Mortality rates among carriers of ataxia-telangiectasia mutant alleles

BACKGROUND: Mutations at the ataxia-telangiectasia locus cause a distinctive autosomal recessive syndrome in homozygotes and predispose heterozygotes to cancer and ischemic heart disease. OBJECTIVE: To examine mortality rates among persons carrying a mutated ataxia-telangiectasia gene. DESIGN: Retrospective cohort study. SETTING: The United States and Canada. PARTICIPANTS: 405 grandparents of patients with ataxia-telangiectasia. MEASUREMENTS: Ages at death and risk for death (from all causes, cancer, ischemic heart disease, and other causes) among carriers and noncarriers of ataxia-telangiectasia mutations. RESULTS: Compared with noncarriers, carriers of a mutated ataxia-telangiectasia allele had a significantly increased risk for death at 20 through 79 years of age (relative risk, 1.9 [95% CI, 1.3 to 2.8]) (P < 0.001). On average, carriers died 7 to 8 years earlier than noncarriers. Cancer caused most of the excess deaths, and ischemic heart disease caused the remainder. Among carriers, relative risk for death from cancer and ischemic heart disease before 80 years of age was 2.6 (CI, 1.4 to 4.7; P = 0.002) and 2.0 (CI, 1.0 to 4.0; P = 0.062), respectively. Compared with noncarriers, carriers who died of cancer were a mean of 4 years younger (P > 0.2) and carriers who died of ischemic heart disease were a mean of 11 years younger (P = 0.006). CONCLUSION: Carriers of mutations at the ataxia-telangiectasia locus, who make up 1.4% to 2% of the general population, have a higher mortality rate and an earlier age at death from cancer and ischemic heart disease than noncarriers.     

Bone marrow transplantation restores immune system function and prevents lymphoma in Atm-deficient mice

Ataxia-telangiectasia (A-T) is a human autosomal recessive disease caused by mutations in the gene encoding ataxia-telangiectasia mutated (ATM). A-T is characterized by progressive cerebellar degeneration, variable immunodeficiency, and a high incidence of leukemia and lymphoma. Recurrent sino-pulmonary infections secondary to immunodeficiency and hematopoietic malignancies are major causes of morbidity and mortality in A-T patients. In mice, an introduced mutation in Atm leads to a phenotype that recapitulates many of the symptoms of A-T, including immune system abnormalities and susceptibility to malignancy. Here we show that the replacement of the bone marrow compartment in Atm knockout mice (Atm(-/-)) using a clinically relevant, nonmyeloablative host-conditioning regimen can be used to overcome the immune deficiencies and prevent the malignancies observed in these mice. Therefore, bone marrow transplantation may prove to be of therapeutic benefit in A-T patients.     

Analysis of ataxia-telangiectasia mutated (ATM)- and Nijmegen breakage syndrome (NBS)-regulated gene expression patterns

Purpose Ataxia-telangiectasia (A-T) is a progressive, degenerative, complex autosomal recessive disease characterized by cerebellar degeneration, immunodeficiency, premature aging, radiosensitivity, and a predisposition to cancer. Mutations in the ataxia-telangiectasia mutated (atm) gene, which phosphorylates downstream effector proteins, are linked to A-T. One of the proteins phosphorylated by the ATM protein is Nijmegen Breakage Syndrome protein (NBS, p95/nibrin), which was recently shown to be encoded by a gene mutated in the Nijmegen breakage syndrome (nbs), an autosomal recessive disease with a phenotype virtually similar to that of A-T. The similarities in the clinical and cellular features of NBS and A-T have led us to hypothesize that the two corresponding gene products may function in similar ways in the cellular signaling pathway. Thus, we sought to identify genes whose expression is mediated by the atm and nbs gene products.Material and methods To identify genes, we performed an analysis of oligonucleotide microarrays using the appropriate cell lines, isogenic A-T (ATM^-) and control cells (ATM⁺), and isogenic NBS (NBS^-) and control cells (NBS⁺).Results We examined genes regulated by ATM and NBS, respectively. To determine the effect of ATM and NBS on gene expression in detail, we classified these genes into different functional categories, including those involved in apoptosis, cell cycle/DNA replication, growth/differentiation, signal transduction, cell-cell adhesion, and metabolism. In addition, we compared the genes regulated by the ATM and NBS to determine the relationship of their signaling pathways and to better understand their functional relationship.Conclusions We found that, while ATM and NBS regulate several genes in common, both of these proteins also have distinct patterns of gene regulation, findings consistent with the functional overlap and distinctiveness of these two conditions. Due to the role of ATM and NBS in tumor suppression and the response to chemotherapy and radiotherapy, these findings may assist in the development of a more rational approach to cancer treatment, as well as a better understanding of tumorigenesis.     

