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Background Ionizing radiation is a known mutagen and an established breast carcinogen. The ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation. We investigated whether genetic variants in ATM play a clinically significant role in radiation-induced contralateral breast cancer in women. Methods The Women's Environmental, Cancer, and Radiation Epidemiology Study is an international population-based case--control study nested within a cohort of 52536 survivors of unilateral breast cancer diagnosed between 1985 and 2000. The 708 case subjects were women with contralateral breast cancer, and the 1397 control subjects were women with unilateral breast cancer matched to the case subjects on age, follow-up time, registry reporting region, and race and/or ethnicity. All women were interviewed and underwent full mutation screening of the entire ATM gene. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Rate ratios (RRs) and corresponding 95% confidence intervals (CIs) were estimated by using multivariable conditional logistic regression. All P values are two-sided. Results Among women who carried a rare ATM missense variant (ie, one carried by Conclusions Women who carry rare deleterious ATM missense variants and who are treated with radiation may have an elevated risk of developing contralateral breast cancer. However, the rarity of these deleterious missense variants in human populations implies that ATM mutations could account for only a small portion of second primary breast cancers. DOI: 10.1093/jnci/djq055

Background Results from randomized trials indicate that treatment with tamoxifen or chemotherapy for primary breast cancer reduces the risk for contralateral breast cancer. However, less is known about how long the risk is reduced and the impact of factors such as age and menopausal status. Methods The study included 634 women with contralateral breast cancer (case patients) and 1158 women with unilateral breast cancer (control subjects) from the Women's Environment, Cancer and Radiation Epidemiology Study. The women were younger than age 55 when they were first diagnosed with breast cancer during 1985-1999. Rate ratios (RRs) and 95% confidence intervals (CIs) for contralateral breast cancer after treatment with chemotherapy or tamoxifen were assessed by multivariable adjusted conditional logistic regression analyses. Results Chemotherapy was associated with a lower risk for contralateral breast cancer (RR = 0.57, 95% CI = 0.42 to 0.75) than no chemotherapy. A statistically significant association between chemotherapy and reduced risk for contralateral breast cancer persisted up to 10 years after the first breast cancer diagnosis and was stronger among women who became postmenopausal within 1 year of the first breast cancer diagnosis (RR = 0.28, 95% CI = 0.11 to 0.76). Tamoxifen use was also associated with reduced risk for contralateral breast cancer (RR = 0.66, 95% CI = 0.50 to 0.88) compared with no use, and the association was statistically significant for 5 years after the first diagnosis. Conclusion The associations between chemotherapy and tamoxifen treatment and reduced risk for contralateral breast cancer appear to continue for 10 and 5 years, respectively, after the initial breast cancer is diagnosed. Ovarian suppression may have a role in the association between chemotherapy and reduced risk for contralateral breast cancer.

Background parenchymal enhancement measured quantitatively at breast MRI is associated with increased odds of breast cancer for both premenopausal and postmenopausal women after accounting for breast cancer risk factors.

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10−9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10−10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10−8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10−11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10−10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10−9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10−10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10−10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10−9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10−8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10−10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10−11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10−9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Introduction Deficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated.Design To examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses.Conclusions Our study design improves the potential for detecting gene–environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case–control sets and enhanced our ability to detect radiation–genotype interactions.

The role of ataxia-telangiectasia mutated (ATM) heterozygosity in cancer is uncertain. In vitrostudies of cells from ATMheterozygotes provide strong evidence of radiation sensitivity. Some, but not all, clinical studies suggest an increased risk of breast cancer among ATMgene carriers, and this risk may be greater among those exposed to radiation. This possible excess risk of breast cancer associated with ATMheterozygosity constitutes the basis for several genetic epidemiological studies designed to clarify the role that the ATMgene plays in the etiology of breast and other cancers. The primary focus of this international, multidisciplinary, National Cancer Institute-sponsored workshop was to discuss ongoing and planned epidemiologic studies aimed at understanding the complexities of the ATMgene and its role in carcinogenesis. The invited participants were from diverse disciplines including molecular and clinical genetics, radiation biology and physics, epidemiology, biostatistics, pathology, and medicine. In the present meeting report, the aims of each project are described.

All 62 coding exons of the ATM gene, along with 10–20 bases of the intronic region flanking each exon, were screened for DNA base sequence alterations by using denaturing high-performance liquid chromatography (DHPLC) in a series of 52 breast cancer patients. Six (12%) of these patients exhibited a total of eight different novel germ-line mutations that do not represent common polymorphisms. Of these, three patients possessed four nonconservative missense mutations while two conservative missense and two synonymous mutations were detected in the other three patients. In addition, 43 patients were found to have a total of 141 DNA sequence variations representing 21 different common polymorphisms and rare variants. An analysis of the relationship between the presence of a novel ATM mutation and either patient demographics or tumor properties demonstrated a significant difference between African Americans (3/7 = 43%) and other ethnic groups (3/45 = 7%, P = 0.026). None of the other characteristics examined was found to be related to mutation status. Environ. Mol. Mutagen. 38:200–208, 2001. © 2001 Wiley-Liss, Inc.

All 62 coding exons of the ATMgene, along with 10–20 bases of the intronic region flanking each exon, were screened for DNA base sequence alterations by using denaturing high‐performance liquid chromatography (DHPLC) in a series of 52 breast cancer patients. Six (12%) of these patients exhibited a total of eight different novel germ‐line mutations that do not represent common polymorphisms. Of these, three patients possessed four nonconservative missense mutations while two conservative missense and two synonymous mutations were detected in the other three patients. In addition, 43 patients were found to have a total of 141 DNA sequence variations representing 21 different common polymorphisms and rare variants. An analysis of the relationship between the presence of a novel ATMmutation and either patient demographics or tumor properties demonstrated a significant difference between African Americans (3/7 = 43%) and other ethnic groups (3/45 = 7%, P= 0.026). None of the other characteristics examined was found to be related to mutation status. Environ. Mol. Mutagen. 38:200–208, 2001. © 2001 Wiley‐Liss, Inc.

