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L’article donne une vue d’ensemble des contributions a la conference sur les indicateurs de progres societal organisee en decembre 2014 par l’IWEPS et le BFP ainsi que de ses principaux enseignements. La mise en œuvre des decisions politiques pionnieres en cette matiere en Wallonie et au niveau federal belge est situee dans le cadre des developpements en cours des projets internationaux concernant les indicateurs. L’article montre la richesse et la diversite de la dynamique regionale, nationale et internationale alimentant le debat sur les meilleures facons de mesurer le progres des societes, ainsi que les efforts de convergence en cours. Ces balises permettent notamment de comprendre les processus de decision, de construction et d’usage determinant la conception des indicateurs complementaires au PIB et des indicateurs de developpement durable.

Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.

OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome. METHODS: In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data. RESULTS: The strongest prognostic factors were stage at diagnosis (p = 2.72e-15) and treatment modality (p = 3.87e-13). For FIGO stages II-IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p = 0.002). Patients aged ≥40 had a worse outcome than younger patients (p = 0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed

O princípio da precaução está inserido em um contexto decisional em evolução, marcado por uma incerteza multidimensional com relação às conseqüências ambientais, econômicas, sociais, éticas e políticas das inovações tecnológicas. Na ciência política de língua francesa, o princípio funciona como uma ferramenta estratégica, uma resposta política ao surgimento de um novo fluxo de incerteza social, voltada principalmente para as inseguranças do mundo científico. Neste trabalho, afirmamos que o princípio da precaução redefine a forma de gerir a incerteza científica, em uma sociedade caracterizada pela indefinição das fronteiras entre atores políticos e subpolíticos. Em sua aplicação, há uma linha de ruptura que reduz a margem de manobra decisória de determinadas entidades subpolíticas, enquanto incentiva outras a agirem. Contudo, enfatizamos que, em um mundo cada vez mais globalizado e interligado, os efeitos da aplicação do princípio da precaução são temporários e locais. Ainda assim, o princípio pode contribuir para os importantes debates a serem desenvolvidos em espaços institucionais, para uma ação reflexiva antecipatória e de apoio à decisão².

We present an integrated approach for the enriched detection of genes subject to cis-acting variation in the mouse genome. Gene expression profiling was performed with lung tissue from a panel of recombinant congenic strains (RCS) derived from A/J and C57BL/6J inbred mouse strains. A multiple-regression model measuring the association between gene expression level, donor strain of origin (DSO), and predominant strain background identified over 1,500 genes ( P < 0.05) whose expression profiles differed according to the DSO. This model also identified over 1,200 genes whose expression showed dependence on background ( P < 0.05), indicating the influence of background genetic context on transcription levels. Sequences obtained from 1-kb segments of 3′-untranslated regions identified single nucleotide polymorphisms in 64% of genes whose expression levels correlated with DSO status, compared with 29% of genes that displayed no association ( P < 0.01, Fisher exact test). Allelic imbalance was identified in 50% of genes positive for expression-DSO association, compared with 22% of negative genes ( P < 0.05, Fisher exact test). Together, these results demonstrate the utility of RCS mice for identifying the roles of proximal genetic determinants and background genetic context in determining gene expression levels. We propose the use of this integrated experimental approach in multiple tissues from this and other RCS panels as a means for genome-wide cataloging of genetic regulatory mechanisms in laboratory strains of mice.

Aims To evaluate the effects of food and formulation on the pharmacokinetics of bismuth biskalcitrate, metronidazole and tetracycline when combined in a new 3-in-1 single capsule (BMT) for eradication of Helicobacter pylori. Methods In a randomized, 3 × 3 cross-over design, 23 healthy males received one dose of BMT in the fed and fasting states and equivalent doses of the three drugs given together but as separate capsules while fasting. Bioequivalence was evaluated according to 90% confidence intervals (CIs) of ratios of geometric least square means for Cmax, AUCt, and AUC∞. Results With respect to food, none of the three drugs met bioequivalence guidelines. Bismuth had lower limit CIs ranging from 12% for Cmax to 25% for AUC∞. The corresponding values for tetracycline were 59% and 51%. Metronidazole had a lower limit CI of 74% for Cmax. With respect to formulation, bismuth had lower limits of CIs ranging from 39% for Cmax to 50% for AUCt and higher limits of 146% for AUCt, metronidazole met bioequivalence guidelines, and tetracycline had lower limits of CIs between 72% for AUCt and 74% for AUC∞. Conclusions Food significantly decreased the relative bioavailability of each drug but formulation was without effect. This decrease may be beneficial when a local gastric action is needed, as confirmed by a near 90% eradication rate when this combined capsule is administered with food to treat gastro-duodenal local infection by H. pylori.

