatment methods for breast cancer, but its clinical benefit depends largely on the characteristics of the patient. This study aimed to explore the relationship between the expression of zinc finger (ZNF) gene family proteins and the radiosensitivity of breast cancer patients. Clinical and gene expression data on a total of 976 breast cancer samples were obtained from The Cancer Genome Atlas (TCGA) database. ZNF gene expression was dichotomized into groups with a higher or lower level than the median level of expression. Univariate and multivariate Cox regression analyses were used to evaluate the relationship between ZNF gene expression levels and radiosensitivity. The Molecular Taxonomy Data of the International Federation of Breast Cancer (METABRIC) database was used for validation. The results revealed that 4 ZNF genes were possible radiosensitivity markers. High expression of ZNF644 and low expression levels of the other 3 genes (ZNF341, ZNF541, and ZNF653) were related to the radiosensitivity of breast cancer. Hierarchical cluster, Cox, and CoxBoost analysis based on these 4 ZNF genes indicated that patients with a favorable 4-gene signature had better overall survival on radiotherapy. Thus, this 4-gene signature may have value for selecting those patients most likely to benefit from radiotherapy. ZNF gene clusters could act as radiosensitivity signatures for breast cancer patients and may be involved in determining the radiosensitivity of cancer.
Collapse
|
|
12
|
Predictive value of ERCC2, ABCC2 and MMP2 of response and long-term survival in locally advanced head and neck cancer patients treated with chemoradiotherapy. Cancer Chemother Pharmacol 2021; 88:813-823. [PMID: 34309735 DOI: 10.1007/s00280-021-04330-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 07/10/2021] [Indexed: 12/19/2022]
Abstract
PURPOSE Genetic variants in genes involved in the distribution, metabolism, accumulation or repair of lesions are likely to influence the response of drugs used in the treatment of Head and Neck Cancer (HNC). We examine the effect of 36 SNPs on clinical outcomes in patients with locally advanced HNC who were receiving platinum-based chemoradiotherapy (CRT). METHODS These SNPs were genotyped in 110 patients using the iPLEX Gold assay on the MassARRAY method in blood DNA samples and used Kaplan-Meier and Cox regression analyses to compare genotype groups with the survival. RESULTS Two SNPs, rs717620 (ABCC2) and rs12934241 (MMP2) were strongly associated with overall survival (OS) and disease-free survival (DFS). At a median follow-up of 64.4 months, the allele A of rs717620 (ABCC2) had an increased risk of disease progression {hazard ratio [HR] = 1.79, p = 0.0018} and death (HR = 2.0, p = 0.00027). ABCC2 was associated with OS after a Bonferroni adjustment for multiple testing. The MMP2 rs12934241-T allele was associated with an increased risk of worse OS and DFS (p = 0.0098 and p = 0.0015, respectively). One SNP of ABCB1 and three SNPs located in the ERCC2 gene showed an association with response in the subgroup of HNC patients treated with definitive CRT. CONCLUSIONS Our findings highlight the potential usefulness of SNPs in different genes involved in drug metabolism and repair DNA to predict the response and survival to CRT. ABCC2 is a potential predictor of OS in patients with HNC.
Collapse
|
|
13
|
Gupta A, Mathew D, Bhat SA, Ghoshal S, Pal A. Genetic Variants of DNA Repair Genes as Predictors of Radiation-Induced Subcutaneous Fibrosis in Oropharyngeal Carcinoma. Front Oncol 2021; 11:652049. [PMID: 34079756 PMCID: PMC8165303 DOI: 10.3389/fonc.2021.652049] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/28/2021] [Indexed: 11/13/2022] Open
Abstract
Purpose To investigate the impact of genetic variants of DNA repair and pro-fibrotic pathway genes on the severity of radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radical radiotherapy. Materials and Methods Patients of newly diagnosed squamous cell carcinoma of oropharynx being treated with two-dimensional radical radiotherapy were enrolled in the study. Patients who had undergone surgery or were receiving concurrent chemotherapy were excluded. Patients were followed up at 6 weeks post completion of radiotherapy and every 3 months thereafter for a median of 16 months. Subcutaneous fibrosis was graded according to the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) grading system and the maximum grade was recorded over the length of the patient’s follow-up. Patients with severe fibrosis (≥G3), were compared to patients with minor (≤G2) fibrotic reactions. Eight single nucleotide polymorphisms of 7 DNA repair genes and 2 polymorphisms of a single pro-fibrotic pathway gene were analyzed by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism and were correlated with the severity of subcutaneous fibrosis. Results 179 patients were included in the analysis. Subcutaneous fibrosis was seen in 168 (93.9%) patients. 36 (20.1%) patients had severe (grade 3) fibrosis. On multivariate logistic regression analysis, Homozygous CC genotype of XRCC3 (722C>T, rs861539) (p=0.013*, OR 2.350, 95% CI 1.089-5.382), Homozygous AA genotype of ERCC4 Ex8 (1244G>A, rs1800067) (p=0.001**, OR 11.626, 95% CI 2.490-275.901) and Homozygous TT genotype of XRCC5 (1401G>T, rs828907) (p=0.020*, OR 2.188, 95% CI 1.652-7.334) were found to be predictive of severe subcutaneous fibrosis. On haplotype analysis, the cumulative risk of developing severe fibrosis was observed in patients carrying both haplotypes of variant Homozygous AA genotype of ERCC4 Ex8 (1244G>A, rs1800067) and Homozygous TT genotype of XRCC5 (1401 G>T, rs828907) (p=0.010*, OR 26.340, 95% CI 4.014-76.568). Conclusion We demonstrated significant associations between single nucleotide polymorphisms of DNA repair genes and radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radiotherapy. We propose to incorporate these genetic markers into predictive models for identifying patients genetically predisposed to the development of radiation-induced fibrosis, thus guiding personalized treatment protocols.
Collapse
Affiliation(s)
- Ankita Gupta
- Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Don Mathew
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Shabir Ahmad Bhat
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sushmita Ghoshal
- Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Arnab Pal
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| |
Collapse
|
|
14
|
Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors. Sci Rep 2021; 11:10176. [PMID: 33986314 PMCID: PMC8119685 DOI: 10.1038/s41598-021-89216-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 04/16/2021] [Indexed: 01/29/2023] Open
Abstract
The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18-69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.
Collapse
|
|
15
|
Bodei L, Schöder H, Baum RP, Herrmann K, Strosberg J, Caplin M, Öberg K, Modlin IM. Molecular profiling of neuroendocrine tumours to predict response and toxicity to peptide receptor radionuclide therapy. Lancet Oncol 2020; 21:e431-e443. [PMID: 32888472 DOI: 10.1016/s1470-2045(20)30323-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/07/2020] [Accepted: 05/15/2020] [Indexed: 12/20/2022]
Abstract
Peptide receptor radionuclide therapy (PRRT) is a type of radiotherapy that targets peptide receptors and is typically used for neuroendocrine tumours (NETs). Some of the key challenges in its use are the prediction of efficacy and toxicity, patient selection, and response optimisation. In this Review, we assess current knowledge on the molecular profile of NETs and the strategies and tools used to predict, monitor, and assess the toxicity of PRRT. The few mutations in tumour genes that can be evaluated (eg, ATM and DAXX) are limited to pancreatic NETs and are most likely not informative. Assays that are transcriptomic or based on genes are effective in the prediction of radiotherapy response in other cancers. A blood-based assay for eight genes (the PRRT prediction quotient [PPQ]) has an overall accuracy of 95% for predicting responses to PRRT in NETs. No molecular markers exist that can predict the toxicity of PRRT. Candidate molecular targets include seven single nucleotide polymorphisms (SNPs) that are susceptible to radiation. Transcriptomic evaluations of blood and a combination of gene expression and specific SNPs, assessed by machine learning with algorithms that are tumour-specific, might yield molecular tools to enhance the efficacy and safety of PRRT.
Collapse
Affiliation(s)
- Lisa Bodei
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Heiko Schöder
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Richard P Baum
- CURANOSTICUM, Center for Advanced Radiomolecular Precision Oncology, Wiesbaden, Germany
| | - Ken Herrmann
- Department of Nuclear Medicine, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Jonathan Strosberg
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Martyn Caplin
- Neuroendocrine Tumour Unit, Department of Gastroenterology, Royal Free Hospital, London, UK
| | - Kjell Öberg
- Department of Endocrine Oncology, University Hospital, Uppsala, Sweden
| | - Irvin M Modlin
- Department of Surgery, Yale University School of Medicine, Yale University, New Haven, CT, USA
| |
Collapse
|
|
16
|
Catto V, Stronati G, Porro B, Fiorelli S, Ricci V, Vavassori C, Russo E, Guerra F, Gasperetti A, Ribatti V, Sicuso R, Dello Russo A, Veglia F, Tondo C, Cavalca V, Colombo GI, Tremoli E, Casella M. Cardiac arrhythmia catheter ablation procedures guided by x-ray imaging: N-acetylcysteine protection against radiation-induced cellular damage (CARAPACE study): study design. J Interv Card Electrophysiol 2020; 61:577-582. [PMID: 32833109 DOI: 10.1007/s10840-020-00853-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 08/12/2020] [Indexed: 11/29/2022]
Abstract
PURPOSE Catheter ablation (CA) procedures are characterized by exposure to ionizing radiations (IR). IR can cause DNA damage and may lead to carcinogenesis if not efficiently repaired. The primary endpoint of this study is to investigate whether intravenous administration of N-acetylcysteine prior to CA procedure may prevent systemic oxidative stress and genomic DNA damage induced by exposure to IR. METHODS The "Cardiac Arrhythmia catheter ablation procedures guided by x-Ray imaging: N-Acetylcysteine Protection Against radiation induced Cellular damagE" (CARAPACE) study is a prospective, randomized, single-blinded, parallel-arm monocenter study enrolling 550 consecutive patients undergoing CA at the Arrhythmology Unit of Centro Cardiologico Monzino (CCM). Inclusion criteria are age ≥ 18, indication for CA procedure guided by IR imaging, and written informed consent. IR levels will be measured via fluoroscopy time, effective dose, and dose area product. Glutathione and glutathione disulfide concentrations will be measured, and urinary levels of 8-iso-prostaglandin-F2α and 8-hydroxy-2-deoxyguanosine will be quantified. The enrolled patients will be randomized 1:1 to the N-acetylcysteine group or to the control group. RESULTS We expect that pre-operative administration of N-acetylcysteine will prevent IR-induced systemic oxidative stress. The study will provide data on oxidative DNA damage assessed by urinary 8-hydroxy-2-deoxyguanosine levels and direct evidence of genomic DNA damage in blood cells by comet assay. CONCLUSION Catheter ablation procedures can lead to IR exposure and subsequent DNA damage. N-acetylcysteine administration prior to the procedure may prevent them and therefore lead to less possible complications. TRIAL REGISTRATION www.clinicaltrials.gov (NCT04154982).
