Showing papers by "Dominique Stoppa-Lyonnet published in 2006"
TL;DR: Oophorectomy is associated with reduced risk of ovarian and fallopian tube cancer in high-risk women, although there is a substantial residual risk for peritoneal cancer in BRCA1 and BRCa2 mutation carriers following prophylactic salpingo-oophoreCTomy.
Abstract: ContextWomen with BRCA1 or BRCA2 mutation are often advised to undergo preventive oophorectomy. The effectiveness of this intervention has not been prospectively evaluated in a large cohort.ObjectivesTo estimate the incidence of ovarian, fallopian tube, and primary peritoneal cancer in women who carry a deleterious mutation in BRCA1 or BRCA2. To estimate the reduction in risk of these cancers associated with a bilateral prophylactic salpingo-oophorectomy.Design, Setting, and ParticipantsWomen known to carry a BRCA1 or BRCA2 mutation were identified from an international registry between 1992 and 2003. A total of 1828 carriers at 1 of 32 centers in Canada, the United States, Europe, and Israel completed questionnaires at baseline and follow-up. Participants were observed from the date of study entry until: diagnosis of ovarian, fallopian tube, or peritoneal cancer; death; or the date of the most recent follow-up.InterventionParticipants were divided into women who had undergone bilateral prophylactic oophorectomy and those who had not.Main Outcome MeasureThe incidence of ovarian, peritoneal, and fallopian tube cancer was determined by survival analysis. The risk reduction associated with prophylactic salpingo-oophorectomy was evaluated by a time-dependent survival analysis, adjusting for covariates.ResultsAfter a mean follow-up of 3.5 years, 50 incident ovarian, fallopian tube, and peritoneal cancer cases were reported in the cohort. Of the 1828 women, 555 (30%) underwent a bilateral prophylactic salpingo-oophorectomy prior to study entry, 490 (27%) underwent the procedure after entering the study, and 783 (43%) did not undergo the procedure. There were 32 incident cancers diagnosed in women with intact ovaries (1015/100 000 per year). Eleven cancer cases were identified at the time of prophylactic oophorectomy and 7 were diagnosed following prophylactic oophorectomy (217/100 000 per year). The estimated cumulative incidence of peritoneal cancer is 4.3% at 20 years after oophorectomy. The overall (adjusted) reduction in cancer risk associated with bilateral oophorectomy is 80% (multivariate hazard ratio = 0.20; 95% confidence interval, 0.07-0.58; P = .003).ConclusionOophorectomy is associated with reduced risk of ovarian and fallopian tube cancer in high-risk women, although there is a substantial residual risk for peritoneal cancer in BRCA1 and BRCA2 mutation carriers following prophylactic salpingo-oophorectomy.
541 citations
TL;DR: The results confirm the impact of the MDM2 SNP309 G allele on the age of tumour onset in germline p53 mutation carriers, and suggest that this effect may be amplified by the p53 72Arg allele.
Abstract: Li‐Fraumeni syndrome, resulting from p53 (TP53) germline mutations, represents one of the most devastating genetic predispositions to cancer. Recently, the MDM2 SNP309 (T→G variation) was shown to be associated with accelerated tumour formation in p53 mutation carriers. The impact of the common p53 codon 72 polymorphism on cancer risk remains controversial. We therefore investigated the effect of these two polymorphisms in 61 French carriers of the p53 germline mutation. The mean age of tumour onset in MDMD2 SNP309 G allele carriers (19.6 years) was significantly different from that observed in patients homozygous for the T allele (29.9 years, p<0.05). For the p53 codon 72 polymorphism, the mean age of tumour onset in Arg allele carriers (21.8 years) was also different from that of Pro/Pro patients (34.4 years, p<0.05). We observed a cumulative effect of both polymorphisms because the mean ages of tumour onset in carriers of the MDM2G and p53Arg alleles (16.9 years) and those with the MDM2T/T and p53Pro/Pro genotypes (43 years) were clearly different (p<0.02). Therefore, our results confirm the impact of the MDM2 SNP309 G allele on the age of tumour onset in germline p53 mutation carriers, and suggest that this effect may be amplified by the p53 72Arg allele. Polymorphisms affecting p53 degradation therefore represent one of the rare examples of modifier genetic factors identified to date in mendelian predispositions to cancer.
207 citations
TL;DR: High evolutionary conservation of ATIP amino-acid sequences suggests important biological roles for this new family of proteins in tumor suppression and/or brain function.
82 citations
TL;DR: It is concluded that NMD can recognize PTCs up to 4.5 kb upstream of the nearest EEJ, demonstrating that a general inability of NMD to recognize P TCs in exon 11 is unlikely to explain the genotype–phenotype correlation associated with the OCCR.