Purpose: BRCA1-related breast cancer frequently has a basal epithelial phenotype, and P-cadherin is a basal marker. We undertook a detailed evaluation of the relationship among P-cadherin, prognostic markers in breast cancer, and outcome. Experimental Design: This study was restricted to 292 cases of first primary invasive breast cancer diagnosed in Ashkenazi Jewish women between 1980 and 1995. All available blocks were stained for P-cadherin, and 261 were included in the final statistical analyses, including 27 germ line BRCA1 mutation carriers and 8 BRCA2 mutation carriers. Descriptive analyses were done followed by survival analyses and a Poisson regression analysis. Results: P-cadherin was present in 80 of the 261 breast cancers (31%) and was more frequently present in tumors that have a basal epithelial phenotype [i.e., high-grade, estrogen receptor– and KIP1 (p27Kip1)–negative tumors, with expression of cytokeratin 5/6, cyclin E, TP53, and presence of BRCA1 mutations and vascular nests (all P < 0.001)]. In a univariate survival model, expression of P-cadherin was associated with a relative risk (RR) of death from breast cancer at a 10-year follow-up of 2.9 (95% confidence interval, 1.8-4.7; P < 0.0001) and was a predictor of poor univariate survival in both lymph node–negative and –positive breast cancers. In a multivariate analysis, the effect of P-cadherin levels was not independent of other basal-related markers. Multivariable interaction modeling showed that P-cadherin positivity was highly predictive of a poor prognosis in small, node-negative breast cancers (RR, 7.1; P = 0.006). Conclusions: P-cadherin is a marker for basal-like breast cancers and is strongly associated with the presence of a BRCA1 mutation. It is an adverse prognostic factor, particularly in small, node-negative breast cancers.

Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27Kip1, or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27Kip1, p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27Kip1 levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.

BACKGROUND A positive correlation between breast tumor size and the number of axillary lymph nodes containing tumor is well established. It has been reported that patients with BRCA1-related breast carcinoma are more likely than patients with nonhereditary breast carcinoma to have negative lymph node status. Therefore, the authors questioned whether the known positive correlation between tumor size and lymph node status also was present in women with BRCA1-related breast carcinomas. METHODS The relation between the greatest dimension of the resected breast tumor (size) and the presence of positive axillary lymph nodes (expressed as a percentage of all lymph nodes examined) was evaluated in 1555 women with invasive breast carcinoma who were ascertained at 10 centers in North America between 1975 and 1997. There were 276 BRCA1 mutation carriers, 136 BRCA2 carriers, and 1143 women without a known mutation (208 BRCA1/BRCA2 noncarriers and 935 untested women). Patients were stratified according to tumor size, and odds ratios were estimated for the presence of positive lymph nodes with increasing tumor size. RESULTS A highly significant positive correlation between tumor size and the frequency of positive axillary lymph nodes was seen for BRCA1/BRCA2 noncarriers, for BRCA2 carriers, and for untested women (overall P < 0.0001 for each). In contrast, there was no clear correlation between tumor size and positive lymph node status in BRCA1 carriers (overall P = 0.20). CONCLUSIONS The relation between tumor size and lymph node status in patients with breast carcinoma appears to be different in BRCA1 carriers compared with BRCA2 carriers and noncarriers. These findings have important implications for estimating the route of metastatic spread and for evaluating the effectiveness of early diagnosis in patients with BRCA1-related breast carcinoma. Cancer 2003. ©2003 American Cancer Society. DOI 10.1002/cncr.11688

Summary Background Early age at first full-term pregnancy and increasing parity are associated with a reduced risk of breast cancer. However, whether pregnancy decreases the risk of early-onset hereditary breast cancer is unknown. There is concern that pregnancy may increase breast-cancer risk in carriers of BRCA1 and BRCA2 germline mutations. We aimed to establish whether pregnancy is a risk factor for hereditary breast cancer. Methods We did a matched case-control study of breast cancer in women who carry deleterious BRCA1 or BRCA2 mutations. Cases were carriers who developed breast cancer by age 40 years, and controls were carriers of the same age without breast cancer, or who were diagnosed with breast cancer after age 40 years. Women who had undergone preventive mastectomy, hysterectomy, or oophorectomy, or who were diagnosed with ovarian cancer before the age at which breast cancer was diagnosed in the matched case were excluded. Information about pregnancies and pregnancy outcome was derived from a questionnaire completed by women in the course of genetic counselling. Findings A higher proportion of cases than controls had had a full term pregnancy (173/236 vs 146/236; odds ratio 1·71 [95% CI 1·13–2·62], p=0·01). The mean number of births was also greater for cases than for controls (1.62 vs 1·38, p=0·04). The risk increased with the number of births and did not diminish with time since last pregnancy. There were no significant differences in age at first birth or age at last birth between cases and controls. Interpretation Carriers of the BRCA1 and BRCA2 mutations who have children are significantly more likely to develop breast cancer by age 40 than carriers who are nulliparous. Each pregnancy is associated with an increased cancer risk. An early first pregnancy does not confer protection for carriers of BRCA1 or BRCA2 mutations.

