Christine Lasset

Claude Bernard University Lyon 1, Villeurbanne, Rhône-Alpes, France

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Publications (191)1281.41 Total impact

  • Cancer Research 05/2015; 75(9 Supplement):OT1-2-04-OT1-2-04. DOI:10.1158/1538-7445.SABCS14-OT1-2-04 · 9.28 Impact Factor
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    ABSTRACT: Individuals carrying pathogenic mutations in BRCA1/2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals from different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. Here we test the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. We genotyped 22214 (11421 affected, 10793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched for affected or unaffected individuals. We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers than the rest of clade T, (Hazard Ratio (HR) = 0.55 (95% Confidence Interval (CI) 0.34-0.88, p-value = 0.01). Compared with the most frequent haplogroup in the general population i.e. H and T clade, the T1a1 haplogroup has an HR = 0.62 (95% CI = 0.40-0.95, p-value = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. This study illustrates how original approaches like the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
    Breast cancer research: BCR 04/2015; 17(1):61. DOI:10.1186/s13058-015-0567-2 · 5.88 Impact Factor
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    ABSTRACT: IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE:To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS:Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES:Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS:Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
    JAMA The Journal of the American Medical Association 04/2015; 313(13):1347-61. DOI:10.1001/jama.2014.5985 · 30.39 Impact Factor
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    ABSTRACT: While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10-4 (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers. PMID: 25830658 [PubMed - in process]
    PLoS ONE 04/2015; 10(4). · 3.53 Impact Factor
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    ABSTRACT: Background: Mutations in BRCA1/2 confer a high risk of breast cancer (BC), but literature values of this risk vary. A genotype-phenotype correlation has been found in both genes and the effect of reproductive factors differs according to mutation location. We hypothesize that such a variation may exist for other factors related to estrogen exposure. Methods: We used a weighted Cox regression model to assess variation in BC risk with these factors using location of mutation in homogeneous BC risk region of BRCA1/2 in the GENEPSO study. Results: We found that late age at menarche reduced BC risk by 31% and that among BRCA1 carriers, a long or a short menstrual cycle increased risk (by 35% and 48%, respectively). Among premenopausal women, overweight was associated with a 39% decrease in BC risk while underweight was associated with an increased risk (hazard ratio [HR]=2.09). A natural menopause, mainly after age 50, was associated with a high BC risk (HR=2.46) and a significant interaction between menopause status and the location of mutations was found leading up to 10% variation in absolute risk according to the age at menopause. Conclusions: As observed in the general population, late menarche, long or short menstrual cycle, over- or under-weight, and being post-menopausal were associated with BC risk in BRCA1/2 carriers. The association with the menopause was observed only when the mutation was located in the "high-risk" zones. Impact: Taking into account modifier factors, location of mutation might be important for the clinical management of BRCA1/2 carriers. Copyright © 2015, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 01/2015; 24(4). DOI:10.1158/1055-9965.EPI-14-0884 · 4.32 Impact Factor
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    ABSTRACT: Gestational choriocarcinoma (CC) represents the most aggressive form of gestational tumours. In Europe and North America, gestational CC occurs in approximately 1/50 000 deliveries.1 We report the detection, in a gestational CC developed in a female partner of a patient with Li-Fraumeni syndrome (LFS) (MIM #151623), of the germline TP53 mutation initially detected in this LFS patient. In the French LFS series, we identified 78 fathers who were carriers of a germline TP53 mutation. Among the 213 corresponding pregnancies, we found two other cases of gestational CC in their partners. We estimate that gestational CC occurs in approximately 1% of the deliveries in female partners of TP53 mutation carriers. Gestational trophoblastic disease (GTD), which can occur after either abnormal or normal fertilisation, is characterised by the uncontrolled proliferation of trophoblastic cells normally producing the placenta. GTD includes premalignant (complete and partial hydatidiform moles) and malignant (invasive mole, gestational CC, placental-site trophoblastic and epithelioid trophoblastic tumours) lesions.1 We considered the diagnosis of LFS, a remarkable cancer predisposition characterised by the extent of tumour spectrum,2 in the family described in figure 1. The male index case had developed a cholangiocarcinoma at 37 years of age, … [Full text of this article]
    Journal of Medical Genetics 01/2015; 52(3). DOI:10.1136/jmedgenet-2014-102853 · 5.64 Impact Factor
