Risk factors for breast cancer in young women by oestrogen receptor and progesterone receptor status

We used data from 765 cases and 564 controls in the population-based Australian Breast Cancer Family Study to investigate whether, in women under the age of 40, the profile of risk factors differed between breast cancer subtypes defined by joint oestrogen and progesterone receptor status. As hypothesised, no significant differences were found

Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age

BACKGROUND: BRCA1 and BRCA2 mutations are found in a proportion of families with multiple early-onset breast cancers. There are a large number of different deleterious mutations in both genes, none of which would be detectable using standard genetic association studies. Single common variants and haplotypes of common variants may capture groups of deleterious mutations since some low prevalence haplotypes of common variants occur more frequently among chromosomes that carry rare, deleterious mutations than chromosomes that do not. METHODS: DNA sequence data for BRCA1 and BRCA2 was obtained from 571 participants from the Australian Breast Cancer Family Study. Genetic variants were classified as either deleterious mutations or common genetic variants. Variants tagging common polymorphisms were selected and haplotypes resolved using Haploview. Their frequency was compared to those with and without deleterious mutations using a permutation test. RESULTS: A common genetic variant in BRCA1 (3232A > G) was found to be over-represented in deleterious mutation carriers (p = 0.05), whereas a common genetic variant in BRCA2 (1342A > C) occurred less frequently in deleterious mutation carriers (p = 0.04). All four of the common BRCA1 variants used to form haplotypes occurred more frequently in the deleterious mutation carriers when compared to the non-carriers, but there was no evidence of a difference in the distributions between the two groups (p = 0.34). In BRCA2, all four common variants were found to occur less frequently in the deleterious mutation carriers when compared to non-carriers, but the evidence for difference in the distribution between the two groups was weak (p = 0.16). Several less common haplotypes of common BRCA1 variants were found to be over-represented among deleterious mutation carriers but there was no evidence for this at the population level. In BRCA2, only the most common haplotype was found to occur more frequently in deleterious mutation carriers, with again no evidence at the population level. CONCLUSIONS: We observed differences in the frequency of common genetic variants of the BRCA1 and BRCA2 and their haplotypes between early-onset breast cancer cases who did and did not carry deleterious mutations in these genes. Although our data provide only weak evidence for a difference in frequencies at the population level, the number of deleterious mutation carriers was low and the results may yet be substantiated in a larger study using pooled data

Interactions between genes involved in the antioxidant defence system and breast cancer risk

The aim of the study is to examine the association between multilocus genotypes across 10 genes encoding proteins in the antioxidant defence system and breast cancer. The 10 genes are SOD1, SOD2, GPX1, GPX4, GSR, CAT, TXN, TXN2, TXNRD1 and TXNRD2. In all, 2271 cases and 2280 controls were used to examine gene–gene interactions between 52 single nucleotide polymorphisms (SNPs) that are hypothesised to tag all common variants in the 10 genes. The statistical analysis is based on three methods: unconditional logistic regression, multifactor dimensionality reduction and hierarchical cluster analysis. We examined all two- and three-way combinations with unconditional logistic regression and multifactor dimensionality reduction, and used a global approach with all SNPs in the hierarchical cluster analysis. Single-locus studies of an association of genetic variants in the antioxidant defence genes and breast cancer have been contradictory and inconclusive. It is the first time, to our knowledge, the association between multilocus genotypes across genes coding for antioxidant defence enzymes and breast cancer is investigated. We found no evidence of an association with breast cancer with our multilocus approach. The search for two-way interactions gave experiment-wise significance levels of P=0.24 (TXN [t2715c] and TXNRD2 [g23524a]) and P=0.58 (GSR [c39396t] and TXNRD2 [a442g]), for the unconditional logistic regression and multifactor dimensionality reduction, respectively. The experiment-wise significance levels for the three-way interactions were P=0.94 (GPX4 [t2572c], TXN [t2715c] and TXNRD2 [g23524a]) and P=0.29 (GSR [c39396t], TXN [t2715c] and TXNRD2 [a442g]) for the unconditional logistic regression and multifactor dimensionality reduction, respectively. In the hierarchical cluster analysis neither the average across four rounds with replacement of missing values at random (P=0.12) nor a fifth round with more balanced proportion of missing values between cases and controls (P=0.17) was significant

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Cytomegalovirus, Epstein–Barr virus and risk of breast cancer before age 40 years: a case–control study

