Chromosomal radiosensitivity in head and neck cancer patients: evidence for genetic predisposition?

The association between chromosomal radiosensitivity and genetic predisposition to head and neck cancer was investigated in this study. In all, 101 head and neck cancer patients and 75 healthy control individuals were included in the study. The G2 assay was used to measure chromosomal radiosensitivity. The results demonstrated that head and neck cancer patients had a statistically higher number of radiation-induced chromatid breaks than controls, with mean values of 1.23 and 1.10 breaks per cell, respectively (P<0.001). Using the 90th percentile of the G2 scores of the healthy individuals as a cutoff value for chromosomal radiosensitivity, 26% of the cancer patients were radiosensitive compared with 9% of the healthy controls (P=0.008). The mean number of radiation-induced chromatid breaks and the proportion of radiosensitive individuals were highest for oral cavity cancer patients (1.26 breaks per cell, 38%) and pharynx cancer patients (1.27 breaks per cell, 35%). The difference between patients and controls was most pronounced in the lower age group (⩽50 years, 1.32 breaks per cell, 38%) and in the non- and light smoking patient group (⩽10 pack-years, 1.28 breaks per cell, 46%). In conclusion, enhanced chromosomal radiosensitivity is a marker of genetic predisposition to head and neck cancer, and the genetic contribution is highest for oral cavity and pharynx cancer patients and for early onset and non- and light smoking patients

Chromosomal radiosensitivity and acute radiation side effects after radiotherapy in tumour patients - a follow-up study

Radiotherapists are highly interested in optimizing doses especially for patients who tend to suffer from side effects of radiotherapy (RT). It seems to be helpful to identify radiosensitive individuals before RT. Thus we examined aberrations in FISH painted chromosomes in in vitro irradiated blood samples of a group of patients suffering from breast cancer. In parallel, a follow-up of side effects in these patients was registered and compared to detected chromosome aberrations. METHODS: Blood samples (taken before radiotherapy) were irradiated in vitro with 3 Gy X-rays and analysed by FISH-painting to obtain aberration frequencies of first cycle metaphases for each patient. Aberration frequencies were analysed statistically to identify individuals with an elevated or reduced radiation response. Clinical data of patients have been recorded in parallel to gain knowledge on acute side effects of radiotherapy. RESULTS: Eight patients with a significantly elevated or reduced aberration yield were identified by use of a t-test criterion. A comparison with clinical side effects revealed that among patients with elevated aberration yields one exhibited a higher degree of acute toxicity and two patients a premature onset of skin reaction already after a cumulative dose of only 10 Gy. A significant relationship existed between translocations in vitro and the time dependent occurrence of side effects of the skin during the therapy period. CONCLUSIONS: The results suggest that translocations can be used as a test to identify individuals with a potentially elevated radiosensitivity

Radiation-Induced Bystander Effects in Cultured Human Stem Cells

The radiation-induced "bystander effect" (RIBE) was shown to occur in a number of experimental systems both in vitro and in vivo as a result of exposure to ionizing radiation (IR). RIBE manifests itself by intercellular communication from irradiated cells to non-irradiated cells which may cause DNA damage and eventual death in these bystander cells. It is known that human stem cells (hSC) are ultimately involved in numerous crucial biological processes such as embryologic development; maintenance of normal homeostasis; aging; and aging-related pathologies such as cancerogenesis and other diseases. However, very little is known about radiation-induced bystander effect in hSC. To mechanistically interrogate RIBE responses and to gain novel insights into RIBE specifically in hSC compartment, both medium transfer and cell co-culture bystander protocols were employed.Human bone-marrow mesenchymal stem cells (hMSC) and embryonic stem cells (hESC) were irradiated with doses 0.2 Gy, 2 Gy and 10 Gy of X-rays, allowed to recover either for 1 hr or 24 hr. Then conditioned medium was collected and transferred to non-irradiated hSC for time course studies. In addition, irradiated hMSC were labeled with a vital CMRA dye and co-cultured with non-irradiated bystander hMSC. The medium transfer data showed no evidence for RIBE either in hMSC and hESC by the criteria of induction of DNA damage and for apoptotic cell death compared to non-irradiated cells (p>0.05). A lack of robust RIBE was also demonstrated in hMSC co-cultured with irradiated cells (p>0.05).These data indicate that hSC might not be susceptible to damaging effects of RIBE signaling compared to differentiated adult human somatic cells as shown previously. This finding could have profound implications in a field of radiation biology/oncology, in evaluating radiation risk of IR exposures, and for the safety and efficacy of hSC regenerative-based therapies

Avaliação dos danos do DNA na mucosa esofágica e sangue periférico de portadores da doença do refluxo gastroesofágico Evaluation of DNA damage in the esophageal mucosa and peripheral blood of patients with gastroesophageal reflux disease