Radiation effects in fluoroscopically guided cardiac interventions--keeping them under control

It would appear that a significant number of cardiologists are unaware that skin injuries ranging from erythema to telangiectasia or even dermal necrosis can be caused by the procedures they perform. Conditions that have been reported to be associated with radiation-induced skin injuries include: the high values of the exposure factors required with thick patients; prolonged or multiple procedures; elevated radiosensitivity of some patients (ataxia telangiectasia); connective tissue disease and diabetes mellitus. The total number of reported severe injuries worldwide so far is 100-200, or over 200 when all degrees of skin injuries are included, but the real number may be substantially larger since initial symptoms often appear only weeks after the procedure and the cardiologist may not be notified, unless a procedure for systematic follow up is in place. Besides skin injuries, patients-more so, the younger ones-incur a risk of radiation-induced cancer at some stage in the future. Experience shows that, with awareness of radiation safety aspects, proper equipment performance, the use of proper techniques, and the monitoring of patient doses, severe skin injuries should not occur in patients undergoing 5-10 PTCA-s. However, for those patients whose radiation doses approach the thresholds for radiation injuries a systematic follow up is required. These issues are addressed here.     

Identification of insulin‐like growth factor 2 mRNA‐binding protein 3 as a radioresistance factor in squamous esophageal cancer cells

Identification of reliable markers of radiosensitivity and the key molecules that donate susceptibility to anticancer treatments to esophageal cancer cells would be highly desirable. We found that the mRNA expression of insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3) was higher in radioresistant TE‐5 and TE‐9 cells than in radiosensitive TE‐12 cloneA1 cells. Conversely, knocking down expression of IGF2BP3 mRNA in TE‐5 and TE‐9 cells using small interfering RNA significantly enhanced their radiosensitivity. Furthermore, patients with squamous cell esophageal cancers strongly expressing IGF2BP3 tended to respond poorly to chemoradiation. These data suggest that IGF2BP3 may be a key marker of radiosensitivity that diminishes the susceptibility of squamous cell esophageal cancer cells to radiotherapy. IGF2BP3 may, thus, be a useful target for improving radiotherapy for patients with esophageal squamous cell carcinoma.     

Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system

Ataxia-telangiectasia is a hereditary multisystemic disease resulting from mutations of ataxia telangiectasia, mutated (ATM) and is characterized by neurodegeneration, cancer, immune defects, and hypersensitivity to ionizing radiation. The molecular details of ATM function in the nervous system are unclear, although the neurological lesion in ataxia-telangiectasia becomes apparent early in life, suggesting a developmental origin. The central nervous system (CNS) of Atm-null mice shows a pronounced defect in apoptosis induced by genotoxic stress, suggesting ATM functions to eliminate neurons with excessive genomic damage. Here, we report that the death effector Bax is required for a large proportion of Atm-dependent apoptosis in the developing CNS after ionizing radiation (IR). Although many of the same regions of the CNS in both Bax-/- and Atm-/- mice were radioresistant, mice nullizygous for both Bax and Atm showed additional reduction in IR-induced apoptosis in the CNS. Therefore, although the major IR-induced apoptotic pathway in the CNS requires Atm and Bax, a p53-dependent collateral pathway exists that has both Atm- and Bax-independent branches. Further, Atm- and Bax-dependent apoptosis in the CNS also required caspase-3 activation. These data implicate Bax and caspase-3 as death effectors in neurodegenerative pathways.     

Chromosomal radiosensitivity during the G2 cell-cycle period of skin fibroblasts from individuals with familial cancer.