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    ABSTRACT: For carriers of germline mutations in DNA mismatch repair genes, the most relevant statistic for cancer prevention is colorectal cancer (Lynch syndrome) risk, particularly in the short term. We conducted a meta-analysis of all independent published Lynch syndrome studies reporting age- and sex-dependent colorectal cancer risks. We estimated 5-year colorectal cancer risk over different age groups, separately for male and female mutation carriers, and number needed to screen to prevent one death. We pooled estimates from analyses of 1,114 Lynch syndrome families (508 with MLH1 mutations and 606 with MSH2 mutations). On average, one in 71 male and one in 102 female MLH1 or MSH2 mutation carriers in their 20s will be diagnosed with colorectal cancer in the next 5 years. These colorectal cancer risks increase with age, peaking in the 50s (one in seven males and one in 12 females), and then decrease with age (one in 13 males and one in 19 females in their 70s). Annual colonoscopy in 16 males or 25 females in their 50s would prevent one death from colorectal cancer over 5 years while resulting in almost no serious complications. In comparison, annual colonoscopy in 155 males or 217 females in their 20s would prevent one death while resulting in approximately one serious complication. For MLH1 or MSH2 mutation carriers, current guidelines recommend colonoscopy every 1 to 2 years starting in their 20s. Our findings support this regimen from age 30 years; however, it might not be justifiable for carriers who are in their 20s. © 2014 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 12/2014; 33(4). DOI:10.1200/JCO.2014.55.8536 · 17.88 Impact Factor
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    ABSTRACT: Introduction We aimed to study the relationships between educational level, women's knowledge about cervical cancer (CC), and acceptance of HPV vaccination for their daughters. Methods We analysed data from a quantitative (self-administrated questionnaire) and qualitative (semi-structured interviews) cross-sectional study performed in 2008 among 1,229 French 18–65-year-old women recruited by general practitioners. Women were categorized into three educational level groups: low (LEL: 43.9%), medium (MEL: 33.4%) and high (HEL: 22.6%). Results Knowledge about CC and its prevention was lower among LEL women. In the 180 mothers of 14–18-year-old daughters (99 LEL, 54 MEL, 45 HEL), acceptance of HPV vaccine was higher in LEL (60.4%) and MEL (68.6%) than in HEL mothers (46.8%). Among LEL mothers, those who were favourable to HPV vaccination were more likely to be young (OR = 8.44 [2.10–34.00]), to be vaccinated against hepatitis B (OR = 4.59 [1.14–18.52]), to have vaccinated their children against pneumococcus (OR = 3.52 [0.99–12.48]) and to present a history of abnormal Pap smear (OR = 6.71 [0.70–64.01]). Conclusion Although LEL women had poorer knowledge about CC and its prevention, they were more likely to accept HPV vaccination than HEL mothers.
    PLoS ONE 10/2014; 9(10):e109320. DOI:10.1371/journal.pone.0109320 · 3.53 Impact Factor
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    ABSTRACT: Background Due to underestimation, surgical excision is recommended for atypical ductal hyperplasia (ADH) diagnosed on directional vacuum-assisted biopsies (DVAB). The following guidelines have been established according to our retrospective study published in 2008: excision for lesions ≥ 21 mm, follow-up for lesions < 6 mm with complete removal of microcalcifications, follow-up or excision for 6-21 mm lesions with respectively less or more than 2 ADH foci. Methods and Results These guidelines were assessed in a prospective series of 124 patients with a median follow-up of 30 months. Conformity rate was 92%. Upgrading was 28% (15 patients out of 53) for conformed surgery and absent for surgery performed beyond the scope of guidelines. For the patients with benign surgery (n=38) or just followed (n=61), 3 cancers occurred in either breast at 1 to 3 years. Conclusions These convenient guidelines can safely spare surgery for a subset of patients. However, annual mammographic follow-up is recommended since the risk of subsequent cancer remains high for both breasts.
    American journal of surgery 08/2014; 208(2). DOI:10.1016/j.amjsurg.2013.10.029 · 2.41 Impact Factor
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    ABSTRACT: Purpose:This study aimed to measure patients' smoking patterns for 5 years after BRCA1/2 test result disclosure.Methods:A national cohort consisting of 621 French cancer-free women from families with BRCA1/2 mutations (mean age (SD): 40.5 years (11.5 years)) were included from December 1999 to January 2006, before disclosure of genetic test results, and followed for 5 years. They completed self-administered questionnaires about their cigarette smoking behaviors before receiving their test results (baseline) and 6, 12, 24, and 60 months after disclosure. Multivariate statistical analyses of the changes in participants' smoking behaviors were performed using a zero-inflated Poisson mixed model.Results:Baseline smoking was found to depend on age, educational level, marital status, alcohol consumption, body mass index, and cancer risk perception. The zero-inflated part of the model showed the occurrence of no significant changes in the percentage of smokers during the 5 years after disclosure of the BRCA1/2 test results; however, daily smoking among BRCA1/2 carriers decreased significantly compared with that of noncarriers (adjusted hazard ratio = 0.83; (95% confidence interval: 0.69-0.99); P = 0.04) after adjusting for baseline smoking behavior.Conclusion:It would be worth investigating the possibility of counseling women during the genetic testing process about the multiple risk factors involved in cancer, such as genetic and lifestyle factors.Genet Med advance online publication 10 July 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.82.