Collapse
Affiliation(s)
- Valentina Catto
- Heart Rhythm Center, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Giulia Stronati
- Cardiology and Arrhythmology Clinic, Marche Polytechnic University, University Hospital "Ospedali Riuniti", Via Conca 71, Torrette (AN), 60126, Ancona, Italy.
| | - Benedetta Porro
- Unit of Metabolomics and Cellular Biochemistry of Atherothrombosis, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Susanna Fiorelli
- Unit of Metabolomics and Cellular Biochemistry of Atherothrombosis, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Veronica Ricci
- Unit of Immunology and Functional Genomics, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Chiara Vavassori
- Unit of Immunology and Functional Genomics, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Eleonora Russo
- Department of Cardiovascular Disease, Division of Cardiac Surgery, Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo, Italy
| | - Federico Guerra
- Cardiology and Arrhythmology Clinic, Marche Polytechnic University, University Hospital "Ospedali Riuniti", Via Conca 71, Torrette (AN), 60126, Ancona, Italy
| | | | - Valentina Ribatti
- Heart Rhythm Center, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Rita Sicuso
- Heart Rhythm Center, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Antonio Dello Russo
- Cardiology and Arrhythmology Clinic, Marche Polytechnic University, University Hospital "Ospedali Riuniti", Via Conca 71, Torrette (AN), 60126, Ancona, Italy
| | - Fabrizio Veglia
- Unit of Biostatistics, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Claudio Tondo
- Heart Rhythm Center, Centro Cardiologico Monzino IRCCS, Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Viviana Cavalca
- Unit of Metabolomics and Cellular Biochemistry of Atherothrombosis, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Gualtiero I Colombo
- Unit of Immunology and Functional Genomics, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Elena Tremoli
- Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy
| | - Michela Casella
- Heart Rhythm Center, Centro Cardiologico Monzino IRCCS, Milan, Italy.,Department of Clinical, Special and Dental Sciences, Marche Polytechnic University, University Hospital "Ospedali Riuniti", Ancona, Italy
| |
Collapse
|
|
17
|
Lin M, Guo L, Cheng Z, Huan X, Huang Y, Xu K. Association of hMSH5 C85T polymorphism with radiation sensitivity of testicular cell lines GC-1, GC-2, TM3, and TM4. Andrology 2020; 8:1174-1183. [PMID: 32306546 DOI: 10.1111/andr.12803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 03/12/2020] [Accepted: 04/14/2020] [Indexed: 12/01/2022]
Abstract
BACKGROUND The hMSH5 C85T polymorphism, which encodes hMSH5 P29S, is associated with individual differences in spermatogenic abnormalities caused by ionizing radiation (IR), but the molecular mechanisms remain unclear. OBJECTIVES This manuscript aims to explore the role of hMSH5 C85T polymorphism in IR-induced individual differences in spermatogenic abnormalities. MATERIAL AND METHODS We transfected pcDNA-hMSH5P29S vector into mouse spermatogonia GC-1, mouse spermatocytes GC-2, mouse testicular mesenchymal cells TM3, and mouse testicular support cells TM4. After radiation, we evaluated cell survival with colony formation assay, apoptosis with TUNEL assay and caspase-3 activity assay, DNA damage with comet assay and an in vivo NHEJ activity assay. RESULTS Results showed that only spermatocytes GC-2 transfected with pcDNA-hMSH5P29S vector had significant differences in IR-induced cell survival and apoptosis when compared to that transfected with pcDNA empty vector and pcDNA-wild-hMSH5 vector, while there was no statistical difference in GC-1, TM3, and TM4. In addition, comet assay showed that the DNA damage of GC-2 transfected with pcDNA-hMSH5P29S vector increased significantly compared to that transfected with pcDNA empty vector and pcDNA-wild-hMSH5 vector after IR. And in vivo NHEJ activity assay showed that the NHEJ activity of GC-2 transfected with pcDNA-hMSH5P29S vector was statistically higher than that transfected with pcDNA empty vector and pcDNA-wild-hMSH5 vector. CONCLUSION Our study indicates that the hMSH5 C85T polymorphism leads to an abnormal increase in apoptosis and lessen the control on error-prone NHEJ of spermatocyte GC-2, thereby altering the difference of radiation sensitivity of spermatogenesis.
Collapse
Affiliation(s)
- Mingyue Lin
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.,Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China
| | - Lihuang Guo
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.,Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China
| | - Zhenbo Cheng
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.,Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China
| | - Xisha Huan
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.,Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China
| | - Yue Huang
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.,Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China
| | - Keqian Xu
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.,Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China
| |
Collapse
|
|
18
|
Low Expression of GLIS2 Gene Might Associate with Radiosensitivity of Gastric Cancer. JOURNAL OF ONCOLOGY 2019; 2019:2934925. [PMID: 31281358 PMCID: PMC6590498 DOI: 10.1155/2019/2934925] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/30/2019] [Accepted: 05/20/2019] [Indexed: 01/05/2023]
Abstract
Human gene GLIS family zinc finger 2 (GLIS2) is a member of GLI-similar zinc finger protein family. Previous studies indicated GLIS2 gene involved in tumorigenesis mechanisms. However, the association between GLIS2 expression and radiosensitivity of gastric cancer has not been well understood. In this study, we used the gastric cancer database in TCGA, and significant association was observed between the low expression of GLIS2 and radiosensitivity of patients with gastric cancer. The adjusted HR values for radiotherapy were 0.162(0.035-0.756) and 0.089(0.014-0.564), with p values 0.021 and 0.010, respectively, in training and testing data, for these patients with low expression of GLIS2, while for patients with high expression of GLIS2, there was no significant survival difference between radiotherapy and nonradiotherapy groups. The adjusted HR were 0.676(0.288-1.586) and 0.508(0.178-1.450), with p values 0.368 and 0.206 in training and testing data, respectively. Further study showed that, for low expression patients, radiotherapy did not significantly increase new tumor event rate and disease progression rate, which partially supported our assumption. These results suggested that low expression of GLIS2 might significantly associate with the radiosensitivity of patients with gastric cancer. The GLIS2 gene might be a potential effective molecular marker of gastric cancer for precise radiotherapy.
Collapse
|
|
19
|
Thiagarajan A, Iyer NG. Genomics of radiation sensitivity in squamous cell carcinomas. Pharmacogenomics 2019; 20:457-466. [PMID: 30983507 DOI: 10.2217/pgs-2018-0154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Radiotherapy is an important modality in the management of squamous cell cancers with 50% of patients receiving radiotherapy at some point. Despite technological advances, the risk of severe toxicity in a proportion of radiosensitive patients limits radiation doses that can be safely prescribed affecting the potential for cure. While comorbidities, lifestyle and treatment factors can influence interindividual variations, genetic factors are thought to play a major role, accounting for approximately 80% of the variance observed. Over the last decade, substantial progress has been made in the field of radiogenomics, with compelling associations for SNPs identified in genes involved in DNA-damage response, cell-cycle control, apoptosis, antioxidant defenses and cytokine production. Future research efforts should be collaborative, focused on validating and broadening their clinical applicability. Numerous obstacles exist to the clinical application of this knowledge, which need to be overcome before personalized radiation therapy becomes a routine component of oncologic care.
Collapse
Affiliation(s)
- Anuradha Thiagarajan
- Division of Radiation Oncology, National Cancer Centre, 11 Hospital Drive, 169610, Singapore
| | - N Gopalakrishna Iyer
- Division of Surgical Oncology, National Cancer Centre, 11 Hospital Drive, 169610, Singapore.,Cancer Therapeutics Research Laboratory, National Cancer Centre, 11 Hospital Drive, 169610, Singapore
| |
Collapse
|
|
20
|
Wang L, Zhao Y, Wang Y, Wu X. The Role of Galectins in Cervical Cancer Biology and Progression. BIOMED RESEARCH INTERNATIONAL 2018; 2018:2175927. [PMID: 29854732 PMCID: PMC5964433 DOI: 10.1155/2018/2175927] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Revised: 03/18/2018] [Accepted: 03/27/2018] [Indexed: 02/06/2023]
Abstract
Cervical cancer is one of the malignant tumors with high incidence and high mortality among women in developing countries. The main factors affecting the prognosis of cervical cancer are the late recurrence and metastasis and the effective adjuvant treatment, which is radiation and chemotherapy or combination therapy. Galectins, a family containing many carbohydrate binding proteins, are closely involved in the occurrence and development of tumor. They are involved in tumor cells transformation, angiogenesis, metastasis, immune escape, and sensitivity against radiation and chemotherapy. Therefore, galectins are deemed as the targets of multifunctional cancer treatment. In this review, we mainly focus on the role of galectins, especially galectin-1, galectin-3, galectin-7, and galectin-9 in cervical cancer, and provide theoretical basis for potential targeted treatment of cervical cancer.