The I1307K polymorphism in APC has been found to predispose to colorectal cancer in Ashkenazi Jews, and has recently been associated with an increased risk for breast cancer in the same population. In that study, we genotyped 205 paraffin-embedded breast cancers from Ashkenazi Jewish women diagnosed below the age of 65. We now present an extended analysis, with clinicopathological correlations between carriers of I1307K and non-carriers. Twenty-four of 209 cases (11.5%, 95% confidence interval 7.5–16.6) were found to carry the I1307K polymorphism. When stratifying the data by other relevant clinicopathological variables, we observed no association between the presence of this polymorphism and age at diagnosis (P = 0.52), grade (P = 0.074), tumour size (P = 0.99), lymph node status (P = 0.82), oestrogen receptor status (P = 0.23) or P53 immunoreactivity (P = 0.80). The breast-cancer specific 5-year survival for women with I1307 K polymorphism was 88.9% compared with 81.6% in women without I1307K (P = 0.34). Using microdissected samples and direct sequencing, no somatic mutations were observed in any of the 24 I1307K-positive cases. Single-strand conformation analysis of 158 of the I1307K-negative breast cancers that were available for study revealed no mobility shifts. We conclude that the presence of the I1307K polymorphism does not appear to be associated with any particular clinicopathological feature of breast cancer and importantly, does not affect the prognosis. © 1999 Cancer Research Campaign

Approximately 2.0%-2.5% of Ashkenazi Jewish women carry one of three founding mutations in the BRCA1 and BRCA2 genes, and each mutation is associated with a high lifetime risk of invasive breast cancer. We investigated the extent to which these three mutations contribute to breast cancer incidence in the Ashkenazi Jewish population.We ascertained 457 Jewish women with prevalent cases of breast cancer who were unselected for age or family history of the disease; 412 of these women were tested for the three founder mutations (case patients). Control subjects consisted of 360 non-Jewish women with breast cancer (control patients) and 380 healthy Jewish women with no history of cancer (control subjects).Mutations were found in 48 (11.7%) of 412 Jewish case patients. Forty-six of 48 mutations occurred in women with early-onset breast cancer (50 years) or a history of ovarian or early-onset breast cancer in a first-, second-, or third-degree relative. The estimated penetrance to age 70 years for breast cancer was 59.9% for the BRCA1 gene mutations and 28.3% for the BRCA2 gene mutation. Compared with Jewish control subjects, the relative risk (RR) of breast cancer for first-degree relatives of mutation carriers was 5.16 (95% confidence interval [CI] = 3.14-8. 48), but risk was also increased for relatives of noncarriers (RR = 1.66; 95% CI = 1.18-2.33). The RR of prostate cancer for first-degree relatives of Jewish case patients was 3.36 (95% CI = 1. 49-7.56).Approximately 12% of breast cancers in the Ashkenazi Jewish population are attributable to mutations in the BRCA1 or BRCA2 gene. Genetic testing may be useful when Jewish women with breast cancer are diagnosed before age 50 years or have a close relative with ovarian or early-onset breast cancer. An association between breast and prostate cancers was observed in our study population.

Two biallelic polymorphisms in introns 3 and 6 of the p53 gene were analysed for a possible risk-modifying effect for ovarian cancer. Germline DNA was genotyped from 310 German Caucasian ovarian cancer patients and 364 healthy controls. We also typed 124 affected and 276 unaffected female carriers with known deleterious BRCA1 or BRCA2 germline mutation from high-risk breast-ovarian cancer families. Genotyping was based on PCR and high-resolution gel electrophoresis. German ovarian cancer patients who carried the rare allele of the MspI restriction fragment length polymorphism (RELP) in intron 6 were found to have an overall 1.93-fold increased risk (95% confidence internal (CI) 1.27–2.91) which further increased with the age at diagnosis of 41–60 years (odds ratio (OR) 2.71, 95% CI 1.10–6.71 for 41–50 and OR 2.44, 95% CI 1.12–5.28 for 51–60). The 16 bp duplication polymorphism in intron 3 was in a strong linkage to the MspI RFLP. In BRCA1 or BRCA2 mutation carriers, no difference in allele frequency was observed for carriers affected or unaffected with ovarian cancer. Our data suggest that intronic polymorphisms of the p53 gene modify the risk for ovarian cancer patients but not in carriers with BRCA1 or BRCA2 mutations. © 1999 Cancer Research Campaign

