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Mohamed Hassanein,
Laetitia Huiart,
Violaine Bourdon,
Laetitia Rabayrol,
Jeanine Geneix,
Catherine Nogues,
Jean Philippe Peyrat, Paul Gesta,
Paule Meynard,
Helene Dreyfus,
Dominique Petrot,
Rosette Lidereau,
Tetsuro Noguchi,
François Eisinger,
Jean Marc Extra,
Patrice Viens,
Jocelyne Jacquemier,
Hagay Sobol
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ABSTRACT: Family structure, lack of reliable information, cost, and delay are usual concerns when deciding to perform BRCA analyses. Testing breast cancer tissues with four antibodies (MS110, lys27H3, vimentin, and KI67) in addition to grade evaluation enabled us to rapidly select patients for genetic testing identification. We constituted an initial breast cancer tissue microarray, considered as a learning set, comprising 27 BRCA1 and 81 sporadic tumors. A second independent validation set of 28 BRCA1 tumors was matched to 28 sporadic tumors using the same original conditions. We investigated morphological parameters and 21 markers by immunohistochemistry. A logistic regression model was used to select the minimal number of markers providing the best model to predict BRCA1 status. The model was applied to the validation set to estimate specificity and sensibility. In the initial set, univariate analyses identified 11 markers significantly associated with BRCA1 status. Then, the best multivariate model comprised only grade 3, MS110, Lys27H3, vimentin, and KI67. When applied to the validation set, BRCA1 tumors were correctly classified with a sensitivity of 83% and a specificity of 81%. The performance of this model was superior when compared to other profiles. This study offers a new rapid and cost-effective method for the prescreening of patients at high risk of being BRCA1 mutation carriers, to guide genetic testing, and finally to provide appropriate preventive measures, advice, and treatments including targeted therapy to patients and their families.
Pathobiology 04/2013; 80(5):219-227. · 1.18 Impact Factor
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Julie Lecarpentier,
Catherine Noguès,
Emmanuelle Mouret-Fourme,
Marion Gauthier-Villars,
Christine Lasset,
Jean-Pierre Fricker,
Olivier Caron,
Dominique Stoppa-Lyonnet,
Pascaline Berthet,
Laurence Faivre, [......],
Marc Frénay,
Elisabeth Luporsi,
Alain Lortholary,
Chrystelle Colas,
Catherine Dugast,
Michel Longy,
Pascal Pujol,
Julie Tinat,
Rosette Lidereau,
Nadine Andrieu
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ABSTRACT: INTRODUCTION: Mutations in BRCA1 and BRCA2 confer a high risk of breast cancer (BC), but the magnitude of this risk seems to vary according to the study and various factors. Although controversial, there are data to support the hypothesis of allelic risk heterogeneity. METHODS: We assessed variation in BC risk according to factors related to pregnancies by location of mutation in the homogeneous risk region of BRCA1 and BRCA2 in 990 women in the French study GENEPSO by using a weighted Cox regression model. RESULTS: Our results confirm the existence of the protective effect of an increasing number of full-term pregnancies (FTPs) toward BC among BRCA1 and BRCA2 mutation carriers (≥3 versus 0 FTPs: hazard ratio (HR) = 0.51, 95% confidence interval (CI) = 0.33 to 0.81). Additionally, the HR shows an association between incomplete pregnancies and a higher BC risk, which reached 2.39 (95% CI = 1.28 to 4.45) among women who had at least three incomplete pregnancies when compared with women with zero incomplete pregnancies. This increased risk appeared to be restricted to incomplete pregnancies occurring before the first FTP (HR = 1.77, 95% CI = 1.19 to 2.63). We defined the TMAP score (defined as the Time of Breast Mitotic Activity during Pregnancies) to take into account simultaneously the opposite effect of full-term and interrupted pregnancies. Compared with women with a TMAP score of less than 0.35, an increasing TMAP score was associated with a statistically significant increase in the risk of BC (P trend = 0.02) which reached 1.97 (95% CI = 1.19 to 3.29) for a TMAP score >0.5 (versus TMAP ≤0.35). All these results appeared to be similar in BRCA1 and BRCA2. Nevertheless, our results suggest a variation in BC risk associated with parity according to the location of the mutation in BRCA1. Indeed, parity seems to be associated with a significantly decreased risk of BC only among women with a mutation in the central region of BRCA1 (low-risk region) (≥1 versus 0 FTP: HR = 0.27, 95% CI = 0.13 to 0.55) (Pinteraction <10-3). CONCLUSIONS: Our findings show that, taking into account environmental and lifestyle modifiers, mutation position might be important for the clinical management of BRCA1 and BRCA2 mutation carriers and could also be helpful in understanding how BRCA1 and BRCA2 genes are involved in BC.