Collapse
Affiliation(s)
- Lufang Wang
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yanyan Zhao
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yanshi Wang
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xin Wu
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| |
Collapse
|
|
21
|
Domínguez ER, Orona J, Lin K, Pérez CJ, Benavides F, Kusewitt DF, Johnson DG. The p53 R72P polymorphism does not affect the physiological response to ionizing radiation in a mouse model. Cell Cycle 2017; 16:1153-1163. [PMID: 28594296 DOI: 10.1080/15384101.2017.1312234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Tissue culture and mouse model studies show that the presence of the arginine (R) or proline (P) coding single nucleotide polymorphism (SNP) of the tumor suppressor gene p53 at codon 72 (p53 R72P) differentially affects the responses to genotoxic insult. Compared to the P variant, the R variant shows increased apoptosis in most cell cultures and mouse model tissues in response to genotoxins, and epidemiological studies suggest that the R variant may enhance cancer survival and reduce the risks of adverse reactions to genotoxic cancer treatment. As ionizing radiation (IR) treatment is often used in cancer therapy, we sought to test the physiological effects of IR in mouse models of the p53 R72P polymorphism. By performing blood counts, immunohistochemical (IHC) staining and survival studies in mouse populations rigorously controlled for strain background, sex and age, we discovered that p53 R72P polymorphism did not differentially affect the physiological response to IR. Our findings suggest that genotyping for this polymorphism to personalize IR therapy may have little clinical utility.
Collapse
Affiliation(s)
- Emily R Domínguez
- a Department of Epigenetics and Molecular Carcinogenesis , The University of Texas MD Anderson Cancer Center , Smithville , TX , USA
| | - Jennifer Orona
- a Department of Epigenetics and Molecular Carcinogenesis , The University of Texas MD Anderson Cancer Center , Smithville , TX , USA
| | - Kevin Lin
- a Department of Epigenetics and Molecular Carcinogenesis , The University of Texas MD Anderson Cancer Center , Smithville , TX , USA
| | - Carlos J Pérez
- a Department of Epigenetics and Molecular Carcinogenesis , The University of Texas MD Anderson Cancer Center , Smithville , TX , USA
| | - Fernando Benavides
- a Department of Epigenetics and Molecular Carcinogenesis , The University of Texas MD Anderson Cancer Center , Smithville , TX , USA
| | - Donna F Kusewitt
- b Department of Pathology , The University of Mexico School of Medicine , Albuquerque , NM , USA
| | - David G Johnson
- a Department of Epigenetics and Molecular Carcinogenesis , The University of Texas MD Anderson Cancer Center , Smithville , TX , USA
| |
Collapse
|
|
22
|
Zhu L, Sturgis EM, Lu Z, Zhang H, Wei P, Wei Q, Li G. Association between miRNA-binding site polymorphisms in double-strand break repair genes and risk of recurrence in patients with squamous cell carcinomas of the non-oropharynx. Carcinogenesis 2017; 38:432-438. [PMID: 28334093 DOI: 10.1093/carcin/bgx019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 02/17/2017] [Indexed: 01/15/2023] Open
Abstract
Genetic polymorphisms at miRNA-binding sites may affect miRNA-mediated gene regulation. Thus, miRNA-binding site polymorphisms in double-strand break (DSB) repair genes may affect DNA repair capacity, which in turn could affect cancer prognosis. To determine whether miRNA-binding site polymorphisms in DSB repair genes are associated with the risk of recurrence of squamous cell carcinoma of the non-oropharynx (SCCNOP), we used a log-rank test and multivariable Cox models to evaluate the associations between miRNA-binding site polymorphisms in DSB repair genes and SCCNOP recurrence. Compared with patients without common homozygous genotypes, patients with the variant genotypes of ATM rs227091, LIG3 rs4796030, and RAD51 rs7180135 had significantly better disease-free survival (DFS) (log-rank P = 0.046, 0.002, and 0.041, respectively) and lower risk of disease recurrence [HR (95% CI) = 0.7 (0.6-0.9), 0.6 (0.5-0.9), and 0.7 (0.6-0.9), respectively]. Furthermore, patients with the variant genotypes of these 3 polymorphisms had significantly lower recurrence risk than those without common homozygous genotypes did [HR = 0.3 (95% CI = 0.2-0.7)]. Among patients who received chemoradiation, those with the individual or combined variant genotypes of the three polymorphisms had a significantly lower risk of disease recurrence than those with the individual or combined common homozygous genotypes did. The individual or combined variant genotypes of the ATM rs227091, LIG3 rs4796030, and RAD51 rs7180135 polymorphisms significantly modify the risk of SCCNOP recurrence, particularly for patients treated with chemoradiation. Future prospective studies with larger sample sizes are warranted to validate these findings to enable more effective personalized treatment for SCCNOP patients.
Collapse
Affiliation(s)
- Lijun Zhu
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Unit 1445, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.,Department of Oral and Maxillofacial Surgery, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510515, China
| | - Erich M Sturgis
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Unit 1445, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.,Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhongming Lu
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Unit 1445, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.,Department of Otorhinolaryngology Head and Neck, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Hua Zhang
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Unit 1445, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.,Department of Otorhinolaryngology-Head & Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, 264000, China
| | - Peng Wei
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Unit 1445, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.,Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, FCT4.6044, Houston, TX 77030, USA and
| | - Qingyi Wei
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Unit 1445, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.,Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Guojun Li
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Unit 1445, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.,Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
23
|
Borchiellini D, Etienne-Grimaldi M, Bensadoun R, Benezery K, Dassonville O, Poissonnet G, Llorca L, Ebran N, Formento P, Château Y, Thariat J, Milano G. Candidate apoptotic and DNA repair gene approach confirms involvement of ERCC1, ERCC5, TP53 and MDM2 in radiation-induced toxicity in head and neck cancer. Oral Oncol 2017; 67:70-76. [DOI: 10.1016/j.oraloncology.2017.02.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 02/01/2017] [Accepted: 02/03/2017] [Indexed: 02/07/2023]
|
|
24
|
Wang TL, Ren YW, Wang HT, Yu H, Zhao YX. Association of Topoisomerase II (TOP2A) and Dual-Specificity Phosphatase 6 (DUSP6) Single Nucleotide Polymorphisms with Radiation Treatment Response and Prognosis of Lung Cancer in Han Chinese. Med Sci Monit 2017; 23:984-993. [PMID: 28231233 PMCID: PMC5335646 DOI: 10.12659/msm.899060] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background Mutations of DNA topoisomerase II (TOP2A) are associated with chemotherapy resistance, whereas dual-specificity phosphatase 6 (DUSP6) negatively regulates members of the mitogen-activated protein (MAP) kinase superfamily to control cell proliferation. This study assessed TOP2A and DUSP6 single nucleotide polymorphisms (SNPs) in non-small cell lung cancer (NSCLC) patients for association with chemoradiotherapy responses and prognosis. Material/Methods A total of 140 Chinese patients with histologically confirmed NSCLC were enrolled and subjected to genotyping of TOP2A rs471692 and DUSP6 rs2279574 using Taqman PCR. An independent sample t test was used to analyze differences in tumor regression after radiotherapy versus SNP risk factors. Kaplan-Meier curves analyzed overall survival, followed by the log-rank test and Cox proportional hazard models. Results There were no significant associations of TOP2A rs471692 and DUSP6 rs2279574 polymorphisms or clinicopathological variables with response to chemoradiotherapy (p>0.05). Comparing overall survival of 87 patients with stage I–III NSCLC treated with radiotherapy or chemoradiotherapy to clinicopathological variables, the data showed that tumor regression, weight loss, clinical stage, and cigarette smoking were independent prognostic predictors (p=0.009, 0.043, 0.004, and 0.025, respectively). Tumor regression rate >0.34 was associated with patent survival versus tumor regression rate ≤0.34 (p=0.007). Conclusions TOP2A rs471692 and DUSP6 rs2279574 SNPs were not associated with chemoradiotherapy response, whereas tumor regression, weight loss, clinical stage, and cigarette smoking were independent prognostic predictors for these Chinese patients with NSCLC.
Collapse
Affiliation(s)
- Tian-Lu Wang
- Department of Radiotherapy Oncology, The Fourth Hospital of China Medical University, Shenyang, Liaoning, China (mainland).,Department of Radiotherapy Oncology, Liaoning Cancer Hospital
| | - Yang-Wu Ren
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning, China (mainland).,Liaoning Provincial Department of Education, The Key Laboratory of Cancer Etiologic and Prevention, The First Hospital of China Medical University, Liaoning, Liaoning, China (mainland)
| | - He-Tong Wang
- Department of Radiotherapy Oncology, The Fourth Hospital of China Medical University, Shenyang, Liaoning, China (mainland).,Department of Radiotherapy Oncology, Shenyang Chest Hospital, Shenyang, Liaoning, China (mainland)
| | - Hong Yu
- Department of Radiotherapy Oncology, Liaoning Cancer Hospital
| | - Yu-Xia Zhao
- Department of Radiotherapy Oncology, The Fourth Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| |
Collapse
|
|
25
|
van Oorschot B, Uitterhoeve L, Oomen I, Ten Cate R, Medema JP, Vrieling H, Stalpers LJA, Moerland PD, Franken NAP. Prostate Cancer Patients with Late Radiation Toxicity Exhibit Reduced Expression of Genes Involved in DNA Double-Strand Break Repair and Homologous Recombination. Cancer Res 2017; 77:1485-1491. [PMID: 28108515 DOI: 10.1158/0008-5472.can-16-1966] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 11/17/2016] [Accepted: 11/18/2016] [Indexed: 11/16/2022]
Abstract
Severe late damage to normal tissue is a major limitation of cancer radiotherapy in prostate cancer patients. In a recent retrospective study, late radiation toxicity was found to relate to a decreased decay of γ-H2AX foci and reduced induction of DNA double-strand break repair genes. Here, we report evidence of prognostic utility in prostate cancer for γ-H2AX foci decay ratios and gene expression profiles derived from ex vivo-irradiated patient lymphocytes. Patients were followed ≥2 years after radiotherapy. Clinical characteristics were assembled, and toxicity was recorded using the Common Terminology Criteria (CTCAE) v4.0. No clinical factor was correlated with late radiation toxicity. The γ-H2AX foci decay ratio correlated negatively with toxicity grade, with a significant difference between grade ≥3 and grade 0 patients (P = 0.02). A threshold foci decay ratio, determined in our retrospective study, correctly classified 23 of 28 patients with grade ≥3 toxicity (sensitivity 82%) and 9 of 14 patients with grade 0 toxicity (specificity 64%). Induction of homologous recombination (HR) repair genes was reduced with increasing toxicity grade. The difference in fold induction of the HR gene set was most pronounced between grade 0 and grade ≥3 toxicity (P = 0.008). Notably, reduced responsiveness of HR repair genes to irradiation and inefficient double-strand break repair correlated with severe late radiation toxicity. Using a decay ratio classifier, we correctly classified 82% of patients with grade ≥3 toxicity, suggesting a prognostic biomarker for cancer patients with a genetically enhanced risk for late radiation toxicity to normal tissues after radiotherapy. Cancer Res; 77(6); 1485-91. ©2017 AACR.