Objective To determine the contribution of inheritance to the incidence of squamous cell carcinoma of the head and neck. Design Historical cohort study. First degree relatives of cases with squamous cell carcinoma of the head and neck made up the exposed cohort and first degree relatives of spouses of cases made up the comparison unexposed cohort. Setting Ear, nose, and throat clinic in a large metropolitan teaching hospital. Subjects 1429 first degree relatives of 242 index cases of squamous cell carcinoma of the head and neck; as controls, 934 first degree relatives of the spouses of 156 index cases. Main outcome measures Relative risk of developing squamous cell carcinoma in first degree relatives of cases compared with risk in first degree relatives of spouses. Results The adjusted relative risk for developing head and neck cancer if the index case had squamous cell carcinoma of the head and neck was 3.79 (95% confidence interval 1.11 to 13.0). There were no significantly increased risks associated with a family history of cancer at other sites. The adjusted relative risk for squamous cell carcinoma of the head and neck was 7.89 (1.50 to 41.6) in first degree relatives of patients with multiple primary head and neck tumours. Conclusions These data suggest that genetic factors are important in the aetiology of head and neck cancer, in particular for patients with multiple primary cancers. Given the prolonged exposure of these subjects to carcinogens, these genetic factors may have a role in modifying carcinogen activity or in host resistance to carcinogens. Inherited factors may be important in persons with environmentally induced cancers.

Une maison explose en plein cœur de la ville de Liege, piegeant plusieurs victimes sous les decombres… C’est le declenchement de nombreuses actions menees dans l’urgence par des professionnels du risque et de la gestion de crise (services d’incendie, policiers, ambulanciers, secouristes, services communaux et provinciaux, etc.). Partant de l’analyse de cet evenement et de ses enseignements, cet ouvrage, fruit de rencontres entre chercheurs et professionnels, tente d’articuler risques, planification d’urgence et gestion de crise. La diversite des phenomenes auxquels nos societes sont confrontees est grande et l’organisation de l’action publique dans ce domaine necessite la coordination d’acteurs et d’institutions aux competences et horizons differents. Cet ouvrage a pour ambition de decortiquer cette realite en l’eclairant ici avec des considerations theoriques et la avec des exemples concrets issus de l’experience de terrain. Les auteurs abordent notamment les aspects suivants: le cadre institutionnel et juridique de la gestion de crise; la pragmatique de la planification; les responsabilites fonctionnelles civile et penale des organes communaux; les risques naturels; la diversite des notions de risque;l’evaluation et la gestion des risques.

Purpose: Triple-negative (TN; estrogen receptor, progesterone receptor, and HER-2 negative) cancer and basal-like breast cancer (BLBC) are associated with poor outcome and lack the benefit of targeted therapy. It is widely perceived that BLBC and TN tumors are synonymous and BLBC can be defined using a TN definition without the need for the expression of basal markers. Experimental Design: We have used two well-defined cohorts of breast cancers with a large panel of biomarkers, BRCA1 mutation status, and follow-up data to compare the clinicopathologic and immunohistochemical features of TN tumors expressing one or more of the specific basal markers (CK5/6, CK17, CK14, and epidermal growth factor receptor; BLBC) with those TN tumors that express none of these markers (TN3BKE−). Results: Here, we show that although the morphologic features of BLBC are not significantly different from that of TN3BKE- tumors, BLBC showed distinct clinical and immunophenotypic differences. BLBC showed a statistically significant association with the expression of the hypoxia-associated factor (CA9), neuroendocrine markers, and other markers of poor prognosis such as p53. A difference in the expression of cell cycle-associated proteins and biomarkers involved in the immunologic portrait of tumors was seen. Compared with TN3BKE- tumors, BLBC was positively associated with BRCA1 mutation status and showed a unique pattern of distant metastasis, better response to chemotherapy, and shorter survival. Conclusion: TN breast cancers encompass a remarkably heterogeneous group of tumors. Expression of basal markers identifies a biologically and clinically distinct subgroup of TN tumors, justifying the use of basal markers (in TN tumors) to define BLBC.