We reported previously that human cells after neoplastic transformation in culture had acquired an increased susceptibility to chromatid damage induced by x-irradiation during the G2 phase of the cell cycle. Evidence suggested that this results from deficient DNA repair during G2 phase. Cells derived from human tumors also showed enhanced G2-phase chromosomal radiosensitivity. Furthermore, skin fibroblasts from individuals with genetic diseases predisposing to a high risk of cancer, including ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, and xeroderma pigmentosum exhibited enhanced G2-phase chromosomal radiosensitivity. The present study shows that apparently normal skin fibroblasts from individuals with familial cancer--i.e., from families with a history of neoplastic disease--also exhibit enhanced G2-phase chromosomal radiosensitivity. This radiosensitivity appears, therefore, to be associated with both a genetic predisposition to cancer and a malignant neoplastic state. Furthermore, enhanced G2-phase chromosomal radiosensitivity may provide the basis for an assay to detect genetic susceptibility to cancer.     

Cancer Risk Related to Gastrointestinal Diagnostic Radiation Exposure

Exposure to ionizing radiation is associated with an increased risk of cancer. With the growing use of diagnostic imaging studies, there is concern for increasing the risk of radiation associated malignancy of the gastrointestinal tract. The purpose of this review is to summarize the existing literature for risk of gastrointestinal malignancy after ionizing radiation exposure from diagnostic imaging studies. Estimates of organ specific effective doses of radiation vary widely based on the method of measurement and patient factors. Most of the current data are based on calculations of organ effective doses from anthropomorphic phantoms and estimated cancer risk based on radiation exposure from environmental sources. Radiation associated cancer risk is dependent on both the cumulative radiation dose and the radiosensitivity of the particular organ. The majority of radiation exposure and risk associated with gastrointestinal malignancy comes from CT scans, especially of the abdomen/pelvis. Of the abdominal organs, the colon carries the highest lifetime attributable risk of radiation associated malignancy. The attributable risk of malignancy for an individual diagnostic imaging study is low, but measurable, and therefore imaging studies without radiation such as MRI and ultrasound should be considered, especially in patients who require repeated imaging studies. There is a shortage of epidemiological data and an absence of prospective data with adequate follow-up to describe accurate risk estimates of gastrointestinal cancers after diagnostic imaging. More studies are needed to better determine the risks of malignancy from diagnostic imaging.     

Cystic fibrosis transmembrane regulator (CFTR) DeltaF508 mutation and 5T allele in patients with chronic pancreatitis and exocrine pancreatic cancer. PANKRAS II Study Group

BACKGROUND: An increased risk of chronic pancreatitis has been described among carriers of the cystic fibrosis transmembrane regulator (CFTR) mutation. In addition, patients with cystic fibrosis may have a higher risk of exocrine pancreatic cancer. AIMS: To determine the prevalence of the DeltaF508 mutation and 5T allele, the most common CFTR disease related variants, and to assess their association with lifestyle factors in an unselected series of patients with chronic pancreatitis or pancreatic cancer. SUBJECTS: Patients recruited to the multicentre PANKRAS II study with a diagnosis of chronic pancreatitis and pancreatic cancer from whom normal DNA was available. METHODS: The DeltaF508 mutation and 5T allele were analysed using polymerase chain reaction amplified normal DNA. Information on clinical and lifestyle factors was obtained through personal interviews. RESULTS: Among patients with pancreatitis, no DeltaF508 alleles were found and the prevalence of the 5T allele was 10.5%, similar to that described in the general population. Among patients with pancreatic cancer, the prevalence of the DeltaF508 mutation and the 5T allele was 2.4% and 5.5%, respectively. 5T allele carriers with cancer consumed significantly less alcohol than non-carriers (p=0.038). CONCLUSIONS: Our findings do not support the view that the DeltaF508 mutation and 5T allele confer a higher risk of chronic pancreatitis or pancreatic cancer. Nevertheless, our data suggest that interactions between CFTR polymorphism and environmental factors may play a role in the pathogenesis of these diseases. Our study emphasises the need for a multinational study to conclusively establish the role of CFTR variants as genetic susceptibility factors for chronic pancreatitis and pancreatic cancer.     