Collapse
Affiliation(s)
- Bregje van Oorschot
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
| | - Lon Uitterhoeve
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Ilja Oomen
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Rosemarie Ten Cate
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Harry Vrieling
- Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Lukas J A Stalpers
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Perry D Moerland
- Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Nicolaas A P Franken
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| |
Collapse
|
|
26
|
Genetic Variants in CD44 and MAT1A Confer Susceptibility to Acute Skin Reaction in Breast Cancer Patients Undergoing Radiation Therapy. Int J Radiat Oncol Biol Phys 2016; 97:118-127. [PMID: 27816361 DOI: 10.1016/j.ijrobp.2016.09.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 07/09/2016] [Accepted: 09/14/2016] [Indexed: 11/23/2022]
Abstract
PURPOSE Heterogeneity in radiation therapy (RT)-induced normal tissue toxicity is observed in 10% of cancer patients, limiting the therapeutic outcomes. In addition to treatment-related factors, normal tissue adverse reactions also manifest from genetic alterations in distinct pathways majorly involving DNA damage-repair genes, inflammatory cytokine genes, cell cycle regulation, and antioxidant response. Therefore, the common sequence variants in these radioresponsive genes might modify the severity of normal tissue toxicity, and the identification of the same could have clinical relevance as a predictive biomarker. METHODS AND MATERIALS The present study was conducted in a cohort of patients with breast cancer to evaluate the possible associations between genetic variants in radioresponsive genes described previously and the risk of developing RT-induced acute skin adverse reactions. We tested 22 genetic variants reported in 18 genes (ie, NFE2L2, OGG1, NEIL3, RAD17, PTTG1, REV3L, ALAD, CD44, RAD9A, TGFβR3, MAD2L2, MAP3K7, MAT1A, RPS6KB2, ZNF830, SH3GL1, BAX, and XRCC1) using TaqMan assay-based real-time polymerase chain reaction. At the end of RT, the severity of skin damage was scored, and the subjects were dichotomized as nonoverresponders (Radiation Therapy Oncology Group grade <2) and overresponders (Radiation Therapy Oncology Group grade ≥2) for analysis. RESULTS Of the 22 single nucleotide polymorphisms studied, the rs8193 polymorphism lying in the micro-RNA binding site of 3'-UTR of CD44 was significantly (P=.0270) associated with RT-induced adverse skin reactions. Generalized multifactor dimensionality reduction analysis showed significant (P=.0107) gene-gene interactions between MAT1A and CD44. Furthermore, an increase in the total number of risk alleles was associated with increasing occurrence of overresponses (P=.0302). CONCLUSIONS The genetic polymorphisms in radioresponsive genes act as genetic modifiers of acute normal tissue toxicity outcomes after RT by acting individually (rs8193), by gene-gene interactions (MAT1A and CD44), and/or by the additive effects of risk alleles.
Collapse
|
|
27
|
Zhu Y, Gao G, Xia L, Li X, Wu X, Her C, Xu K. The polymorphichMSH5C85T allele augments radiotherapy-induced spermatogenic impairment. Andrology 2016; 4:873-9. [DOI: 10.1111/andr.12203] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 03/28/2016] [Accepted: 03/29/2016] [Indexed: 11/29/2022]
Affiliation(s)
- Y. Zhu
- Department of Laboratory Medicine; Xiangya School of Medicine; Central South University; Changsha China
| | - G. Gao
- Department of Laboratory Medicine; Xiangya School of Medicine; Central South University; Changsha China
| | - L. Xia
- Department of Tumor; The Third Xiangya Hospital; Central South University; Changsha China
| | - X. Li
- Department of Tumor; The Third Xiangya Hospital; Central South University; Changsha China
| | - X. Wu
- School of Molecular Biosciences; Washington State University; Pullman WA USA
| | - C. Her
- School of Molecular Biosciences; Washington State University; Pullman WA USA
| | - K. Xu
- Department of Laboratory Medicine; Xiangya School of Medicine; Central South University; Changsha China
| |
Collapse
|
|
28
|
Coates J, Souhami L, El Naqa I. Big Data Analytics for Prostate Radiotherapy. Front Oncol 2016; 6:149. [PMID: 27379211 PMCID: PMC4905980 DOI: 10.3389/fonc.2016.00149] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 05/31/2016] [Indexed: 12/14/2022] Open
Abstract
Radiation therapy is a first-line treatment option for localized prostate cancer and radiation-induced normal tissue damage are often the main limiting factor for modern radiotherapy regimens. Conversely, under-dosing of target volumes in an attempt to spare adjacent healthy tissues limits the likelihood of achieving local, long-term control. Thus, the ability to generate personalized data-driven risk profiles for radiotherapy outcomes would provide valuable prognostic information to help guide both clinicians and patients alike. Big data applied to radiation oncology promises to deliver better understanding of outcomes by harvesting and integrating heterogeneous data types, including patient-specific clinical parameters, treatment-related dose-volume metrics, and biological risk factors. When taken together, such variables make up the basis for a multi-dimensional space (the "RadoncSpace") in which the presented modeling techniques search in order to identify significant predictors. Herein, we review outcome modeling and big data-mining techniques for both tumor control and radiotherapy-induced normal tissue effects. We apply many of the presented modeling approaches onto a cohort of hypofractionated prostate cancer patients taking into account different data types and a large heterogeneous mix of physical and biological parameters. Cross-validation techniques are also reviewed for the refinement of the proposed framework architecture and checking individual model performance. We conclude by considering advanced modeling techniques that borrow concepts from big data analytics, such as machine learning and artificial intelligence, before discussing the potential future impact of systems radiobiology approaches.
Collapse
Affiliation(s)
- James Coates
- Department of Oncology, University of Oxford, Oxford, UK
| | - Luis Souhami
- Division of Radiation Oncology, McGill University Health Centre, Montreal, QC, Canada
| | - Issam El Naqa
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
| |
Collapse
|
|
29
|
Rumiato E, Boldrin E, Malacrida S, Battaglia G, Bocus P, Castoro C, Cagol M, Chiarion-Sileni V, Ruol A, Amadori A, Saggioro D. A germline predictive signature of response to platinum chemotherapy in esophageal cancer. Transl Res 2016; 171:29-37.e1. [PMID: 26772957 DOI: 10.1016/j.trsl.2015.12.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Revised: 11/26/2015] [Accepted: 12/16/2015] [Indexed: 11/25/2022]
Abstract
Platinum-based neoadjuvant therapy is the standard treatment for esophageal cancer (EC). At present, no reliable response markers exist, and patient therapeutic outcome is variable and very often unpredictable. The aim of this study was to understand the contribution of host constitutive DNA polymorphisms in discriminating between responder and nonresponder patients. DNA collected from 120 EC patients treated with platinum-based neoadjuvant chemotherapy was analyzed using drug metabolism enzymes and transporters (DMET) array platform that interrogates polymorphisms in 225 genes of drug metabolism and disposition. Four gene variants of DNA repair machinery, 2 in ERCC1 (rs11615; rs3212986), and 2 in XPD (rs1799793; rs13181) were also studied. Association analysis was performed with pTest software and corrected by permutation test. Predictive models of response were created using the receiver-operating characteristics curve approach and adjusted by the bootstrap procedure. Sixteen single nucleotide polymorphisms (SNPs) of the DMET array resulted significantly associated with either good or poor response; no association was found for the 4 variants mapping in DNA repair genes. The predictive power of 5 DMET SNPs mapping in ABCC2, ABCC3, CYP2A6, PPARG, and SLC7A8 genes was greater than that of clinical factors alone (area under the curve [AUC] = 0.74 vs 0.62). Interestingly, their combination with the clinical variables significantly increased the predictivity of the model (AUC = 0.78 vs 0.62, P = 0.0016). In conclusion, we identified a genetic signature of response to platinum-based neoadjuvant chemotherapy in EC patients. Our results also disclose the potential benefit of combining genetic and clinical variables for personalized EC management.