Abstract: BRCA2 (BReast CAncer susceptibility gene 2) germline mutation carriers are at increased risk for breast and ovarian cancers. Mutations occurring in the ovarian cancer cluster region (OCCR) are linked to higher ovarian cancer and/or lower breast cancer risk(s) than mutations occurring elsewhere in BRCA2. Most BRCA2 germline mutations introduce premature termination codons (PTCs), making their mRNAs likely targets of nonsense-mediated mRNA decay (NMD), a mechanism that eliminates PTC-bearing transcripts to prevent expression of truncated proteins. Contradictory evidence exists regarding whether NMD can be triggered by PTCs located far upstream of the nearest exon-exon junction (EEJ). Since the OCCR comprises a major portion of the 4.9 kb exon 11 of BRCA2, we investigated if transcripts bearing PTCs in this large exon are unable to trigger NMD, and if this might contribute to the phenotypic difference associated with the OCCR. We examined cDNA from 18 carriers of PTC-introducing germline mutations located throughout BRCA2, and found that PTC-bearing transcripts were 1.4-3.3-fold less prevalent than their nonmutated counterparts irregardless of PTC position. We conclude that NMD can recognize PTCs up to 4.5 kb upstream of the nearest EEJ, demonstrating that a general inability of NMD to recognize PTCs in exon 11 is unlikely to explain the genotype-phenotype correlation associated with the OCCR.
60 citations
TL;DR: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCa2 defects.
Abstract: Background: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer. Objective: To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects. Methods: Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2 . Results: We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of ⩽50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum. Conclusion: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.
59 citations
TL;DR: In addition to a consultation providing more tailored information, a standardized written document improved the decision-making process involved in giving informed consent to genetic testing.
48 citations
TL;DR: Five major nucleotide substitutions were identified in the 17 coding exons of ATIP/MTUS1, all located in exons used by the ATIP3 transcript which is the only ATIP transcript variant expressed in liver, suggesting potential deleterious effects on AtIP3 function and/or expression.
44 citations
TL;DR: The aim of this study was to present baseline data on the access to Internet by French breast cancer patients attending genetic clinics and to examine factors affecting Internet health-related use.
Abstract: The aim of this study was to present baseline data on the access to Internet by French breast cancer patients attending genetic clinics and to examine factors affecting Internet health-related use. Twenty-four percent of participants used Internet to obtain information about the disease. This rate was higher among patients with health occupations [adjusted odds ratio (adjOR) 2.6; 95% confidence interval (CI) 1.3–5.1], the most highly educated (adjOR 2.1; 95% CI 1.1–4.0) and those under 41 years of age (adjOR 7.3; 95% CI 2.1–26.2). Almost one of every three women was dissatisfied of this source of information.
43 citations
TL;DR: An analysis of the missed mutations suggest that the success rate could be improved up to about 97%, simply by redesigning the amplicons, while retaining the speed, cost effectiveness, and simplicity of the method.
Abstract: A new method for the detection of unknown mutations, enhanced mismatch mutation analysis (EMMA), is proposed. It is based on electrophoretic heteroduplex analysis (HDA). The resolution is considerably improved, thanks to the combination of high-resolution block-copolymer sieving matrix, and nucleosides as additives in the electrophoretic medium. The EMMA method is compared to denaturing HPLC (DHPLC) in a large-scale study of mutations in the breast cancer-associated gene BRCA2, involving 4655 DNA amplicons from 94 patients. The rate of false positives was 0.09%. The raw success rate, without optimization of the amplicons tiling, was 94%, a value much higher than that achieved earlier with HDA, and comparable with that obtained with DHPLC. An analysis of the missed mutations suggest that the success rate could be improved up to about 97%, simply by redesigning the amplicons, while retaining the speed, cost effectiveness, and simplicity of the method.
12 citations
TL;DR: While unidirectional transfer of information from the geneticist to the counselee has been the preferred method in cancer genetics for a long time, a model based on patient-centered communication is more adequate in predictive medicine and allows shared decision making.
Abstract: Cancer genetic counselling represents a very special situation of interaction between the geneticist and the counselee, marked by a number of specificities that account for its complexity. Cancer genetic counselling has multiple repercussions, such as identification of a deleterious genetic mutation associated with a high probability of developing breast and/or ovarian cancer, the implementation of preventive measures ranging from close surveillance to the decision to perform mutilating prophylactic surgical procedures, or the impact of the information on the other members of the counselee's family also concerned by the genetic risk. This chapter is based on a review of the literature that has been rapidly growing over recent years and on our clinical expertise as psycho-oncologists and geneticists. We will first present the reasons that make the information so critical. These reasons are both objective (complexity of the genetic information per se, difficulties of understanding the concept of risk) and subjective (information given to people with an emotionally charged family history and a perception of risks closely linked to their representation of cancer). At the same time, the counsellees are charged with the transmission of this information to members of their own family. We will then discuss the various modalities of communication in this setting. While unidirectional transfer of information from the geneticist to the counselee has been the preferred method in cancer genetics for a long time, a model based on patient-centered communication is more adequate in predictive medicine and allows shared decision making. In all cases, the different professionals involved in the process have to learn how to work in a performing cohesion. We also present the main guidelines on the subject and the various underlying objectives with regard to information delivery and the subject's personal experience. Although the psychological impact of genetic counselling consultations raises a number of questions, the results of preliminary studies are reassuring, demonstrating psychological benefits. However, a number of aspects concerning communication in predictive medicine remain to be investigated and improved.
