Genetic predictors of acute toxicities related to radiation therapy following lumpectomy for breast cancer: a case-series study

INTRODUCTION: The cytotoxic effects of radiation therapy are mediated primarily through increased formation of hydroxyl radicals and reactive oxygen species, which can damage cells, proteins and DNA; the glutathione S-transferases (GSTs) function to protect against oxidative stress. We hypothesized that polymorphisms encoding reduced or absent activity in the GSTs might result in greater risk for radiation-associated toxicity. METHODS: Women receiving therapy in radiation units in Germany following lumpectomy for breast cancer (1998–2001) provided a blood sample and completed an epidemiological questionnaire (n = 446). Genotypes were determined using Sequonom MALDI-TOF (GSTA1, GSTP1) and Masscode (GSTM1, GSTT1). Biologically effective radiotherapy dose (BED) was calculated, accounting for differences in fractionation and overall treatment time. Side effects considered were grade 2c and above, as classified using the modified Common Toxicity Criteria. Predictors of toxicity were modelled using Cox regression models in relation to BED, with adjustment for treating clinic, photon field, beam energy and boost method, and potential confounding variables. RESULTS: Low activity GSTP1 genotypes were associated with a greater than twofold increase in risk for acute skin toxicities (adjusted hazard ratio 2.28, 95% confidence interval 1.04–4.99). No associations were noted for the other GST genotypes. CONCLUSION: These data indicate that GSTP1 plays an important role in protecting normal cells from damage associated with radiation therapy. Studies examining the effects of GSTP1 polymorphisms on toxicity, recurrence and survival will further inform individualized therapeutics based on genotypes

Consortium analysis of 7 candidate SNPs for ovarian cancer

The Ovarian Cancer Association Consortium selected 7 candidate single nucleotide polymorphisms (SNPs), for which there is evidence from previous studies of an association with variation in ovarian cancer or breast cancer risks. The SNPs selected for analysis were F31I (rs2273535) in AURKA, N372H (rs144848) in BRCA2, rs2854344 in intron 17 of RB1, rs2811712 5′ flanking CDKN2A, rs523349 in the 3′ UTR of SRD5A2, D302H (rs1045485) in CASP8 and L10P (rs1982073) in TGFB1. Fourteen studies genotyped 4,624 invasive epithelial ovarian cancer cases and 8,113 controls of white non-Hispanic origin. A marginally significant association was found for RB1 when all studies were included [ordinal odds ratio (OR) 0.88 (95% confidence interval (CI) 0.79-1.00) p = 0.041 and dominant OR 0.87 (95% CI 0.76-0.98) p = 0.025]; when the studies that originally suggested an association were excluded, the result was suggestive although no longer statistically significant (ordinal OR 0.92, 95% CI 0.79-1.06). This SNP has also been shown to have an association with decreased risk in breast cancer. There was a suggestion of an association for AURKA, when one study that caused significant study heterogeneity was excluded [ordinal OR 1.10 (95% CI 1.01-1.20) p = 0.027; dominant OR 1.12 (95% CI 1.01-1.24) p = 0.03]. The other 5 SNPs in BRCA2, CDKN2A, SRD5A2, CASP8 and TGFB1 showed no association with ovarian cancer risk; given the large sample size, these results can also be considered to be informative. These null results for SNPs identified from relatively large initial studies shows the importance of replicating associations by a consortium approach

A common coding variant in CASP8 is associated with breast cancer risk

The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 -202 C --> A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3' UTR A --> G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9-15 studies, comprising 11,391-18,290 cases and 14,753-22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.: 0.62-0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P(trend) = 1.1 x 10(-7)) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02-1.13) and 1.16 (95% c.i.: 1.08-1.25), respectively; P(trend) = 2.8 x 10(-5)). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies

Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27–1.36)) than ER-negative (1.08 (1.03–1.14)) disease (P for heterogeneity = 10−13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10−5, 10−8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10−4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09–1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83–0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment

International collaboration to assess the risk of Guillain Barre Syndrome following Influenza A (H1N1) 2009 monovalent vaccines

<p>Background: The global spread of the 2009 novel pandemic influenza A (H1N1) virus led to the accelerated production and distribution of monovalent 2009 Influenza A (H1N1) vaccines (pH1N1). This pandemic provided the opportunity to evaluate the risk of Guillain-Barre syndrome (GBS), which has been an influenza vaccine safety concern since the swine flu pandemic of 1976, using a common protocol among high and middle-income countries. The primary objective of this project was to demonstrate the feasibility and utility of global collaboration in the assessment of vaccine safety, including countries both with and without an established infrastructure for vaccine active safety surveillance. A second objective, included a priori, was to assess the risk of GBS following pH1N1 vaccination.</p><p>Methods: The primary analysis used the self-controlled case series (SCCS) design to estimate the relative incidence (RI) of GBS in the 42 days following vaccination with pH1N1 vaccine in a pooled analysis across databases and in analysis using a meta-analytic approach.</p><p>Results: We found a relative incidence of GBS of 2.42(95% CI 1.58-3.72) in the 42 days following exposure to pH1N1 vaccine in analysis of pooled data and 2.09(95% CI 1.28-3.42) using the meta-analytic approach.</p><p>Conclusions: This study demonstrates that international collaboration to evaluate serious outcomes using a common protocol is feasible. The significance and consistency of our findings support a conclusion of an association between 2009 H1N1 vaccination and GBS. Given the rarity of the event the relative incidence found does not provide evidence in contradiction to international recommendations for the continued use of influenza vaccines. (C) 2013 Elsevier Ltd. All rights reserved.</p>