Background Basal-like breast cancer has been extensively characterized on the basis of gene expression profiles, but it is becoming increasingly common for these tumors to be defined on the basis of immunohistochemical (IHC) staining patterns, particularly in retrospective studies where material for expression profiling may not be available. The IHC pattern that best defines basal-like tumors is under investigation and various combinations of ER, PR, HER2-, CK5/6+ and EGFR+ have been tested. Methods Using datasets from two different hospitals we describe how using different combinations of immunohistochemical patterns has different effects on estimating prognosis at different time intervals after diagnosis. As our baseline, we used two IHC patterns ER-/PR-/HER2-("triple negative phenotype", TNP) and ER-/HER2-/CK5/6+ and/or EGFR+ ("core basal phenotype", CBP). Results There was no overall difference in survival between the two hospital-based series, but there was a difference between the TNP and non-TNP groups which was most marked at 3 years (76.8% vs 93.5%, p < .0001). This difference reduced with time, suggesting that long term survivors (beyond 10 years) in the TNP group may have comparable survival to non-TNP cases. A similar difference was seen if CBP was used instead of TNP. However when CK5/6 and/or EGFR expressing tumors were analyzed without consideration of ER/PR status, the reduction in survival increased with time, becoming more pronounced at 10 years than at 3 years. Conclusion Our findings suggests that CK5/6 and/or EGFR expressing tumor types have a persistently poorer prognosis over the longer term, an observation that may have important therapeutic implications as drugs that target the EGFR are currently being evaluated in breast cancer.

Background: Elevated levels of the cell cycle protein cyclin E, and low levels of its inhibitor, p27 Kip1 , have been associated with a poor prognosis following breast cancer. Some studies have found that germline mutations in the breast cancer susceptibility gene, BRCA1, are also associated with an inferior survival rate. The relationship between cyclin E/p27 Kip1 levels, BRCA1 status and outcome has not been studied in detail. Patients and methods: We analyzed a historical cohort of 288 Ashkenazi Jewish women who were diagnosed with breast cancer between 1980 and 1995 and were previously tested for BRCA1/2 mutations. Protein levels of cyclin E and p27 Kip1 were assessed by immunohistochemistry. Breast cancer-specific survival (BCSS) was the main outcome measured. Results: The median follow-up was 8 years. Thirty tumors carried germline BRCA1 mutations. These tumors were more likely to have high cyclin E protein levels [odds ratio (OR) 9.5; P

Glomeruloid microvascular proliferation (GMP) in breast cancer independently adversely affected survival (relative risk 1.9, 95% CI: 1.2–3.0), particularly among women who received adjuvant chemotherapy (10-year survival 27 vs 69%, P=0.0003), and was significantly associated with p53 overexpression and BRCA1 germline mutations. The presence of GMP may influence treatment decisions.

BACKGROUND Overexpression of p53 has been associated with poor survival following breast carcinoma. BRCA1 interacts biochemically with p53 and may also contribute to poor outcome when constitutionally mutated. The joint effect of both abnormalities has not been studied. The primary objective of this study was to assess the impact of germline BRCA1 mutations and p53 overexpression on survival after 10 years of follow-up. METHODS A historical cohort of Ashkenazi Jewish women 65 years or younger with invasive breast carcinoma was tested for BRCA1 founder mutations. p53 overexpression was assessed by immunohistochemistry. Clinicopathologic information was obtained by chart review. RESULTS In total, 278 women were analyzed. On univariate analysis, p53 overexpression (n = 63) was prognostic for worse overall survival (relative risk [RR] 2.6, P = 0.001) whereas BRCA1 germline mutations (n = 30) were of borderline significance (RR 1.9, P = 0.052). In the lymph node-negative subpopulation, BRCA1 mutation status conferred a higher mortality on univariate (RR 5.6, P < 0.001) and multivariate (RR 3.5, P = 0.03) analyses. There was a trend in favor of a worse prognosis for women who carried a germline BRCA1 mutation and whose tumor overexpressed p53. When compared with noncarriers, BRCA1 mutation carriers had a worse overall survival if they did not receive adjuvant chemotherapy (RR 3.3, P= 0.01) or adjuvant hormonal therapy (RR 2.3, P = 0.02). CONCLUSIONS Germline BRCA1 mutations and p53 overexpression carry a negative prognosis that is not additive to known prognostic factors. Given the experimental sensitivity of BRCA1-mutated cells to chemotherapy, the worse survival among BRCA1 mutation-carrying lymph node-negative breast carcinoma patients may be partly explained by the significantly lower proportion of lymph node-negative patients who received adjuvant chemotherapy (P < 0.001). Cancer 2003;97:527–36. © 2003 American Cancer Society. DOI 10.1002/cncr.11080