Breast cancer research: BCR 07/2012; 14(4):R99. · 5.24 Impact Factor
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Claire Julian-Reynier,
Roxane Fabre,
Isabelle Coupier,
Dominique Stoppa-Lyonnet,
Christine Lasset,
Olivier Caron,
Emmanuelle Mouret-Fourme,
Pascaline Berthet,
Laurence Faivre,
Marc Frenay, Paul Gesta,
Laurence Gladieff,
Anne-Deborah Bouhnik,
Christel Protière,
Catherine Noguès
[show abstract]
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ABSTRACT: To assess the impact of BRCA1/2 test results on carriers' reproductive decision-making and the factors determining their theoretical intentions about preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND).
Unaffected BRCA1/2 mutation carriers of childbearing age (N = 605; 449 women; 151 men) were included at least 1 year after the disclosure of their test results in a cross-sectional survey nested in a national cohort. Multivariate adjustment was performed on the data obtained in self-administered questionnaires.
Response rate was 81.0%. Overall, 32.5% and 50% said that they would undergo PGD/PND, respectively, at a theoretical next pregnancy, whereas only 12.1% found termination of pregnancy (TOP) acceptable. Theoretical intentions toward PGD did not depend on gender/age, but were higher among those with no future childbearing plans (adjusted odds ratio (AOR) 95% confidence interval (CI): 3.5 (1.9-6.4)) and those having fewer relatives with cancer (AOR 1.5 95% CI (1.0-2.3)). Greater TOP acceptability was observed among males and those with lower educational levels; 85.4% of respondents agreed that information about PGD/PND should be systematically delivered with the test results.
The closer to reproductive decision-making BRCA1/2 carriers are, i.e., when they are more likely to be making future reproductive plans, the less frequently they intend to have PGD. Carriers' theoretical intentions toward PND are discussed further.
Genetics in medicine: official journal of the American College of Medical Genetics 01/2012; 14(5):527-34. · 3.92 Impact Factor
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Pascal Pujol,
Christine Lasset,
Pascaline Berthet,
Catherine Dugast,
Suzette Delaloge,
Jean-Pierre Fricker,
Isabelle Tennevet,
Nathalie Chabbert-Buffet,
Pascale This,
Karen Baudry, [......],
Philippe Vennin,
Capucine Delnatte,
Yves Jean Bignon,
Alain Lortholary,
Fabienne Prieur,
Laurence Gladieff,
Anne Lesur,
Krishna B Clough,
Catherine Nogues,
Anne-Laure Martin
[show abstract]
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ABSTRACT: Women with germline BRCA1 or BRCA2 (BRCA1/2) mutations are considered as an extreme risk population for developing breast cancer. Prophylactic mastectomy provides a valid option to reduce such risk, impacting however, the quality of life. Medical prevention by aromatase inhibitor that has also recently shown to have preventive effect may thus be considered as an alternative. LIBER is an ongoing double-blind, randomized phase III trial to evaluate the efficacy of 5-year letrozole versus placebo to decrease breast cancer incidence in post-menopausal BRCA1/2 mutation carriers (NCT00673335). We present data on the uptake of this trial. We compared characteristics of women in the LIBER trial (n = 113) to those of women enrolled in the prospective ongoing national GENEPSO cohort (n = 1,505). Uptake was evaluated through a survey sent to all active centres, with responses obtained from 17 to the 20 (85%) centres. According to the characteristics of the women enrolled in the GENEPSO cohort and the survey, approximately one-third of BRCA1/2 mutation carriers were eligible for the trial. Five hundred and thirty-four women eligible from chart review have been informed by mail about the prevention trial and were invited to an oral information by participating centres. Forty-four percentage of them came to the dedicated medical visit. Uptake of drug prevention trial was 32% among women informed orally and 15% of all the eligible women. The main reasons of refusal were: potential side effects, probability to receive the placebo and lack of support from their physicians. Additionally, we noticed that prior prophylactic oophorectomy and previous unilateral breast cancer were more frequent in women enrolled in the LIBER trial than in the French cohort (93% vs. 60% and 50% vs. 39%, respectively). Based on an overall 15% uptake among all eligible subjects, greater and wider information of the trial should be offered to women with BRCA1/2 mutation to improve recruitment. Women with previous unilateral breast cancer or prior prophylactic oophorectomy are more likely to enter a medical prevention trial.