10 citations
01 Jan 2006
TL;DR: Dans certaines situations familiales bien documentees and severes, des tests genetiques sont proposes de rassurer les apparentees non predisposees, et de mettre en route une surveillance mammaire des l’âge de 30 ans.
Abstract: Aujourd’hui, dans certaines situations familiales bien documentees et severes, des tests genetiques sont proposes. Leurs enjeux principaux sont de rassurer les apparentees non predisposees, et, pour les apparentees predisposees, de mettre en route une surveillance mammaire des l’âge de 30 ans, voire des 25 ans, et de recommander une chirurgie ovarienne prophylactique a 40 ou 50 ans en fonction du contexte.
TL;DR: In this article, the authors present l'organisation de la consultation pluridisciplinaire d'oncogenetique de l'Institut Curie, ses intervenants, son deroulement temporel et les enjeux de chaque etape.
Abstract: Cet article presente l’organisation de la consultation pluridisciplinaire d’oncogenetique de l’Institut Curie, ses intervenants, son deroulement temporel et les enjeux de chaque etape. Un cas clinique permet d’illustrer les enjeux personnels et familiaux qui doivent etre explores lors de la mise en œuvre de cette demarche et lors de l’accompagnement et du suivi de la consultante ainsi que le subtilmelange entre les aspects objectifs de comprehension et de retention d’une information complexe et ceux—plus subjectifs—des representations et des intuitions de la personne qui consulte. Il souligne l’importance d’une collaboration renforcee entre les equipes de genetique et de psycho-oncologie.
TL;DR: Les deux premiers types de polypose juvenile sont associes, dans environ 50% des cas, a des mutations constitutionnelles heterozygotes des genes BMPR1A ou SMAD4 [3].
Abstract: 912 > La polypose juvenile se caracterise par la presence de multiples polypes juveniles dans le tractus gastro-intestinal, predisposant non seulement a la survenue de cancers colo-rectaux mais aussi, dans une moindre mesure, de tumeurs gastriques [1]. Elle a ete subdivisee en trois groupes par Sachatello en 1975 [2] : la polypose juvenile colique, la polypose juvenile generalisee et la polypose juvenile infantile [2]. Ces trois types se differencient essentiellement par l’âge au diagnostic, la localisation des polypes et la severite de la symptomatologie digestive. La polypose duit Sachatello et al. a evoquer une transmission autosomique recessive. Nous avons caracterise sur le plan genetique quatre enfants atteints de polypose juvenile infantile [4]. S’ajoutaient aux tableaux digestifs, dans trois cas, une macrocephalie, une legere dysmorphie faciale et pour l’un des enfants la presence de lipomes et d’hemangiomes. L’association de ces signes cliniques nous avait fait evoquer dans un premier temps le diagnostic de syndrome de Bannayan-Riley-Ruvalcaba. Afin de confirmer cette hypothese diagnostique, nous juvenile infantile definie par Sachatello et al. est caracterisee par la survenue des symptomes avant l’âge de 6 ans, l’atteinte generalisee du tractus digestif et par la gravite de la symptomatologie pouvant mettre en jeu le pronostic vital [2]. Les deux premiers types de polypose juvenile sont associes, dans environ 50% des cas, a des mutations constitutionnelles heterozygotes des genes BMPR1A ou SMAD4 [3]. Aucun gene n’a ete identifie jusque-la dans les cas de polypose juvenile infantile. L’absence de forme familiale a conNOUVELLE
TL;DR: In 2006, a quarantaine of genes were found to be associees a un risque eleve de cancers ont ete identifies as mentioned in this paper, and les localisations tumorales, the valeur du risque, l’âge moyen au diagnostic sont tres variables d’une situation de predisposition a l'autre.
Abstract: L’oncogenetique, nouvelle discipline a la frontiere de l’oncologie et de la genetique, s’est considerablement developpee dans les quinze dernieres annees, avec notamment la mise en evidence de certains facteurs genetiques de predisposition permettant de mieux apprehender l’histoire de certaines familles marquees par la survenue d’un grand nombre de cancers. En 2006, une quarantaine de genes dont les alterations sont associees a un risque eleve de cancers ont ete identifies. Les localisations tumorales, la valeur du risque, l’âge moyen au diagnostic sont tres variables d’une situation de predisposition a l’autre.
01 Nov 2006