Collapse
Affiliation(s)
- Enrica Rumiato
- Immunology and Molecular Oncology, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Elisa Boldrin
- Immunology and Molecular Oncology, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Sandro Malacrida
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Giorgio Battaglia
- Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Paolo Bocus
- Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Carlo Castoro
- Oncological Surgery, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Matteo Cagol
- Oncological Surgery, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | | | - Alberto Ruol
- Department of Surgical Sciences, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Alberto Amadori
- Immunology and Molecular Oncology, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; Department of Surgical Sciences, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Daniela Saggioro
- Immunology and Molecular Oncology, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy.
| |
Collapse
|
|
30
|
Zhang H, Wang M, Shi T, Shen L, Liang L, Deng Y, Li G, Zhu J, Wu Y, Fan M, Deng W, Wei Q, Zhang Z. TNF rs1799964 as a Predictive Factor of Acute Toxicities in Chinese Rectal Cancer Patients Treated With Chemoradiotherapy. Medicine (Baltimore) 2015; 94:e1955. [PMID: 26559268 PMCID: PMC4912262 DOI: 10.1097/md.0000000000001955] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Acute toxicity is the main dose-limiting factor in the chemoradiotherapy of rectal cancer patients and depends on several pro-inflammatory factors, including interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-α). It is unknown whether genetic factors, such as single-nucleotide polymorphisms (SNPs) in the IL-1, IL-6, and TNF genes, are also associated with acute toxicity in the process.We genotyped 5 potentially functional SNPs in these 3 genes (TNF rs1799964, TNF rs1800629, IL-6 rs1800796, and IL-1 rs1143623, IL-1 rs1143627) and estimated their associations with severe acute radiation injury (grade ≥2) in 356 rectal cancer patients.We found a predictive role of the TNF rs1799964 T variant allele in the development of acute injury (for CT vs CC: adjusted odds ratio [OR] = 4.718, 95% confidence interval [CI] = 1.152-19.328, P = 0.031; for TT vs CC: adjusted OR = 4.443, 95% CI = 1.123-17.581, P = 0.034). In the dominant model, for CT/TT vs CC, the adjusted OR = 4.132, 95% CI = 1.069-15.966, and P = 0.04.Our results suggested that genetic variants in the TNF gene may influence acute injury in rectal cancer patients treated with chemoradiotherapy and may be a predictor for personalized treatment. Additional larger and independent studies are needed to confirm our findings.
Collapse
Affiliation(s)
- Hui Zhang
- From the Department of Radiation Oncology (HZ, LS, LL, GL, JZ, YW, MF, WD, ZZ); Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China (MW, YD, QW); Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina (QW); Department of Obstetrics and Gynocology, Zhongshan Hospital (TS); and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China (HZ, MW, LS, LL, YD, GL, JZ, YW, MF, WD, ZZ)
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Zhang H, Wang M, Shi T, Shen L, Zhu J, Sun M, Deng Y, Liang L, Li G, Wu Y, Fan M, Wei Q, Zhang Z. Genetic polymorphisms of PAI-1 and PAR-1 are associated with acute normal tissue toxicity in Chinese rectal cancer patients treated with pelvic radiotherapy. Onco Targets Ther 2015; 8:2291-301. [PMID: 26347502 PMCID: PMC4556037 DOI: 10.2147/ott.s83723] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Plasminogen activator inhibitor type 1 (PAI-1) and protease-activated receptor-1 (PAR-1) are crucial mediators of the intestinal microenvironment and are involved in radiation-induced acute and chronic injury. To evaluate whether genetic polymorphisms of PAI-1 and PAR-1 were predictors of radiation-induced injury in patients with rectal cancer, we retrospectively evaluated 356 rectal cancer patients who had received pelvic radiotherapy and analyzed the association of genetic polymorphisms of PAI-1 and PAR-1 with acute toxicities after radiotherapy. Acute adverse events were scored, including dermatitis, fecal incontinence (anal toxicity), hematological toxicity, diarrhea, and vomiting. The patients were grouped into grade ≥2 and grade 0-1 toxicity groups to analyze the acute toxicities. Genotyping of six single nucleotide polymorphisms (SNPs) of PAI-1 and PAR-1 was performed using TaqMan assays. A logistic regression model was used to estimate the odds ratios and 95% confidence intervals. Of the 356 individuals, 264 (72.5%) had grade ≥2 total toxicities; within this group, there were 65 (18.3%) individuals who reached grade ≥3 toxicities. There were 19.5% (69/354) and 36.9% (130/352) patients that developed grade ≥2 toxicities for diarrhea and fecal incontinence, respectively. The variant genotype GG of rs1050955 in PAI-1 was found to be negatively associated with the risk of diarrhea and incontinence (P<0.05), whereas the AG and GG genotypes of rs2227631 in PAI-1 were associated with an increased risk of incontinence. The CT genotype of PAR-1 rs32934 was associated with an increased risk of total toxicity compared with the CC allele. Our results demonstrated that SNPs in the PAI-1 and PAR-1 genes were associated with acute injury in rectal cancer patients treated with pelvic irradiation. These SNPs may be useful biomarkers for predicting acute radiotoxicity in patients with rectal cancer if validated in future studies.
Collapse
Affiliation(s)
- Hui Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Mengyun Wang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Tingyan Shi
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Lijun Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Ji Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Menghong Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Yun Deng
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Liping Liang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Guichao Li
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Yongxin Wu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Ming Fan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Qingyi Wei
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| |
Collapse
|
|
32
|
Genetic risk of subsequent esophageal cancer in lymphoma and breast cancer long-term survival patients: a pilot study. THE PHARMACOGENOMICS JOURNAL 2015; 16:266-71. [PMID: 26054330 DOI: 10.1038/tpj.2015.41] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 04/22/2015] [Accepted: 04/28/2015] [Indexed: 02/06/2023]
|
|
33
|
Ree AH, Redalen KR. Personalized radiotherapy: concepts, biomarkers and trial design. Br J Radiol 2015; 88:20150009. [PMID: 25989697 DOI: 10.1259/bjr.20150009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
In the past decade, and pointing onwards to the immediate future, clinical radiotherapy has undergone considerable developments, essentially including technological advances to sculpt radiation delivery, the demonstration of the benefit of adding concomitant cytotoxic agents to radiotherapy for a range of tumour types and, intriguingly, the increasing integration of targeted therapeutics for biological optimization of radiation effects. Recent molecular and imaging insights into radiobiology will provide a unique opportunity for rational patient treatment, enabling the parallel design of next-generation trials that formally examine the therapeutic outcome of adding targeted drugs to radiation, together with the critically important assessment of radiation volume and dose-limiting treatment toxicities. In considering the use of systemic agents with presumed radiosensitizing activity, this may also include the identification of molecular, metabolic and imaging markers of treatment response and tolerability, and will need particular attention on patient eligibility. In addition to providing an overview of clinical biomarker studies relevant for personalized radiotherapy, this communication will highlight principles in addressing clinical evaluation of combined-modality-targeted therapeutics and radiation. The increasing number of translational studies that bridge large-scale omics sciences with quality-assured phenomics end points-given the imperative development of open-source data repositories to allow investigators the access to the complex data sets-will enable radiation oncology to continue to position itself with the highest level of evidence within existing clinical practice.
Collapse
Affiliation(s)
- A H Ree
- 1 Department of Oncology, Akershus University Hospital, Lørenskog, Norway.,2 Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - K R Redalen
- 1 Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| |
Collapse
|
|
34
|
Abstract
Peptide receptor radionuclide therapy with (90)Y-peptides is generally well tolerated. Acute side effects are usually mild; some are related to the coadministration of amino acids and others to the radiopeptide itself. Chronic and permanent effects on target organs, particularly kidneys and bone marrow, are generally mild if necessary precautions are taken. The potential risk to kidney and red marrow limits the amount of radioactivity that may be administered. However, when tumor masses are irradiated with adequate doses, volume reduction may be observed. (90)Y-octreotide has been the most used radiopeptide in the first 8 to 10 years of experience.
Collapse
Affiliation(s)
- Lisa Bodei
- Division of Nuclear Medicine, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy
| | - Marta Cremonesi
- Division of Medical Physics, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy
| | - Giovanni Paganelli
- Division of Nuclear Medicine, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy.
| |
Collapse
|
|
35
|
Pezzolo E, Modena Y, Corso B, Giusti P, Gusella M. Germ line polymorphisms as predictive markers for pre-surgical radiochemotherapy in locally advanced rectal cancer: a 5-year literature update and critical review. Eur J Clin Pharmacol 2015; 71:529-39. [PMID: 25740678 DOI: 10.1007/s00228-015-1824-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 02/11/2015] [Indexed: 12/19/2022]
Abstract
PURPOSE Locally advanced rectal cancer is currently treated with pre-surgical radiotherapy and chemotherapy. Approximately one-half of patients obtain a relevant shrinkage/disappearance of tumour, with major clinical advantages. The remaining patients, in contrast, show no benefit and possibly need alternative treatment. To provide the best therapeutic option for each individual patient, predictive markers have been widely researched. This review was undertaken to evaluate recent progress made in this field. METHODS A systematic literature search was performed using PubMed and Scopus database, focused on germ line gene polymorphisms as biomarkers and response and toxicity as outcomes. Because an exhaustive previous review was available describing findings up to 2008, we restricted our analysis to the last 5 years. RESULTS Ten original research articles were found, reporting promising results for some candidate genes in drug metabolism (TYMS, MTHFR), DNA repair (XRCC1, OGG1, CCND1) and inflammation (SOD2, TGFB1)/immunity (IL13) pathways, but with no firm conclusion. All the studies had small sample size and were defined as exploratory. This review highlights pivotal molecular, clinical, genetic and statistical issues in the investigation of genetic polymorphisms as outcome predictors for rectal cancer and offers suggestions for future development. CONCLUSIONS What emerges is a clear need for new proposals, especially in view of the increasing evidence for tumour-host and gene-gene interactions during anticancer treatment, together with stronger adherence to proper methodological requirements.