Familial Cancer 11/2011; 11(1):77-84. · 1.30 Impact Factor
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Rim El Abed,
Violaine Bourdon,
Ilia Voskoboinik,
Halima Omri,
Yosra Ben Youssef,
Mohamed Adnene Laatiri,
Laetitia Huiart,
François Eisinger,
Laetitia Rabayrol,
Marc Frenay, [......],
Hélène Dreyfus,
Valérie Bonadona,
Catherine Dugast,
Hélène Zattara,
Laurence Faivre,
Monia Zaier,
Saloua Yacoub Jemni,
Testsuro Noguchi,
Hagay Sobol,
Zohra Soua
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ABSTRACT: ABSTRACT: Perforin gene (PRF1) mutations have been identified in some patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH) and in patients with lymphoma. The aim of the present study was to determine whether patients with a familial aggregation of hematological malignancies harbor germline perforin gene mutations. For this purpose, 81 unrelated families from Tunisia and France with aggregated hematological malignancies were investigated. The variants detected in the PRF1 coding region amounted to 3.7% (3/81). Two of the three variants identified were previously described: the p.Ala91Val pathogenic mutation and the p.Asn252Ser polymorphism. A new p.Ala 211Val missense substitution was identified in two related Tunisian patients. In order to assess the pathogenicity of this new variation, bioinformatic tools were used to predict its effects on the perforin protein structure and at the mRNA level. The segregation of the mutant allele was studied in the family of interest and a control population was screened. The fact that this variant was not found to occur in 200 control chromosomes suggests that it may be pathogenic. However, overexpression of mutated PRF1 in rat basophilic leukemia cells did not affect the lytic function of perforin differently from the wild type protein.
Hereditary Cancer in Clinical Practice 09/2011; 9(1):9. · 1.68 Impact Factor
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Julie Lecarpentier,
Catherine Noguès,
Emmanuelle Mouret-Fourme,
Dominique Stoppa-Lyonnet,
Christine Lasset,
Olivier Caron,
Jean-Pierre Fricker,
Laurence Gladieff,
Laurence Faivre,
Hagay Sobol, Paul Gesta,
Marc Frenay,
Elisabeth Luporsi,
Isabelle Coupier,
Rosette Lidereau,
Nadine Andrieu
[show abstract]
[hide abstract]
ABSTRACT: Germline mutations in BRCA1/2 confer a high risk of breast cancer (BC), but the magnitude of this risk varies according to various factors. Although controversial, there are data to support the hypothesis of allelic-risk heterogeneity. We assessed variation in BC risk according to the location of mutations recorded in the French study GENEPSO. Since the women in this study were selected from high-risk families, oversampling of affected women was eliminated by using a weighted Cox-regression model. Women were censored at the date of diagnosis when affected by any cancer, or the date of interview when unaffected. A total of 990 women were selected for the analysis: 379 were classified as affected, 611 as unaffected. For BRCA1, there was some evidence of a central region where the risk of BC is lower (codons 374-1161) (HR = 0.59, P = 0.04). For BRCA2, there was a strong evidence for a region at decreased risk (codons 957-1827) (HR = 0.35, P = 0.005) and for one at increased risk (codons 2546-2968) (HR = 3.56, P = 0.01). Moreover, we found an important association between radiation exposure from chest X-rays and BC risk (HR = 4.29, P < 10(-3)) and a positive association between smoking more than 21 pack-years and BC risk (HR = 2.09, P = 0.04). No significant variation in BC risk associated with chest X-ray exposure, smoking, and alcohol consumption was found according to the location of the mutation in BRCA1 and BRCA2. Our findings are consistent with those suggesting that the risk of BC is lower in the central regions of BRCA1/2. A new high-risk region in BRCA2 is described. Taking into account environmental and lifestyle modifiers, the location of mutations might be important in the clinical management of BRCA mutation carriers.