Gastrointestinal radiation injury:Symptoms,risk factors and mechanisms

Ionising radiation therapy is a common treatment modality for different types of cancer and its use is expected to increase with advances in screening and early detection of cancer.Radiation injury to the gastrointestinal tract is important factor working against better utility of this important therapeutic modality.Cancer survivors can suffer a wide variety of acute and chronic symptoms following radiotherapy,which significantly reduces their quality of life as well as adding an extra burden to the cost of health care.The accurate diagnosis and treatment of intestinal radiation injury often represents a clinical challenge to practicing physicians in both gastroenterology and oncology.Despite the growing recognition of the problem and some advances in understanding the cellular and molecular mechanisms of radiation injury,relatively little is known about the pathophysiology of gastrointestinal radiation injury or any possible susceptibility factors that could aggravate its severity.The aims of this review are to examine the various clinical manifestations of post-radiation gastrointestinal symptoms,to discuss possible patient and treatment factors implicated in normal gastrointestinal tissue radiosensitivity and to outline different mechanisms of intestinal tissue injury.     

Somatic rearrangement of chromosome 14 in human lymphocytes.

Ataxia-telangiectasia is a rare genetic disorder associated with immune deficiency, chromosome instability, and a predisposition to lymphoid malignancy. We have detected chromosomally anomalous clones of lymphocytes in eight patients with this disorder. Chromosome banding disclosed that the clones are consistently marked by structural rearrangement of the long arm (q) of chromosome 14. A translocation involving 14q was found in clones obtained from seven of the eight patients whereas a ring 14 chromosome was found in a clone obtained from the other. These findings as well as data obtained by others for patients with ataxia-telangiectasia suggest that structural rearrangement of 14q is the initial chromosomal change in lymphocyte clones of patients with this disorder. Chromosomes of lymphocytes from one of the patients were studied before and after the onset of chronic lymphocytic leukemia. Before leukemia was diagnosed, the patient had a lymphocyte clone with a 14q translocation. This clone appears to have given rise to the leukemic cells. We hypothesize that structural rearrangement of 14q is directly related to abnormal growth of lymphocytes and that it may be a step toward the development of lymphoid malignancies. Increasing evidence, provided by others, for the nonrandom involvement of 14q in African-type Burkitt's lymphoma and other lymphoid neoplasms further strengthens this hypothesis.     

External beam irradiation for localized prostate cancer--the promise of hypofractionation

Within the field of radiation oncology in the last 10 years, there have been two major thematic advances in the understanding and treatment of prostate cancer. Computerized treatment planning and high precision delivery techniques have already revolutionized the treatment of this disease. Three randomized studies have reported improved biochemical disease-free survival rates in patients from low- to high-risk disease with higher radiation doses. When given conformally, the higher doses do not appear to increase severe toxicity. The second important discovery was that prostate cancer reacts differently than other tumors to radiation whereby higher doses of radiation per day ("hypofractionated radiation") seem to be more effective in killing prostate cancer cells. A meta-summary of four reports summarizing 21 studies presented herein produced an alpha/beta ratio of 1.3 Gy. The early experience of two hypofractionated trials in intermediate- and high-risk prostate cancer where the equivalent of > 80 Gy (in 2 Gy per day fractions) delivered in 5-6 weeks is reported. In summary, hypofractionated radiation coupled with high-precision techniques may allow for better prostate cancer control rates, shorter treatment times and less toxicity.     

Prognostic importance of DNA repair gene polymorphisms of <Emphasis Type="Italic">XRCC1</Emphasis> Arg399Gln and <Emphasis Type="Italic">XPD</Emphasis> Lys751Gln in lung cancer patients from India