Collapse
Affiliation(s)
- Elisa Pezzolo
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Largo Meneghetti, 2, 35131, Padua, Italy,
| | | | | | | | | |
Collapse
|
|
36
|
Predictive SNPs for radiation-induced damage in lung cancer patients with radiotherapy: a potential strategy to individualize treatment. Int J Biol Markers 2015; 30:e1-11. [PMID: 25262703 DOI: 10.5301/jbm.5000108] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2014] [Indexed: 12/25/2022]
Abstract
In the treatment of lung cancer, radiotherapy has become one of the most important therapies, despite its sometimes unpredictable side effects. As such, identifying lung cancer patients who are at high risk of developing severe radiation-induced damage (mainly radiation pneumonitis and radiation-induced esophageal toxicity) and applying effect intervention or monitoring techniques are important. Although human diversity to a certain amount is explained by clinical and dosimetric factors, the presence of specific genetic determinants also influences the occurrence of radiation-induced damage. Here we summarize the data on mechanisms of radiation pneumonitis and radiation-induced esophageal toxicity supporting the involvement of variances of genes in the evolution of radiation-induced damage. Furthermore, the available evidence from current clinical studies of genetic polymorphisms for the prediction of radiation pneumonitis and radiation-induced esophageal toxicity is discussed. Eventually, this may help to truly individualize radiotherapy, using a personal genetic profile of the most relevant genes for each lung cancer patient.
Collapse
|
|
37
|
Brent RL. Protection of the gametes embryo/fetus from prenatal radiation exposure. HEALTH PHYSICS 2015; 108:242-274. [PMID: 25551507 DOI: 10.1097/hp.0000000000000235] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
There is no convincing evidence of germline mutation manifest as heritable disease in the offspring of humans attributable to ionizing radiation, yet radiation clearly induces mutations in microbes and somatic cells of rodents and humans. Doses to the embryo estimated to be in the range of 0.15-0.2 Gy during the pre-implantation and pre-somite stages may increase the risk of embryonic loss. However, an increased risk of congenital malformations or growth retardation has not been observed in the surviving embryos. These results are primarily derived from mammalian animal studies and are referred to as the "all-or-none phenomenon." The tissue reaction effects of ionizing radiation (previously referred to as deterministic effects) are congenital malformations, mental retardation, decreased intelligence quotient, microcephaly, neurobehavioral effects, convulsive disorders, growth retardation (height and weight), and embryonic and fetal death (miscarriage, stillbirth). All these effects are consistent with having a threshold dose below which there is no increased risk. The risk of cancer in offspring that have been exposed to diagnostic x-ray procedures while in utero has been debated for 55 y. High doses to the embryo or fetus (e.g., >0.5 Gy) increase the risk of cancer. Most pregnant women exposed to x-ray procedures and other forms of ionizing radiation today received doses to the embryo or fetus <0.1 Gy. The risk of cancer in offspring exposed in utero at exposures <0.1 Gy is controversial and has not been fully resolved. Diagnostic imaging procedures using ionizing radiation that are clinically indicated for the pregnant patient and her fetus should be performed because the clinical benefits outweigh the potential oncogenic risks.
Collapse
Affiliation(s)
- Robert L Brent
- *Thomas Jefferson University, Alfred I. DuPont Hospital for Children Research Department, Room 308, ARB, 1600 Rockland Road, Wilmington, DE 19803
| |
Collapse
|
|
38
|
Guo Z, Shu Y, Zhou H, Zhang W, Wang H. Radiogenomics helps to achieve personalized therapy by evaluating patient responses to radiation treatment. Carcinogenesis 2015; 36:307-17. [PMID: 25604391 DOI: 10.1093/carcin/bgv007] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Radiogenomics is the whole genome application of radiogenetics, which focuses on uncovering the underlying genetic causes of individual variation in sensitivity to radiation. There is a growing consensus that radiosensitivity is a complex, inherited polygenic trait, dependent on the interaction of many genes involved in multiple cell processes. An understanding of the genes involved in processes such as DNA damage response and oxidative stress response, has evolved toward examination of how genetic variants, most often, single nucleotide polymorphisms (SNPs), may influence interindividual radioresponse. Many experimental approaches, such as candidate SNP association studies, genome-wide association studies and massively parallel sequencing are being proposed to address these questions. We present a review focusing on recent advances in association studies of SNPs to radiotherapy response and discuss challenges and opportunities for further studies. We also highlight the clinical perspective of radiogenomics in the future of personalized treatment in radiation oncology.
Collapse
Affiliation(s)
- Zhen Guo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University and Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, P.R. China
| | - Yan Shu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA and
| | - Honghao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University and Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, P.R. China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University and Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, P.R. China;
| | - Hui Wang
- Department of Radiation Oncology, Hunan Provincial Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha 410013, P.R. China
| |
Collapse
|
|
39
|
Patrono C, Sterpone S, Testa A, Cozzi R. Polymorphisms in base excision repair genes: Breast cancer risk and individual radiosensitivity. World J Clin Oncol 2014; 5:874-882. [PMID: 25493225 PMCID: PMC4259949 DOI: 10.5306/wjco.v5.i5.874] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Revised: 04/03/2014] [Accepted: 04/17/2014] [Indexed: 02/06/2023] Open
Abstract
Breast cancer (BC) is the most common cancer among women worldwide. The aetiology and carcinogenesis of BC are not clearly defined, although genetic, hormonal, lifestyle and environmental risk factors have been established. The most common treatment for BC includes breast-conserving surgery followed by a standard radiotherapy (RT) regimen. However, radiation hypersensitivity and the occurrence of RT-induced toxicity in normal tissue may affect patients’ treatment. The role of DNA repair in cancer has been extensively investigated, and an impaired DNA damage response may increase the risk of BC and individual radiosensitivity. Single nucleotide polymorphisms (SNPs) in DNA repair genes may alter protein function and modulate DNA repair efficiency, influencing the development of various cancers, including BC. SNPs in DNA repair genes have also been studied as potential predictive factors for the risk of RT-induced side effects. Here, we review the literature on the association between SNPs in base excision repair (BER) genes and BC risk. We focused on X-ray repair cross complementing group 1 (XRCC1), which plays a key role in BER, and on 8-oxoguanine DNA glycosylase 1, apurinic/apyrimidinic endonuclease 1 and poly (ADP-ribose) polymerase-1, which encode three important BER enzymes that interact with XRCC1. Although no association between SNPs and radiation toxicity has been validated thus far, we also report published studies on XRCC1 SNPs and variants in other BER genes and RT-induced side effects in BC patients, emphasising that large well-designed studies are needed to determine the genetic components of individual radiosensitivity.
Collapse
|
|
40
|
Bodei L, Kidd M, Baum RP, Modlin IM. PRRT: Defining the paradigm shift to achieve standardization and individualization. J Nucl Med 2014; 55:1753-6. [PMID: 25256058 DOI: 10.2967/jnumed.114.143974] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Peptide receptor radionuclide therapy is a treatment for inoperable or metastatic neuroendocrine tumors. A key issue is the need to standardize the treatment and develop randomized controlled trials. Standardization would help define the characteristics of response, including progression-free survival; provide homogeneous phase II and III studies; delineate the position of peptide receptor radionuclide therapy in the therapeutic algorithm for neuroendocrine tumors; and establish the basis for approval by the regulatory authorities. Standardization of treatments is the starting point to redefine the treatment paradigm from a one-size-fits-all to a personalized treatment. To delineate the treatment paradigm, treatments should be optimized for efficacy and minimization of long-term toxicity, through dosimetry, and adapted to each individual, including relevant patient characteristics. Although differences in therapy outcomes may be explained by the specific absorbed dose (or biologically effective dose), they may also be related to discrete tumor- and patient-specific features. In this respect, a particular area of investigation is the assessment of genetic elements regulating tumor cell proliferation, especially those involved in the response to cytotoxic therapies.
Collapse
Affiliation(s)
- Lisa Bodei
- Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy Department of Gastroenterological Surgery, Yale University School of Medicine, New Haven, Connecticut; and
| | - Mark Kidd
- Department of Gastroenterological Surgery, Yale University School of Medicine, New Haven, Connecticut; and
| | - Richard P Baum
- THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik Bad Berka, Bad Berka, Germany
| | - Irvin M Modlin
- Department of Gastroenterological Surgery, Yale University School of Medicine, New Haven, Connecticut; and
| |
Collapse
|
|
41
|
Minicucci EM, da Silva GN, Salvadori DMF. Relationship between head and neck cancer therapy and some genetic endpoints. World J Clin Oncol 2014; 5:93-102. [PMID: 24829856 PMCID: PMC4014801 DOI: 10.5306/wjco.v5.i2.93] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 02/22/2014] [Accepted: 03/17/2014] [Indexed: 02/06/2023] Open
Abstract
Head and neck cancer (HNC) is the sixth most common human malignancy worldwide. The main forms of treatment for HNC are surgery, radiotherapy (RT) and chemotherapy (CT). However, the choice of therapy depends on the tumor staging and approaches, which are aimed at organ preservation. Because of systemic RT and CT genotoxicity, one of the important side effects is a secondary cancer that can result from the activity of radiation and antineoplastic drugs on healthy cells. Ionizing radiation can affect the DNA, causing single and double-strand breaks, DNA-protein crosslinks and oxidative damage. The severity of radiotoxicity can be directly associated with the radiation dosimetry and the dose-volume differences. Regarding CT, cisplatin is still the standard protocol for the treatment of squamous cell carcinoma, the most common cancer located in the oral cavity. However, simultaneous treatment with cisplatin, bleomycin and 5-fluorouracil or treatment with paclitaxel and cisplatin are also used. These drugs can interact with the DNA, causing DNA crosslinks, double and single-strand breaks and changes in gene expression. Currently, the late effects of therapy have become a recurring problem, mainly due to the increased survival of HNC patients. Herein, we present an update of the systemic activity of RT and CT for HNC, with a focus on their toxicogenetic and toxicogenomic effects.