Breast Cancer Research and Treatment 07/2011; 130(3):927-38. · 4.43 Impact Factor
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Claire Julian-Reynier,
Anne-Déborah Bouhnik,
Emanuelle Mouret-Fourme,
Marion Gauthier-Villars,
Pascaline Berthet,
Christine Lasset,
Jean-Pierre Fricker,
Olivier Caron, Paul Gesta,
Elisabeth Luporsi,
Laurence Faivre,
Michel Longy,
Laurence Gladieff,
Marc Frenay,
Héléne Dreyfus,
Hagay Sobol,
Philippe Vennin,
Catherine Nogués
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[hide abstract]
ABSTRACT: To investigate the medical and psychosocial factors determining the time to prophylactic surgery of unaffected women carriers of a deleterious BRCA1/2 mutation.
Prospective study on a French national cohort of unaffected BRCA1/2 carriers (N = 244); multivariate Cox proportional hazard modeling.
Median follow-up time was 2.33 years (range, 0.04-6.84 years). Time to surgery was shorter when the psychological impact of BRCA1/2 result disclosure was stated to be higher (P ≤ 0.01). Those who intended to opt for prophylactic surgery before being tested did so faster and more frequently after test disclosure than those who were undecided/opposed. The older the women were, the faster their uptake of risk-reducing salpingo-oophorectomy (adjusted hazard ratio >2.95; P < 0.001) was; the uptake of those with at least two children was also faster (adjusted hazard ratio = 2.51; [1.38-4.55]). Those who opted most quickly for risk-reducing mastectomy more frequently had a younger child at the time of testing (adjusted hazard ratio = 4.63 [1.56-13.74]). Time to surgery was shorter when there was a first-degree relative with ovarian/breast cancer (P ≤ 0.01).
Time to prophylactic surgery depends on the stated psychological impact of disclosure and on women's cognitive anticipation of surgery after adjusting on sociodemographic characteristics.
Genetics in medicine: official journal of the American College of Medical Genetics 10/2010; 12(12):801-7. · 3.92 Impact Factor
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Antonis C Antoniou,
Matti Rookus,
Nadine Andrieu,
Richard Brohet,
Jenny Chang-Claude,
Susan Peock,
Margaret Cook,
D Gareth Evans,
Rosalind Eeles,
Catherine Nogues, [......],
Jacques Simard,
Jan Lubinski,
Anne-Marie Gerdes,
Edith Olah,
Christine Fürhauser,
Hakan Olsson,
Brita Arver,
Paolo Radice,
Douglas F Easton,
David E Goldgar
[show abstract]
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ABSTRACT: Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (OC) use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated in a small number of studies.
We used data on 2,281 BRCA1 carriers and 1,038 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study to evaluate the effect of reproductive and hormonal factors on ovarian cancer risk for mutation carriers. Data were analyzed within a weighted Cox proportional hazards framework.
There were no significant differences in the risk of ovarian cancer between parous and nulliparous carriers. For parous BRCA1 mutation carriers, the risk of ovarian cancer was reduced with each additional full-term pregnancy (P trend = 0.002). BRCA1 carriers who had ever used OC were at a significantly reduced risk of developing ovarian cancer (hazard ratio, 0.52; 95% confidence intervals, 0.37-0.73; P = 0.0002) and increasing duration of OC use was associated with a reduced ovarian cancer risk (P trend = 0.0004). The protective effect of OC use for BRCA1 mutation carriers seemed to be greater among more recent users. Tubal ligation was associated with a reduced risk of ovarian cancer for BRCA1 carriers (hazard ratio, 0.42; 95% confidence intervals, 0.22-0.80; P = 0.008). The number of ovarian cancer cases in BRCA2 mutation carriers was too small to draw definitive conclusions.
The results provide further confirmation that OC use, number of full-term pregnancies, and tubal ligation are associated with ovarian cancer risk in BRCA1 carriers to a similar relative extent as in the general population.
Cancer Epidemiology Biomarkers & Prevention 03/2009; 18(2):601-10. · 4.12 Impact Factor
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F Lesueur,
M de Lichy,
M Barrois,
G Durand,
J Bombled,
M-F Avril,
A Chompret,
F Boitier,
G M Lenoir,
B Bressac-de Paillerets, [......],
Laurence Olivier-Faivre,
Vincent Orlandini,
Pascal Pujol,
Bruno Sassolas,
Dominique Stoppa-Lyonnet,
Luc Thomas,
Pierre Vabres,
Laurence Venat,
Ewa Wierzbicka,
Hélène Zattara
[show abstract]
[hide abstract]
ABSTRACT: Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.
British Journal of Cancer 08/2008; 99(2):364-70. · 5.04 Impact Factor