There has been much discussion regarding the penetrance of breast cancer in BRCA1 / 2 mutation carriers (hereafter “carriers”). Both genetic and epigenetic factors could be influencing the reported penetrance estimates. We wanted to establish whether the penetrance of BRCA1 / 2 mutations is changing over time. To limit the genetic variability, we studied a cohort of 292 Ashkenazi Jewish (AJ) women diagnosed with first primary invasive breast cancer between 1 January 1980 and 1 November 1995 at a single Montreal Hospital, without regard to family history. All women were diagnosed at less than 65 years of age. Pathology blocks were identified from all women and the three AJ founder mutations in BRCA1 / 2 (185delAG, 5382insC ( BRCA1 ) and 6174delT ( BRCA2 )) were identified in archival samples using PCR based techniques described previously.1 We identified 41 (14%, 95% CI 10.2-18.6) BRCA1/2 carriers (31 in BRCA1 and 10 in BRCA2 ). The difference in mutation frequency between BRCA1 and BRCA2 carriers (10.6% v 3.4%) is statistically significant (Z=3.40, p=0.0007). Given that the population allele frequencies of AJ founder mutations in BRCA1 and BRCA2 are approximately equal (∼1%), this would suggest that BRCA1 has a higher penetrance than BRCA2 by age 65. This observation supports previous data from Canada.2 We then divided the data into quartiles by year of diagnosis and determined whether the proportion of mutation carriers was changing over time. The number of founder BRCA1 / 2 mutations per quartile of year of diagnosis increased from eight (11.0%) to 15 (20.5%) over the 15 year period of the study, and the χ2 p value for the trend in mean scores was 0.047 (table 1). This suggests that the penetrance of BRCA1 / 2 mutations to the age of 65 years is increasing. This is important, as previous studies of …

In a hospital based case-control study of pancreatic cancer in Ontario and Quebec, a total of 174 incident pancreatic cancer cases and 136 healthy controls were compared for their family history of cancer. Information regarding the ages and sites of cancer was taken for 966 first-degree relatives of the cancer cases and for 903 first-degree relatives of the controls. A total of 150 cancer cases were reported among the relatives of the cases, compared to 122 cases among the relatives of the controls (relative risk 1.15; p = 0.23). Pancreatic cancer was the only site statistically in excess in the case relatives, compared to the control relatives (relative risk = 5.0; p = 0.01). The lifetime risk of pancreatic cancer was 4.7% for the first-degree relatives of the pancreatic cancer cases. The risk was 7.2% for relatives of cases diagnosed before age 60, and was 12.3% for relatives of patients with multiple primary cancers (all ages). These individuals comprise a high-risk group for pancreatic cancer and might benefit from enhanced surveillance or chemoprevention. Familial site-specific pancreatic cancer appears to be a distinct genetic entity, but contributes only modestly to the total burden of pancreatic cancer.

Au départ de quelques textes normatifs de portée nationale et internationale dont l’examen souligne la difficulté de parvenir à une définition opératoire du terrorisme, cet article propose un cadrage différent du phénomène terroriste fondé sur le paradigme des « risques réflexifs » (illustré par des sociologues comme Ulrich Beck et Anthony Giddens). Sous cet éclairage, le risque terroriste agit comme un véritable révélateur de notre rapport à notre environnement politique, social et technique : il est l’occasion de mettre en évidence des rapports de force, des relations politiques de domination et de dépendance qui constituent le contexte structurel de conflits locaux, régionaux ou internationaux ; mais aussi, de manière plus indirecte, en venant nous rappeler la vulnérabilité de nos collectifs, qui reposent de plus en plus sur le fonctionnement en réseaux, l’interdépendance et le développement de macro-systèmes techniques. Les auteurs plaident pour une meilleure prise en compte de la dimension proprement politique du terrorisme, et, plus largement, pour un basculement global vers un modèle de société ouverte plus sensible à des facteurs de risque trouvant leur origine dans nos propres pratiques et notre rapport au monde. Des exemples empruntés au bioterrorisme, en ce que le phénomène paraît emblématique de la réflexivité des risques modernes, forment un fil conducteur exploré tout au long de l’article. On the basis of an examination of several national and international normative texts, this article underlines the difficulty in arriving at an operational definition of terrorism and proposes an alternative framework based on the “reflexive risks” paradigm (as developed by sociologists such as Beck and Giddens). In this sense, the modern risk of terrorism is revelatory of our relationship to our political, social and technological environment: providing an occasion to assess power dynamics, political relations of dependence and domination which constitute the structural context of local, regional or international conflicts and, more indirectly, also reminds us of the vulnerability of societies which increasingly rely on interdependence, networking and technological macro-systems. The author makes the case for a deeper consideration of the specifically political dimensions of terrorism and, more broadly, for a global transformation towards more open societies that would be more receptive to risk factors whose origins emanate from our own practices and relations with the world. Examples taken from bio-terrorism form a common theme throughout the article, as this new threat seems emblematic of the reflexivity of modern risks.