Collapse
|
|
42
|
Among 45 variants in 11 genes, HDM2 promoter polymorphisms emerge as new candidate biomarker associated with radiation toxicity. 3 Biotech 2014; 4:137-148. [PMID: 28324443 PMCID: PMC3964253 DOI: 10.1007/s13205-013-0135-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 04/11/2013] [Indexed: 01/09/2023] Open
Abstract
Due to individual variations in radiosensitivity, biomarkers are needed to tailor radiation treatment to cancer patients. Since single nucleotide polymorphisms (SNPs) are frequent in human, we hypothesized that SNPs in genes that mitigate the radiation response are associated with radiotoxicity, in particular late complications to radiotherapy and could be used as genetic biomarkers for radiation sensitivity. A total of 155 patients with nasopharyngeal cancer were included in the study. Normal tissue fibrosis was scored using RTOG/EORTC grading system. Eleven candidate genes (ATM, XRCC1, XRCC3, XRCC4, XRCC5, PRKDC, LIG4, TP53, HDM2, CDKN1A, TGFB1) were selected for their presumed influence on radiosensitivity. Forty-five SNPs (12 primary and 33 neighboring) were genotyped by direct sequencing of genomic DNA. Patients with severe fibrosis (cases, G3–4, n = 48) were compared to controls (G0–2, n = 107). Results showed statistically significant (P < 0.05) association with radiation complications for six SNPs (ATM G/A rs1801516, HDM2 promoter T/G rs2279744 and T/A rs1196333, XRCC1 G/A rs25487, XRCC5 T/C rs1051677 and TGFB1 C/T rs1800469). We conclude that these six SNPs are candidate genetic biomarkers for radiosensitivity in our patients that have cumulative effects as patients with severe fibrosis harbored significantly higher number of risk alleles than the controls (P < 0.001). Larger cohort, independent replication of these findings and genome-wide association studies are required to confirm these results in order for SNPs to be used as biomarkers to individualize radiotherapy on genetic basis.
Collapse
|
|
43
|
Proud C. Radiogenomics: The Promise of Personalized Treatment in Radiation Oncology? Clin J Oncol Nurs 2014; 18:185-9. [DOI: 10.1188/14.cjon.185-189] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
|
|
44
|
Usmani N, Leong N, Martell K, Lan L, Ghosh S, Pervez N, Pedersen J, Yee D, Murtha A, Amanie J, Sloboda R, Murray D, Parliament M. Single-nucleotide polymorphisms studied for associations with urinary toxicity from (125)I prostate brachytherapy implants. Brachytherapy 2014; 13:285-91. [PMID: 24656733 DOI: 10.1016/j.brachy.2014.02.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 01/31/2014] [Accepted: 02/07/2014] [Indexed: 11/17/2022]
Abstract
PURPOSE To identify clinical, dosimetric, and genetic factors that are associated with late urinary toxicity after a (125)I prostate brachytherapy implant. METHODS AND MATERIALS Genomic DNA from 296 men treated with (125)I prostate brachytherapy monotherapy was extracted from saliva samples for this study. A retrospective database was compiled including clinical, dosimetric, and toxicity data for this cohort of patients. Fourteen candidate single-nucleotide polymorphism (SNPs) from 13 genes (TP53, ERCC2, GSTP1, NOS, TGFβ1, MSH6, RAD51, ATM, LIG4, XRCC1, XRCC3, GSTA1, and SOD2) were tested in this cohort for correlations with toxicity. RESULTS This study identified 217 men with at least 2 years of followup. Of these, 39 patients developed Grade ≥2 late urinary complications with a transurethral resection of prostate, urethral stricture, gross hematuria, or a sustained increase in their International Prostate Symptom Score. The only clinical or dosimetric factor that was associated with late urinary toxicity was age (p = 0.02). None of the 14 SNPs tested in this study were associated with late urinary toxicity in the univariate analysis. CONCLUSIONS This study identified age as the only variable being associated with late urinary toxicity. However, the small sample size and the candidate gene approach used in this study mean that further investigations are essential. Genome-wide association studies are emerging as the preferred approach for future radiogenomic studies to overcome the limitations from a candidate gene approach.
Collapse
Affiliation(s)
- Nawaid Usmani
- Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada; Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
| | - Nelson Leong
- Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada
| | - Kevin Martell
- Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada
| | - Lanna Lan
- Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada
| | - Sunita Ghosh
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada; Division of Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada
| | - Nadeem Pervez
- Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada; Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - John Pedersen
- Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada; Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Don Yee
- Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada; Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Albert Murtha
- Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada; Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - John Amanie
- Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada; Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Ron Sloboda
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada; Division of Medical Physics, Cross Cancer Institute, Edmonton, Alberta, Canada
| | - David Murray
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada; Division of Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada
| | - Matthew Parliament
- Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada; Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
45
|
Venkatesh GH, Manjunath VB, Mumbrekar KD, Negi H, Fernandes DJ, Sharan K, Banerjee S, Bola Sadashiva SR. Polymorphisms in radio-responsive genes and its association with acute toxicity among head and neck cancer patients. PLoS One 2014; 9:e89079. [PMID: 24594932 PMCID: PMC3942321 DOI: 10.1371/journal.pone.0089079] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Accepted: 01/14/2014] [Indexed: 11/18/2022] Open
Abstract
Cellular and molecular approaches are being explored to find a biomarker which can predict the development of radiation induced acute toxicity prior to radiation therapy. SNPs in radiation responsive genes may be considered as an approach to develop tools for finding the inherited basis of clinical radiosensitivity. The current study attempts to screen single nucleotide polymorphisms/deletions in DNA damage response, DNA repair, profibrotic cytokine as well as antioxidant response genes and its predictive potential with the normal tissue adverse reactions from 183 head and neck cancer patients undergoing platinum based chemoradiotherapy or radiotherapy alone. We analysed 22 polymorphisms in 17 genes having functional relevance to radiation response. Radiation therapy induced oral mucositis and skin erythema was considered as end point for clinical radiosensitivity. Direct correlation of heterozygous and mutant alleles with acute reactions as well as haplotype correlation revealed NBN variants to be of predictive significance in analysing oral mucositis prior to radiotherapy. In addition, genetic linkage disequilibrium existed in XRCC1 polymorphisms for >grade 2 oral mucositis and skin reaction indicating the complex inheritance pattern. The current study indicates an association for polymorphism in NBN with normal tissue radiosensitivity and further warrants the replication of such studies in a large set of samples.
Collapse
Affiliation(s)
- Goutham Hassan Venkatesh
- Division of Radiobiology & Toxicology, School of Life Sciences, Manipal University, Manipal, Karnataka, India
| | | | - Kamalesh Dattaram Mumbrekar
- Division of Radiobiology & Toxicology, School of Life Sciences, Manipal University, Manipal, Karnataka, India
| | - Hitendra Negi
- Division of Biotechnology, School of Life Sciences, Manipal University, Manipal, Karnataka, India
| | - Donald Jerard Fernandes
- Department of Radiotherapy & Oncology, Shiridi SaiBaba Cancer Hospital and Research Centre, Kasturba Hospital, Manipal, Karnataka, India
| | - Krishna Sharan
- Department of Radiotherapy & Oncology, Shiridi SaiBaba Cancer Hospital and Research Centre, Kasturba Hospital, Manipal, Karnataka, India
| | - Sourjya Banerjee
- Department of Radiotherapy & Oncology, Kasturba Medical College and Hospital, Mangalore, Karnataka, India
| | - Satish Rao Bola Sadashiva
- Division of Radiobiology & Toxicology, School of Life Sciences, Manipal University, Manipal, Karnataka, India
- * E-mail:
| |
Collapse
|
|
46
|
Van den Broeck T, Joniau S, Clinckemalie L, Helsen C, Prekovic S, Spans L, Tosco L, Van Poppel H, Claessens F. The role of single nucleotide polymorphisms in predicting prostate cancer risk and therapeutic decision making. BIOMED RESEARCH INTERNATIONAL 2014; 2014:627510. [PMID: 24701578 PMCID: PMC3950427 DOI: 10.1155/2014/627510] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 01/07/2014] [Indexed: 12/20/2022]
Abstract
Prostate cancer (PCa) is a major health care problem because of its high prevalence, health-related costs, and mortality. Epidemiological studies have suggested an important role of genetics in PCa development. Because of this, an increasing number of single nucleotide polymorphisms (SNPs) had been suggested to be implicated in the development and progression of PCa. While individual SNPs are only moderately associated with PCa risk, in combination, they have a stronger, dose-dependent association, currently explaining 30% of PCa familial risk. This review aims to give a brief overview of studies in which the possible role of genetic variants was investigated in clinical settings. We will highlight the major research questions in the translation of SNP identification into clinical practice.