We investigated whether there is an association between cytomegalovirus (CMV) and Epstein-Barr virus (EBV) IgG levels and risk of breast cancer before age 40 years. CMV and EBV IgG levels were measured in stored plasma from 208 women with breast cancer and 169 controls who participated in the Australian Breast Cancer Family Study (ABCFS), a population-based case-control study. CMV and EBV IgG values were measured in units of optical density (OD). Cases and controls did not differ in seropositivity for CMV (59 and 57% respectively; P=0.8) or EBV (97 and 96% respectively; P=0.7). In seropositive women, mean IgG values were higher in cases than controls for CMV (1.20 vs 0.98 OD, P=0.005) but not for EBV (2.65 vs 2.57 OD, P=0.5). The adjusted odds ratios per OD unit were 1.46 (95% CI 1.06-2.03) for CMV IgG and 1.11 (0.93-1.33) for EBV IgG. The higher mean CMV IgG levels found in women with breast cancer could be the result of a more recent infection with CMV, and may mean that late exposure to CMV is a risk factor for breast cancer

BRCA1 mutations and other sequence variants in a population-based sample of Australian women with breast cancer

The frequency, in women with breast cancer, of mutations and other variants in the susceptibility gene, BRCA1, was investigated using a population-based case–control-family study. Cases were women living in Melbourne or Sydney, Australia, with histologically confirmed, first primary, invasive breast cancer, diagnosed before the age of 40 years, recorded on the state Cancer Registries. Controls were women without breast cancer, frequency-matched for age, randomly selected from electoral rolls. Full manual sequencing of the coding region of BRCA1 was conducted in a randomly stratified sample of 91 cases; 47 with, and 44 without, a family history of breast cancer in a first- or second-degree relative. All detected variants were tested in a random sample of 67 controls. Three cases with a (protein-truncating) mutation were detected. Only one case had a family history; her mother had breast cancer, but did not carry the mutation. The proportion of Australian women with breast cancer before age 40 who carry a germline mutation in BRCA1 was estimated to be 3.8% (95% Cl 0.3–12.6%). Seven rare variants were also detected, but for none was there evidence of a strong effect on breast cancer susceptibility. Therefore, on a population basis, rare variants are likely to contribute little to breast cancer incidence. © 1999 Cancer Research Campaig

Ellenberg-type indicator values for European vascular plant species

Aims: Ellenberg-type indicator values are expert-based rankings of plant species according to their ecological optima on main environmental gradients. Here we extend the indicator-value system proposed by Heinz Ellenberg and co-authors for Central Europe by incorporating other systems of Ellenberg-type indicator values (i.e., those using scales compatible with Ellenberg values) developed for other European regions. Our aim is to create a harmonized data set of Ellenberg-type indicator values applicable at the European scale. Methods: We collected European data sets of indicator values for vascular plants and selected 13 data sets that used the nine-, ten- or twelve-degree scales defined by Ellenberg for light, temperature, moisture, reaction, nutrients and salinity. We compared these values with the original Ellenberg values and used those that showed consistent trends in regression slope and coefficient of determination. We calculated the average value for each combination of species and indicator values from these data sets. Based on species’ co-occurrences in European vegetation plots, we also calculated new values for species that were not assigned an indicator value. Results: We provide a new data set of Ellenberg-type indicator values for 8908 European vascular plant species (8168 for light, 7400 for temperature, 8030 for moisture, 7282 for reaction, 7193 for nutrients, and 7507 for salinity), of which 398 species have been newly assigned to at least one indicator value. Conclusions: The newly introduced indicator values are compatible with the original Ellenberg values. They can be used for large-scale studies of the European flora and vegetation or for gap-filling in regional data sets. The European indicator values and the original and taxonomically harmonized regional data sets of Ellenberg-type indicator values are available in the Supporting Information and the Zenodo repository

Morphological predictors of BRCA1 germline mutations in young women with breast cancer

BACKGROUND: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data.METHODS: We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation.RESULTS: The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (Po0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6-47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7-25.7) for mitotic index over 50 mitoses per 10 high-powered field (P 0.0003); and 2.7 (1.3-5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P 0.01). The area under the ROC curve was 0.87 (0.83-0.90).CONCLUSION: Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history. British Journal of Cancer (2011) 104, 903-909. doi: 10.1038/ bjc. 2011.41 www. bjcancer. co