RACIONAL: A doença do refluxo gastroesofágico é a afecção digestiva de maior prevalência. Os portadores podem apresentar na evolução algumas complicações, sendo o esôfago de Barrett a de maior importância, tendo em vista seu potencial de malignidade. Todavia os processos inflamatórios do trato gastrointestinal podem apresentar degeneração maligna. OBJETIVOS: Avaliar os possíveis danos do DNA em portadores de esofagite de refluxo gastroesofágico de vários graus e verificar a aplicação do ensaio Cometa na detecção dos mesmos. MÉTODOS: Foram estudados 25 pacientes distribuídos em quatro grupos: controle (n=5), esofagite leve (n=8), esofagite severa (n=5) e câncer (n=7). O ensaio Cometa foi realizado no sangue periférico (linfócitos) e biópsia do terço distal do esôfago. RESULTADOS: O ensaio Cometa detectou danos no DNA nos pacientes com esofagite leve e severa (sangue periférico e biópsia), sendo que na esofagite severa a intensidade dos danos foi maior (p<0,05). Os danos do DNA dos pacientes com esofagite severa e câncer não mostraram diferença significativa e a intensidade dos mesmos corresponde ao ensaio Cometa classe 4 (maior que 95% de danos). CONCLUSÕES: 1) As frequências de quebras do DNA da mucosa esofágica e linfócitos estão diretamente relacionadas ao grau de inflamação; 2) a esofagite severa apresenta praticamente a mesma frequência de danos no DNA do câncer esofágico; 3) o ensaio Cometa mostrou-se muito sensível para a detecção dos danos do DNA.<br>BACKGROUND: The gastroesophageal reflux disease is the most prevalent digestive disorder. Patients with it may present some complications during its development, and Barrett's esophagus is the most important in view of its potential malignancy. However, the inflammatory processes of the gastrointestinal tract may show malignant degeneration. AIM: To assess possible DNA damage in patients with gastroesophageal reflux esophagitis of various degrees and to evaluate the application of the Comet assay in its detection. METHODS: Twenty-five patients were studied. They were divided into four groups: control (n=5), mild esophagitis (n=8), severe esophagitis (n=5) and cancer (n=7). The Comet assay was performed on peripheral blood cells (lymphocytes) and biopsy of the distal esophagus. RESULTS: The Comet assay detected DNA damage in patients with mild and severe esophagitis (peripheral blood and biopsy), and damage intensity was greater in severe esophagitis (p<0,05). DNA damage in patients with severe esophagitis and cancer did not show significant difference, and its intensity corresponds to class-4 Comet assay (greater than 95% of damage). CONCLUSIONS: 1) The frequencies of DNA breakage in the esophageal mucosa and lymphocytes are directly related to inflammation level; 2) severe esophagitis shows virtually the same DNA damage frequency as that of esophageal cancer; 3) the Comet assay showed to be very sensitive for DNA damage detection

Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition

The chromosomal radiosensitivity of breast cancer patients with a known or putative genetic predisposition was investigated and compared to a group of healthy women. The chromosomal radiosensitivity was assessed with the G2 and the G0-micronucleus assay. For the G2 assay lymphocytes were irradiated in vitro with a dose of 0.4 Gy (60)Co γ-rays after 71 h incubation, and chromatid breaks were scored in 50 metaphases. For the micronucleus assay lymphocytes were exposed in vitro to 3.5 Gy (60)Co γ-rays at a high dose rate or low dose rate. 70 h post-irradiation cultures were arrested and micronuclei were scored in 1000 binucleate cells. The results demonstrated that the group of breast cancer patients with a known or putative genetic predisposition was on the average more radiosensitive than a population of healthy women, and this with the G2 as well as with the high dose rate and low dose rate micronucleus assay. With the G2 assay 43% of the patients were found to be radiosensitive. A higher proportion of the patients were radiosensitive with the micronucleus assay (45% with high dose rate and 61% with low dose rate). No correlation was found between the G2 and the G0-micronucleus chromosomal radiosensitivity. Out of the different subgroups considered, the group of the young breast cancer patients without family history showed the highest percentage of radiosensitive cases in the G2 (50%) as well as in the micronucleus assay (75–78%). British Journal of Cancer (2002) 87, 1379–1385. doi:10.1038/sj.bjc.6600628 www.bjcancer.com © 2002 Cancer Research U

G 2 chromosomal radiosensitivity in Danish survivors of childhood and adolescent cancer and their offspring.

In order to investigate the relationship between chromosomal radiosensitivity and early-onset cancer, the G2 chromosomal radiosensitivity assay was undertaken on a group of 23 Danish survivors of childhood and adolescent cancer, a control group comprising their partners and a group of 38 of their offspring. In addition, the previously reported in-house control group from Westlakes Research Institute (WRI) was extended to 27 individuals. When using the 90th percentile cutoff for the WRI control group, the proportion of individuals with elevated radiosensitivity was 11, 35, 52 and 53% for the WRI control, partner control, cancer survivor and the offspring groups, respectively, with significant differences between the WRI control group and the cancer survivor group (P=0.002) and the offspring group (P<0.001). However, while the comparisons with the WRI control group support an association of chromosomal radiosensitivity with cancer predisposition, when the partner control group was used to define the radiosensitivity cutoff point, no significant differences in radiosensitivity profiles were found between the partner control group and either the cancer survivor group or the offspring group. The failure to distinguish between the G2 aberration profiles of the apparently normal group of partners and the cancer survivor group suggests that any association with cancer should be viewed with caution, but also raises questions as to the suitability of the partners of cancer survivors to act as an appropriate control group. Heritability of the radiosensitive phenotype was examined by segregation analysis of the Danish families and suggested that 67.3% of the phenotypic variance of G2 chromosomal radiosensitivity is attributable to a putative major gene locus with dominant effect