Collapse
Affiliation(s)
- Thomas Van den Broeck
- Department of Urology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
- Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O&N1, P.O. Box 901, Herestraat 49, 3000 Leuven, Belgium
| | - Steven Joniau
- Department of Urology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Liesbeth Clinckemalie
- Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O&N1, P.O. Box 901, Herestraat 49, 3000 Leuven, Belgium
| | - Christine Helsen
- Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O&N1, P.O. Box 901, Herestraat 49, 3000 Leuven, Belgium
| | - Stefan Prekovic
- Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O&N1, P.O. Box 901, Herestraat 49, 3000 Leuven, Belgium
| | - Lien Spans
- Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O&N1, P.O. Box 901, Herestraat 49, 3000 Leuven, Belgium
| | - Lorenzo Tosco
- Department of Urology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Hendrik Van Poppel
- Department of Urology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Frank Claessens
- Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O&N1, P.O. Box 901, Herestraat 49, 3000 Leuven, Belgium
| |
Collapse
|
|
47
|
van Oorschot B, Hovingh SE, Moerland PD, Medema JP, Stalpers LJA, Vrieling H, Franken NAP. Reduced activity of double-strand break repair genes in prostate cancer patients with late normal tissue radiation toxicity. Int J Radiat Oncol Biol Phys 2014; 88:664-70. [PMID: 24411188 DOI: 10.1016/j.ijrobp.2013.11.219] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Revised: 11/13/2013] [Accepted: 11/13/2013] [Indexed: 10/25/2022]
Abstract
PURPOSE To investigate clinical parameters and DNA damage response as possible risk factors for radiation toxicity in the setting of prostate cancer. METHODS AND MATERIALS Clinical parameters of 61 prostate cancer patients, 34 with (overresponding, OR) and 27 without (non-responding, NR) severe late radiation toxicity were assembled. In addition, for a matched subset the DNA damage repair kinetics (γ-H2AX assay) and expression profiles of DNA repair genes were determined in ex vivo irradiated lymphocytes. RESULTS Examination of clinical data indicated none of the considered clinical parameters to be correlated with the susceptibility of patients to develop late radiation toxicity. Although frequencies of γ-H2AX foci induced immediately after irradiation were similar (P=.32), significantly higher numbers of γ-H2AX foci were found 24 hours after irradiation in OR compared with NR patients (P=.03). Patient-specific γ-H2AX foci decay ratios were significantly higher in NR patients than in OR patients (P<.0001). Consequently, NR patients seem to repair DNA double-strand breaks (DSBs) more efficiently than OR patients. Moreover, gene expression analysis indicated several genes of the homologous recombination pathway to be stronger induced in NR compared with OR patients (P<.05). A similar trend was observed in genes of the nonhomologous end-joining repair pathway (P=.09). This is congruent with more proficient repair of DNA DSBs in patients without late radiation toxicity. CONCLUSIONS Both gene expression profiling and DNA DSB repair kinetics data imply that less-efficient repair of radiation-induced DSBs may contribute to the development of late normal tissue damage. Induction levels of DSB repair genes (eg, RAD51) may potentially be used to assess the risk for late radiation toxicity.
Collapse
Affiliation(s)
- Bregje van Oorschot
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
| | - Suzanne E Hovingh
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Perry D Moerland
- Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Lukas J A Stalpers
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Harry Vrieling
- Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Nicolaas A P Franken
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Molecular Medicine (CEMM), Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
48
|
Olsen CE, Berg K, Selbo PK, Weyergang A. Circumvention of resistance to photodynamic therapy in doxorubicin-resistant sarcoma by photochemical internalization of gelonin. Free Radic Biol Med 2013; 65:1300-1309. [PMID: 24076428 DOI: 10.1016/j.freeradbiomed.2013.09.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Revised: 09/16/2013] [Accepted: 09/17/2013] [Indexed: 12/14/2022]
Abstract
A wide range of anti-cancer therapies have been shown to induce resistance upon repetitive treatment and such adapted resistance may also cause cross-resistance to other treatment modalities. We here show that MES-SA/Dx5 cells with adapted resistance to doxorubicin (DOX) are cross-resistant to photodynamic therapy (PDT). A DOX-induced increased expression of the reactive oxygen species (ROS)-scavenging proteins glutathione peroxidase (GPx) 1 and GPx4 in MES-SA/Dx5 cells was indicated as the mechanism of resistance to PDT in line with the reduction in PDT-generated ROS observed in this cell line. ROS-induced p38 activation was, in addition, shown to be reduced to one-third of the signal of the parental MES-SA cells 2h after PDT, and addition of the p38 inhibitor SB203580 confirmed p38 activation as a death signal after PDT in the MES-SA cells. The MES-SA/Dx5 cells were also cross-resistant to ionizing radiation in agreement with the increased GPx1 and GPx4 expression. Surprisingly, PDT-induced endo/lysosomal release of the ribosome-inactivating protein gelonin (photochemical internalization (PCI)) was more effective in the PDT-resistant MES-SA/Dx5 cells, as measured by synergy calculations in both cell lines. Analysis of death-inducing signaling indicated a low activation of caspase-3 and a strong PARP I cleavage after PDT and PCI in both cell lines. The PARP I activation was, however, stronger after PCI than after PDT in the MES-SA cells, but not in the MES-SA/Dx5 cells, and therefore cannot explain the strong PCI effect in the MES-SA/Dx5 cells. In conclusion PCI of recombinant gelonin circumvents ROS resistance in an apoptosis-independent manner.
Collapse
Affiliation(s)
- Cathrine Elisabeth Olsen
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway.
| | - Kristian Berg
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway
| | - Pål Kristian Selbo
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway
| | - Anette Weyergang
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway
| |
Collapse
|
|
49
|
Zhang B, Chen J, Ren Z, Chen Y, Li J, Miao X, Song Y, Zhao T, Li Y, Shi Y, Ren D, Liu J. A specific miRNA signature promotes radioresistance of human cervical cancer cells. Cancer Cell Int 2013; 13:118. [PMID: 24283459 PMCID: PMC3867218 DOI: 10.1186/1475-2867-13-118] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 11/24/2013] [Indexed: 01/24/2023] Open
Abstract
Background The mechanisms responsible for cervical cancer radioresistance are still largely unexplored. The present study aimed to identify miRNAs associated with radioresistance of cervical cancer cells. Methods The radioresistant cervical cancer cell variants were established by repeated selection with irradiation. The miRNA profiles of radioresistant cells and their corresponding controls were analyzed and compared using microarray. Differentially expressed miRNAs were confirmed by quantitative real-time PCR. Cervical cancer cells were transfected with miRNA-specific mimics or inhibitors. Radiosensitivity of cervical cancer cells were determined using colony-forming assay. Results Among the differentially expressed miRNAs, 20 miRNAs showed the similar pattern of alteration (14 miRNAs were overexpressed whilst 6 were suppressed) in all three radioresistant cervical cancer cell variants compared to their controls. A miRNA signature consisting of 4 miRNAs (miR-630, miR-1246, miR-1290 and miR-3138) exhibited more than 5 folds of increase in radioresistant cells. Subsequent analysis revealed that these four miRNAs could be up-regulated in cervical cancer cells by radiation treatment in both time-dependent and dose-dependent manners. Ectopic expression of each of these 4 miRNAs can dramatically increase the survival fraction of irradiated cervical cancer cells. Moreover, inhibition of miR-630, one miRNA of the specific signature, could reverse radioresistance of cervical cancer cells. Conclusions The present study indicated that miRNA is involved in radioresistance of human cervical cancer cells and that a specific miRNA signature consisting of miR-630, miR-1246, miR-1290 and miR-3138 could promote radioresistance of cervical cancer cells.
Collapse
Affiliation(s)
- Bin Zhang
- Department of Radiation Medicine, Fourth Military Medical University, 169 Changle Western Road, Xi'an, Shaanxi 710032, China.,State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.,School of Aerospace Medicine, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Jun Chen
- Department of Osteology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Zhenghua Ren
- Department of Radiation Medicine, Fourth Military Medical University, 169 Changle Western Road, Xi'an, Shaanxi 710032, China
| | - Yongbin Chen
- Department of Radiation Medicine, Fourth Military Medical University, 169 Changle Western Road, Xi'an, Shaanxi 710032, China
| | - Jinhui Li
- Department of Radiation Medicine, Fourth Military Medical University, 169 Changle Western Road, Xi'an, Shaanxi 710032, China
| | - Xia Miao
- Department of Radiation Medicine, Fourth Military Medical University, 169 Changle Western Road, Xi'an, Shaanxi 710032, China
| | - Yang Song
- Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Tao Zhao
- Department of Radiation Medicine, Fourth Military Medical University, 169 Changle Western Road, Xi'an, Shaanxi 710032, China
| | - Yurong Li
- Department of Radiation Medicine, Fourth Military Medical University, 169 Changle Western Road, Xi'an, Shaanxi 710032, China
| | - Yongquan Shi
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Dongqing Ren
- Department of Radiation Medicine, Fourth Military Medical University, 169 Changle Western Road, Xi'an, Shaanxi 710032, China
| | - Junye Liu
- Department of Radiation Medicine, Fourth Military Medical University, 169 Changle Western Road, Xi'an, Shaanxi 710032, China
| |
Collapse
|
|
50
|
Investigation of genetic polymorphisms related to the outcome of radiotherapy for prostate cancer patients. DISEASE MARKERS 2013; 35:701-10. [PMID: 24324286 PMCID: PMC3844174 DOI: 10.1155/2013/762685] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 10/08/2013] [Indexed: 11/17/2022]
Abstract
The purpose of this study was to evaluate the association between ATM, TP53 and MDM2 polymorphisms in prostate cancer patients and morbidity after radiotherapy. The presence of ATM (rs1801516), TP53 (rs1042522, rs1800371, rs17878362, rs17883323, and rs35117667), and MDM2 (rs2279744) polymorphisms was assessed by direct sequencing of PCR fragments from 48 patients with histologically proven prostate adenocarcinoma and treated with external beam radiation. The side effects were classified according to the Radiation Therapy Oncology Group (RTOG) score. The results showed no association between clinical characteristics and the development of radiation toxicities (P > 0.05). The C>T transition in the position 16273 (intron 3) of TP53 (rs35117667) was significantly associated with the risk of acute skin toxicity (OR: 0.0072, 95% CI 0.0002–0.227, P = 0.003). The intronic TP53 polymorphism at position 16250 (rs17883323) was associated with chronic urinary toxicity (OR: 0.071, 95%CI 0.006–0.784, P = 0.032). No significant associations were found for the remaining polymorphisms (P > 0.05). The results show that clinical characteristics were not determinant on the developing of radiation sensitivity in prostate cancer patients, and intronic TP53 polymorphisms would be associated with increased acute and chronic radiation toxicities. These observations corroborate the importance of investigating the genetic profile to predict adverse side effects in patients undergoing radiotherapy.
Collapse
|