The association between BRCA1 germ-line mutations and breast cancer prognosis is controversial. A historical cohort study was designed to determine the prognosis for women with axillary lymph node negative hereditary breast cancer.We tested pathology blocks from 118 Ashkenazi Jewish women with axillary lymph node negative breast cancer for the presence of the two common BRCA1 founder mutations, 185delAG and 5382insC. Patients were followed up for a median of 76 months. Somatic TP53 mutations were screened for by immunohistochemistry, and direct sequencing was performed in the BRCA1-positive tumours.Sixteen breast cancer blocks (13.6%) carried a BRCA1 mutation. Young age of onset, high nuclear grade, negative estrogen receptor status and over-expression of p53 were highly associated with BRCA1-positive status (P-values all0.01). BRCA1 mutation carriers had a higher mortality than non-carriers (five-year overall survival, 50% and 89.6%, respectively, P = 0.0001). Young age of onset, estrogen receptor negative status, nuclear grade 3, and over-expression of p53 also predicted a poor outcome. Cox multivariate analyses showed that only germ-line BRCA1 mutation status was an independent prognostic factor for overall survival (P = 0.01). Among nuclear grade 3 tumours, the BRCA1 mutation carrier status was a significant prognostic factor of death (risk ratio 5.8, 95% confidence interval: 1.5-22, P = 0.009). Sequencing of BRCA1-related breast cancers revealed one TP53 missense mutation not previously reported in breast cancer.Using a historical cohort approach, we have identified BRCA1 mutation status as an independent prognostic factor for node negative breast cancer among the Ashkenazi Jewish women. Those managing women carrying a BRCA1 mutation may need take these findings into consideration. Additionally, our preliminary results, taken together with the work of others suggest a different carcinogenic pathway in BRCA1-related breast cancer, compared to non-hereditary cases.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition predisposing to cancers of the colorectum and endometrium. Endometrial cancer is the most commonly occurring extracolonic cancer in HNPCC. Estimates of the cumulative incidence of endometrial cancer in women with mutations in the HNPCC genes range from 22-43%. In order to determine how frequently double primary cancers of the colorectum and endometrium are the result of a hereditary factor, we conducted a registry based study in Ontario and Quebec, Canada. We obtained pedigrees on 80 women diagnosed with double primary cancers of the colorectum and endometrium at less than 70 years of age. Family histories of cancer were obtained for all first degree relatives of these women and cancer rates were compared with age standardised provincial incidence rates in order to estimate the relative risks. There was a total of 82 cancers observed in relatives below the age of 55, compared with 31.2 expected, giving a relative risk of 2.6 (95% confidence interval (CI) 2.1-3.3). The relative risk for colorectal cancer below 55 was 16.1 (95% CI 11.6-21.8). This risk decreased with increasing age of onset of cancers in probands. For probands with both colorectal and endometrial cancer diagnosed under the age of 55, the relative risk of colorectal cancer in relatives below the age of 55 was 30.5 (95% CI 18.8-46.6). Similar patterns were observed for endometrial and pancreatic cancer. There were non-significant increases in rates of cancer of the oesophagus, stomach, small intestine, and bladder. There was no increased risk of breast cancer. The risk of lung cancer was decreased, especially in older relatives. Our findings indicate the presence of a significant genetic component of cancer in women with double primary cancers of the colorectum and endometrium.

Background: Smoking has carcinogenic effects, and possibly antiestrogenic effects as well, but it has not been found to be a risk factor for breast cancer in women in the general population. However, hereditary breast cancer is primarily a disease of premenopausal women, and interactions between genes and hormonal and environmental risk factors may be particularly important in this subgroup. Methods: We conducted a matched case-control study of breast cancer among women who have been identified to be carriers of a deleterious mutation in either the BRCA1 or the BRCA2 gene. These women were assessed for genetic risk at one of several genetic counseling programs for cancer in North America. Information about lifetime smoking history was derived from a questionnaire routinely administered to women who were found to carry a mutation in either gene. Smoking histories of case subjects with breast cancer and age-matched healthy control subjects were compared. Odds ratios for developing breast cancer were determined for smokers versus nonsmokers by use of conditional logistic regression for matched sets after adjustment for other known risk factors. Results: Subjects with BRCA1 or BRCA2 gene mutations and breast cancer were significantly more likely to have been nonsmokers than were subjects with mutations and without breast cancer (two-sided P = .007). In a multivariate analysis, subjects with BRCA1 or BRCA2 mutations who had smoked cigarettes for more than 4 pack-years (i.e., number of packs per day multiplied by the number of years of smoking) were found to have a lower breast cancer risk (odds ratio = 0.46, 95% confidence interval = 0.27-0.80; two-sided P = .006) than subjects with mutations who never smoked. Conclusions : This study raises the possibility that smoking reduces the risk of breast cancer in carriers of BRCA1 or BRCA2 gene mutations.