Purpose Inter individual variation in lung cancer susceptibility may be modulated in part through genetic polymorphisms in the DNA repair genes, especially the genes involved in the Base Excision Repair (BER) and nucleotide excision repair (NER) pathway. Two of the genetic polymorphisms, XRCC1Arg399Gln and XPD Lys751Gln have been extensively studied in the association with lung cancer risk, although published studies have been inconclusive. Methods In order to verify the role of the common variant alleles in the XPD gene, we have genotyped 211 lung cancer patients and 211 healthy controls using PCR-RFLP assays in a hospital based, case-control study in an Indian population. Logistic regression models were fit to examine the relationship between the log odds of lung cancer and each covariate. Overall Survival in relation to various genotypes and clinicopathological factors were analyzed using Kaplan Meier estimates and hazard ratios were calculated using Cox Regression analysis. Results The carriers of XRCC1 399 AA genotypes were at higher risk of lung cancer (OR = 2.1, 95% CI:1.224–3.669, P = 0.007) than carriers of GG genotype. Subjects carrying 751 AC genotype were at an increased risk of carcinoma of the lung (OR = 1.8; 95% CI:1.233–2.807, P = 0.003) than subjects with AA genotypes. Compared to the XRCC1 399 GG/ XPD 751 AA reference genotype, the combined variants, XRCC1 399 GG/ XPD 751 AC+CC (OR = 1.9, 95% CI: 1.037–3.481), P = 0.03), XRCC1 399 GA+AA/ XPD 751 AA (OR = 1.7, 95% CI: 1.020–2.833, P = 0.04), XRCC1 399 GA+AA/XPD 751 AC+CC (OR = 2.7, 95% CI: 1.582–4.864, P = 0.01), had significantly higher odds ratios. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter overall survival, the risk being significant for the XRCC1 gene polymorphism (P = 0.01 by log-rank test). The hazard of dying was significant for the XRCC1 399 AA genotype (HR = 3.04, 95%CI: 1.393–6.670, P = 0.005). Higher tumour stage also came out as significant predictors of patient death. Conclusions These findings suggest that genetic polymorphisms in the DNA repair genes may modulate overall lung cancer susceptibility and that pathological stage and XRCC1 Arg399Gln independently predicted overall survival among Indian lung cancer patients.     

Radioiodine dosimetry in patients with end-stage renal disease receiving continuous ambulatory peritoneal dialysis therapy

In patients with end-stage renal disease (ESRD), Na131I dosages for thyroid cancer may have to be reduced to avoid excess radiation doses to red marrow, because radioiodine is primarily excreted by kidneys. In ESRD patients receiving continuous ambulatory peritoneal dialysis (CAPD) therapy (three to five 2-L exchanges daily) creatinine clearance rates are very low (mean, 7 mL/min), and radioiodine clearance rates may be proportionately reduced. Thus, radioiodine kinetic studies were performed in two hypothyroid CAPD patients with thyroid cancer, in eight euthyroid CAPD patients, and in eight thyroid cancer patients with normal renal function. All received Na131I or Na123I orally, with serial blood, urine, and/or dialysate sampling for 24-70 h. Dosimetry calculations were performed using the MIRDOSE3 computer program. In CAPD patients, serum radioiodine half-times were 5 times longer, and radioiodine clearance rates by urine plus dialysate were 20% of those in patients with normal renal function. Na131I dosages for the two CAPD patients with thyroid cancer were reduced from 150 mCi [5.6 gigabecquerels (GBq)] to 26.6 mCi (0.98 GBq) and 29.9 mCi (1.11 GBq), respectively, resulting in radiation doses to red marrow and total body comparable to those in patients with normal renal function who received a mean of 148 mCi (5.5 GBq) Na131I. Thus, in patients receiving continuous ambulatory peritoneal dialysis therapy, 5-fold reductions in radioiodine clearance rates require 5-fold decreases in Na131I dosages to avoid excessive radiation doses to total body and red marrow.     

Vascular endothelial growth factor-C enhances radiosensitivity of lymphatic endothelial cells

Radiation therapy after lymph node dissection increases the risk of developing painful and incurable lymphedema in breast cancer patients. Lymphedema occurs when lymphatic vessels become unable to maintain proper fluid balance. The sensitivity of lymphatic endothelial cells (LECs) to ionizing radiation has not been reported to date. Here, the radiosensitivity of LECs in vitro has been determined using clonogenic survival assays. The ability of various growth factors to alter LEC radiosensitivity was also examined. Vascular endothelial growth factor (VEGF)-C enhanced radiosensitivity when LECs were treated prior to radiation. VEGF-C-treated LECs exhibited higher levels of entry into the cell cycle at the time of radiation, with a greater number of cells in the S and G2/M phases. These LECs showed higher levels of γH2A.X—an indicator of DNA damage—after radiation. VEGF-C did not increase cell death as a result of radiation. Instead, it increased the relative number of quiescent LECs. These data suggest that abundant VEGF-C or lymphangiogenesis may predispose patients to radiation-induced lymphedema by impairing lymphatic vessel repair through induction of LEC quiescence.     