Based upon the results of several epidemiologic studies, it has been suggested that women who are carriers for a mutation in the ataxia telangiectasia-mutated (ATM) gene are susceptible for the development of breast cancer. Therefore, 37 consecutive breast cancer patients were screened for the presence of a germline ATMmutation using a non-isotopic RNase cleavage-based assay (NIRCA). This paper reports the first use of NIRCA for detection of ATMmutations in breast cancer patients. Using this assay, no ATMmutations were found in our patient population. This result is similar to the findings of other studies that have employed approaches complementary to NIRCA.

• The impact of maternal opiate dependency on birth weight and head circumference of offspring was studied in 150 mother-infant pairs and 150 controls. Mean birth weight and head circumference of drug-dependent offspring were reduced symmetrically compared with drug-free controls of similar socioeconomic status. Although mean gestational ages and rates of prematurity were similar, intrauterine growth retardation occurred in 20% of passively addicted infants vs 4% of controls. A longer period of methadone maintenance was associated with longer gestation and increased birth weight, while higher methadone dosages were associated with higher birth weights and larger head circumferences. Smoking was associated with reduced birth weight by an average of 160 g per pack of cigarettes smoked per day; longer duration of smoking was associated with reductions in both birth weight and head circumference. These data suggest therapeutic strategies to improve these fetal growth characteristics and perhaps improve neurobehavioral outcome of drug-dependent newborns.(AJDC 1987;141:1163-1167)

• Early weight-change patterns were studied in 101 passively addicted neonates. Newborns showing mild abstinence and not requiring pharmacologic treatment lost an average of 4.0% of birth weight, reached a weight nadir on day 3, and regained birth weight by days 7 to 8. Newborns treated with either paregoric or phenobarbital for more severe signs of abstinence lost an average of 6.3% of birth weight, reached a nadir on days 6 to 7, and regained birth weight only by days 13 to 14. Despite comparable birth weights and energy intakes, treated newborns weighed 95 g less than untreated neonates on day 10 when the untreated neonates were discharged. In light of abnormal early weight-change patterns seen with more severe abstinence, both strict control of abstinence and provision of additional individualized nutritional support seem warranted.(AJDC 1986;140:829-832)

To determine the clinical significance of the occurrence of hemodynamic deterioration after the administration of calcium channel blocking drugs, nifedipine (20 mg orally) was administered to 29 patients with severe left ventricular dysfunction. Thirteen patients showed hemodynamic improvement with the drug (Group 1), as shown by a notable increase in cardiac index associated with a modest decrease in mean arterial pressure. The other 16 patients exhibited hemodynamic deterioration after nifedipine (Group 2), as reflected by a decline in right and left ventricular stroke work indexes accompanied by a marked hypotensive response. These differences were not related to differences in the peripheral vascular response to nifedipine, because both groups showed similar decreases in systemic and pulmonary vascular resistances.

A consecutive group of 67 patients (70 eyes) with senile cataract underwent extracapsular cataract extraction and implantation of a Shearing posterior chamber intraocular lens. After two years of follow-up, there was an 11% + 2% decrease in central cell density (P<.001), a 20% + 2% decrease in superior cell density (P<.001), and a 5% + 3% decrease in inferior cell density (P<,005). Complications included corneal edema requiring a corneal transplant (one patient), a sterile nonhealing ulcer that required a conjunctival flap (one patient), and secondary glaucoma (one patient). Nine patients had visual acuities poorer than 20/40 but none had cystoid macular edema. Primary or secondary capsulotomy did not significantly increase endothelial cell loss. Central endothelial cell loss from extracapsular cataract extraction with Shearing posterior chamber intraocular lens implantation was correlated with age, as well as with preoperative superior endothelial cell density (P<.05).

One hundred and twentynine workers chronically exposed to asbestos were interviewed regarding their perceived health status and concerns, their health behaviors, particularly their smoking behavior, and their psychologic wellbeing. In contrast to a nonexposed comparison group of postal workers, asbestos workers exhibited significantly elevated levels of somatic concern P < .03, and significantly lower levels of mental health functioning only when experiencing high levels of stress P < .01. Despite feeling significantly more susceptible to developing cancer P < .0001, 34 of asbestos workers were cigarette smokers compared to 32 of the postal group and longterm mask usage was minimal. Asbestos workers' increased sensitivity to stress and changes in health status along with the lack of adaptation of healthpromotive behaviors indicate the need for interventions to attend to the psychologic effects of increased risk status.

Magnesium abnormalities are common in patients with congestive heart failure but the clinical and prognostic significance of an abnormal serum magnesium concentration in this disorder has not been investigated. Therefore, the relation between serum magnesium concentration and the clinical characteristics and long-term outcome of 199 patients with chronic heart failure was evaluated. The serum magnesium concentration was &lt;1.6 mEq/liter in 38 patients (19%), within the normal range in 134 patients (67%) and >2.1 mEq/liter in 27 patients (14%).

Germline mutations in the BRCA1and BRCA2genes confer a marked increase in risk of breast cancer. Loss-of-function mutations have been identified in the PALB2gene that also increase the risk of breast cancer. PALB2interacts with BRCA1and BRCA2genes. In previous studies, the risk of breast cancer was estimated to be 2 to 4 times higher among carriers of PALB2loss-of-function mutations as the risk among nonmutation carriers. Prior to the present study, the exact lifetime risk of breast cancer conferred by such mutations was unknown.