The functions of the breast cancer susceptibility genes BRCA1 and BRCA2 are not fully elucidated, but appear to include the regulation of X chromosome activity. Xist is a non-coding RNA that accumulates on the inactive X chromosome and is required for X chromosome inactivation during the silencing step.1 The RING domain of BRCA1 and Xist interact in mammalian cells and it has been suggested that BRCA1 contributes to the initiation of X chromosome inactivation.2 Women with ovarian cancer possessing germline mutations in BRCA1 have been found to frequently demonstrate non-random X chromosome inactivation.3 In the light of these findings, a recent report by de la Hoya et al is of interest.4 In this study of 68 Spanish breast/ovarian pedigrees they reported that 67% of the children of women who carried a BRCA1 mutation were female. By contrast, only 54% of the offspring of BRCA2 carriers and 52% of the offspring of non-carriers were female. This highly skewed sex ratio in the offspring of BRCA1 carriers from Spain prompted us to ask whether this is true in other populations as well. To address this question, we examined the sex ratios of the offspring of a total of 1040 women (229 BRCA1 carriers, 104 BRCA2 carriers, and 707 non-carriers) from five different studies which were conducted in …

Ovarian cancer is a component of the autosomal-dominant hereditary breast-ovarian cancer syndrome and may be due to a mutation in either the BRCA1 or BRCA2 genes. Two mutations in BRCA1 (185delAG and 5382insC) and one mutation in BRCA2 (6174delT) are common in the Ashkenazi Jewish population. One of these three mutations is present in approximately 2% of the Jewish population. Each mutation is associated with an increased risk of ovarian cancer, and it is expected that a significant proportion of Jewish women with ovarian cancer will carry one of these mutations. To estimate the proportion of ovarian cancers attributable to founding mutations in BRCA1 and BRCA2 in the Jewish population and the familial cancer risks associated with each, we interviewed 213 Jewish women with ovarian cancer at 11 medical centers in North America and Israel and offered these women genetic testing for the three founder mutations. To establish the presence of nonfounder mutations in this population, we also completed the protein-truncation test on exon 11 of BRCA1 and exons 10 and 11 of BRCA2. We obtained a detailed family history on all women we studied who had cancer and on a control population of 386 Ashkenazi Jewish women without ovarian or breast cancer. A founder mutation was present in 41.3% of the women we studied. The cumulative incidence of ovarian cancer to age 75 years was found to be 6.3% for female first-degree relatives of the patients with ovarian cancer, compared with 2.0% for the female relatives of healthy controls (relative risk 3.2; 95% CI 1.5-6.8; P=.002). The relative risk to age 75 years for breast cancer among the female first-degree relatives was 2.0 (95% CI 1.4-3.0; P=.0001). Only one nonfounder mutation was identified (in this instance, in a woman of mixed ancestry), and the three founding mutations accounted for most of the observed excess risk of ovarian and breast cancer in relatives.

The European Employment Strategy has been adopted in 1997. It organizes a coordination ofnational employment policies around common European objectives. The initial method was basedon mutual learning and peer pressure but it has recently moved towards a more binding form ofgovernance.This thesis focuses on the uses of this strategy in Wallonia. It describes the procedural andcognitive effects of the EES and analyzes the strategies of the social and political actors involved inemployment policies. Finally, it highlights the effective changes in employment policies that can beassociated with this strategy., La stratégie européenne pour l’emploi, adoptée en 1997, organise une coordination des politiquesnationales de l’emploi autour d’objectifs communs. La méthode initiale reposait sur l’apprentissagemutuel et la pression par les pairs. Elle a récemment évolué vers une forme de gouvernance pluscontraignante.Cette thèse porte sur les usages de cette stratégie en Wallonie. Elle décrit les effets procédurauxet cognitifs de la SEE et analyse les comportements et stratégies des acteurs. Enfin, elle met enévidence les changements effectifs des politiques de l’emploi qui peuvent être associés à cettestratégie.