Genetic susceptibility for breast cancer: how many more genes to be found?

Today, breast cancer is the most commonly occurring cancer among women. It accounts for 22% of all female cancers and the estimated annual incidence of breast cancer worldwide is about one million cases. Many risk factors have been identified but a positive family history remains among the most important ones established for breast cancer, with first-degree relatives of patients having an approximately two-fold elevated risk. It is currently estimated that approximately 20-25% of this risk is explained by known breast cancer susceptibility genes, mostly those conferring high risks, such as BRCA1 and BRCA2. However, these genes explain less than 5% of the total breast cancer incidence, even though several studies have suggested that the proportion of breast cancer that can be attributed to a genetic factor may be as high as 30%. It is thus likely that there are still breast cancer susceptibility genes to be found. It is presently not known how many such genes there still are, nor how many will fall into the class of rare high-risk (e.g. BRCAx) or of common low-risk susceptibility genes, nor if and how these factors interact with each other to cause susceptibility (a polygenic model). In this review we will address this question and discuss the different undertaken approaches used in identifying new breast cancer susceptibility genes, such as (genome-wide) linkage analysis, CGH, LOH, association studies and global gene expression analysis.     

Identification of candidate genes involved in the radiosensitivity of esophageal cancer cells by microarray analysis

SUMMARY.  Radiotherapy plays a key role in the control of tumor growth in esophageal cancer patients. To identify the patients who will benefit most from radiation therapy, it is important to know the genes that are involved in the radiosensitivity of esophageal cancer cells. Hence, we examined the global gene expression in radiosensitive and radioresistant esophageal squamous cell carcinoma cell lines. Radiosensitivities of 13 esophageal cancer cell lines were measured. RNA was extracted from each esophageal cancer cell line and a normal esophageal epithelial cell line, and the global gene expression profiles were analyzed using a 34 594-spot oligonucleotide microarray. In the clonogenic assay, one cell line (TE-11) was identified to be highly sensitive to radiation, while the other cell lines were found to be relatively radioresistant. We identified 71 candidate genes that were differentially expressed in TE-11 by microarray analysis. The up-regulated genes included CABPR, FABP5, DSC2, GPX2, NME, CBR3, DOCK8, and ABCC5, while the down-regulated genes included RPA1, LDOC1, NDN, and SKP1A. Our investigation provided comprehensive information on genes related to radiosensitivity of esophageal cancer cells; this information can serve as a basis for further functional studies.     

Effects of radiation exposure from cardiac imaging: how good are the data?

Concerns about medical exposure to ionizing radiation have become heightened in recent years as a result of rapid growth in procedure volumes and the high radiation doses incurred from some procedures. This paper summarizes the evidence base undergirding concerns about radiation exposure in cardiac imaging. After classifying radiation effects, explaining terminology used to quantify the radiation received by patients, and describing typical doses from cardiac imaging procedures, this paper will address the major epidemiological studies having bearing on radiation effects at doses comparable to those received by patients undergoing cardiac imaging. These include studies of atomic bomb survivors, nuclear industry workers, and children exposed in utero to x-rays, all of which have evidenced increased cancer risks at low doses. Additional higher-dose epidemiological studies of cohorts exposed to radiation in the context of medical treatment are described and found to be generally compatible with these cardiac dose-level studies, albeit with exceptions. Using risk projection models developed by the U.S. National Academies that incorporate these data and reflect several evidence-based assumptions, cancer risk from cardiac imaging can be estimated and compared with the benefits from imaging. Several ongoing epidemiological studies will provide better understanding of radiation-associated cancer risks.