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.

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.

Various studies suggest that vitamin D may reduce breast cancer risk. Most studies assessed the effects of dietary intake only, although endogenous production is an important source of vitamin D. Therefore, the measurement of serum 25-hydroxyvitamin D [25(OH)D] better indicates overall vitamin D status. To assess the association of 25(OH)D serum concentrations with post-menopausal breast cancer risk, we used a population-based case-control study in Germany, which recruited incident breast cancer patients aged 50-74 between 2002 and 2005. Information on sociodemographic and breast cancer risk factors was collected by personal interview. For this analysis, we included 1394 cases and 1365 controls, matched on year of birth and time of blood collection. Conditional logistic regression was used to calculate odds ratios (ORs) for breast cancer adjusted for potential confounders. Serum 25(OH)D concentration was significantly inversely associated with post-menopausal breast cancer risk. Compared with the lowest category (<30 nM), OR [95% confidence intervals (CI)] for the higher categories of 25(OH)D (30-45, 45-60, 60-75 and >/=75 nM) were 0.57 (0.45-0.73), 0.49 (0.38-0.64), 0.43 (0.32-0.57) and 0.31 (0.24-0.42), respectively (P(trend) < 0.0001). Analysis using fractional polynomials indicated a non-linear association. The association was stronger in women never using menopausal hormone therapy (HT) compared with past and current users (P(interaction) < 0.0001). Our findings strongly suggest a protective effect for post-menopausal breast cancer through a better vitamin D supply as characterized by serum 25(OH)D measurement, with a stronger inverse association in women with low serum 25(OH)D concentrations (<50 nM).

In a large population-based case-control study in Germany, including 3,464 breast cancer cases aged 50-74 at diagnosis and 6,657 population based and frequency matched controls, we investigated the effects of menopausal hormone therapy (HT) by type, regimen, timing and progestagenic constituent on postmenopausal breast cancer risk overall and according to histological type. Data were collected by face-to-face interviews. Logistic and polytomous logistic regression analysis were used to estimate odds ratios (OR) and 95%-confidence intervals (95% CI). Risk of invasive breast cancer was significantly elevated in current users (OR, 1.73, 95% CI, 1.55-1.94) and heterogeneous by histological type (p < 0.01), being more than 2-fold higher for lobular and tubular than for ductal cancer. Risks for current users varied significantly by type and regimen of HT, with ORs per year of use of 1.05 (95% CI, 1.04-1.06) for continuous combined estrogen-progestagen, 1.03 (95% CI, 1.02-1.04) for cyclical EP and 1.01 (95% CI, 1.00-1.03) for estrogen-only therapy. No statistically significant increase in risk was observed after 5 years of cessation of HT use for any histological type. Analyses of progestagenic content by regimen revealed a significantly higher risk for continuously administered norethisterone-or levonorgestrel-derived progestagens than for continuously administered progesterone-derived progestagens (OR, 2.27, 95% CI, 1.98-2.62 vs. 1.47, 95% CI, 1.12-1.93, respectively, p 5 0.003), which may be explained by dose rather than type of progestagen. These data suggest that the risks associated with menopausal HT differ by type and regimen of HT and histological type of breast cancer and may vary by progestagenic component, depending on the effective dose. ' 2008 Wiley-Liss, Inc.Key words: breast cancer; histological type; hormone therapy; progestin; epidemiology Menopausal hormone therapy (HT) has been established as a risk factor for the development of breast cancer, 1 with combined estrogen-progestagen (EP) therapy posing a greater risk than mono-estrogen therapy.2-7 The extent to which this risk difference is in turn affected by duration and recency of use, particularly for past long-term users, requires further clarification. Recent evidence from observational studies has shown that risk varies according to tumor histology, with current use of both mono-estrogen and EP therapy carrying greater risks for invasive lobular and tubular cancers than for invasive ductal cancer. 4,[8][9][10][11][12][13][14][15][16] The higher risk associated with EP therapy compared to mono-estrogen therapy has also been observed across different histological tumor types. 6,17,18 Several studies have investigated differences in risk by regimen, 2,5,18-21 however, a higher risk for continuous than for cyclical EP therapy was found only in Scandinavian studies. 18,20,22 Less information is available on the role of progestagens in EP therapy, specifically regarding the effects of type, dose and the number of days it is administered each month. Wh...

Vitamin D pathway gene polymorphisms may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D. The association between polymorphisms in the vitamin D binding protein (Gc) and postmenopausal breast cancer risk, with additional focus on the influence of serum 25-hydroxyvitamin D [25(OH)D], the biomarker for vitamin D status in humans, has not been examined thus far. We assessed the combined effects of two known functional polymorphisms in the Gc gene (rs4588 and rs7041), composing the phenotypic alleles Gc1s, Gc1f (combined: Gc1), and Gc2, on postmenopausal breast cancer risk and potential effect modification by 25(OH)D status in a population-based case-control study including 1,402 cases and 2,608 matched controls. Odds ratios (OR) for breast cancer risk adjusted for potential confounders were calculated for Gc genotypes. ANOVA was used to

Purpose: Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility.We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg Asn), with the risk of acute skin reactions following radiotherapy. Design: We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Results: Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of the APE1 148Glu and the XRCC1 399Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1148 Glu and XRCC1 399 Gln alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; P interaction = 0.009). Conclusion: The XRCC1399 Gln or APE1 148

Our study revealed several factors other than radiation dose that may predispose to late complications following radiotherapy. Further understanding of differences in response to irradiation may advance individualized treatment and improve cosmetic outcome.

Matrix metalloproteinases (MMP) play a key role in the breakdown of extracellular matrix and in inflammatory processes. MMP1 is the most highly expressed interstitial collagenase degrading fibrillar collagens. Overexpression of MMP1 has been shown in tumor tissues and has been suggested to be associated with tumor invasion and metastasis. Nine haplotype tagging and additional two intronic single nucleotide polymorphisms (SNP) of MMP1 were genotyped in a case control sample, consisting of 635 lung cancer cases with onset of disease below 51 years of age and 1,300 age-and sex-matched cancer-free controls. Two regions of linkage disequilibrium (LD) of MMP1 could be observed: a region of low LD comprising the 5 ¶ region including the promoter and a region of high LD starting from exon 1 to the end of the gene and including the 3 ¶ flanking region. Several SNPs were identified to be individually significantly associated with risk of early-onset lung cancer. The most significant effect was seen for rs1938901 (P = 0.0089), rs193008 (P = 0.0108), and rs996999 (P = 0.0459). For rs996999, significance vanished after correction for multiple testing. For each of these SNPs, the major allele was associated with an increase in risk with an odds ratio between 1.2 and 1.3 (95% confidence interval, 1.0-1.5). The haplotype analysis supported these findings, especially for subgroups with high smoking intensity. In summary, we identified MMP1 to be associated with an increased risk for lung cancer, which was modified by smoking. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1127 -35)