    Genetics in medicine: official journal of the American College of Medical Genetics 07/2014; 17(2). DOI:10.1038/gim.2014.82 · 6.44 Impact Factor
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    ABSTRACT: Although greater attention is currently being paid to participants in research, no studies have dealt so far with the issue of returning aggregate psychosocial results to cohort participants.
    Health expectations: an international journal of public participation in health care and health policy 05/2014; DOI:10.1111/hex.12211 · 2.85 Impact Factor
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    ABSTRACT: To use both quantitative and qualitative methods to investigate the evolution of practices and opinions regarding human papillomavirus (HPV) vaccination among French general practitioners. A cross-sectional study (self-questionnaires) was performed in 2007 and repeated in 2010 among 271 general practitioners. Semi-structured interviews were conducted on 27 voluntary participants by a sociologist and analyzed according to content analysis. Acceptability of HPV vaccination had increased from 2007 to 2010 (79.9 vs. 87.1 %, respectively), just as the practice of HPV vaccination among 14-year-old girls (19.0 vs. 49.1 %, respectively). Though about 60 % reported complications associated with HPV vaccination, irrespective of year, the types of difficulties have varied: difficulties related to "questions asked by patients" had decreased, though concerns about side effects had remained stable. During interviews, difficulties related to "the reason for medical consultation" and "the target age" were often associated with addressing the issue of sexuality, especially when the parents were present. Although the high level of acceptability of HPV vaccination among general practitioners, which increased from 2007 to 2010, there remain difficulties in addressing this practice.
    International Journal of Public Health 04/2014; 59(3). DOI:10.1007/s00038-014-0555-9 · 1.97 Impact Factor
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    ABSTRACT: The aim of this study is to prospectively determine the factors contributing to whether unaffected women from BRCA1/2 families reported that clinicians proposed psychological consultations and that they had attended these consultations during the genetic testing process. A prospective study was performed on a national cohort, using self-administered questionnaires to determine the rates of proposal and use of psychological services at the time of BRCA1/2 test result disclosure (N = 533) and during the first year after disclosure (N = 478) among unaffected French women from BRCA1/2 families who had undergone genetic testing for BRCA1/2. Multivariate adjustment was carried out using logistic regression models fitted using generalized estimation equations, with the genetic testing centre as the clustering variable. At the time of BRCA1/2 test result disclosure, a psychological consultation was proposed by cancer geneticists to 72% and 32% of the carriers (N = 232) and noncarriers (N = 301), respectively (p < 0.001). One year after disclosure, 21% of the carriers had consulted a psychologist, versus 9% of the noncarriers (p < 0.001). Both the proposal and the uptake depended on the women's BRCA1/2 mutation carrier status (proposal adjusted odds ratio (AOR): 4.9; 95% confidence interval (CI) 3.4-7.2; uptake AOR: 2.2; 95% CI 1.2-4.0), their level of education (proposal AOR: 1.7; 95% CI 1.1-2.7; uptake AOR: 4.5; 95% CI 1.7-12.1) and the distress they experienced about their genetic test results (proposal AOR: 1.02; 95% CI 1.01-1.03; uptake AOR: 1.04; 95% CI 1.02-1.06) CONCLUSIONS: Determinants of the proposal/uptake of psychological consultations in the BRCA1/2 testing process highlight the need for inventive strategies to reach the different types of women's profiles. Copyright © 2013 John Wiley & Sons, Ltd.
    Psycho-Oncology 04/2014; 23(4). DOI:10.1002/pon.3435 · 4.04 Impact Factor
  • Revue d Épidémiologie et de Santé Publique 10/2013; 61:S238. DOI:10.1016/j.respe.2013.07.118 · 0.66 Impact Factor
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    ABSTRACT: To help prevent cervical cancer, three yearly opportunistic Pap smear screening is recommended in France for women aged 25-65 years. Pap smear screening coverage varies with age and socioeconomic level. The aim of this cross-sectional study was to identify factors associated with a low uptake of Pap smear screening among women with no limited access to healthcare. We analyzed data from women aged 25-65 living in the Rhône-Alpes region who completed a self-administered questionnaire given to them by general practitioners between June and August 2008. The questionnaire covered knowledge about cervical cancer and its prevention as well as the women's history of Pap smear screening and other health-related behaviors. The relationship between low uptake of Pap smear screening - defined as not having had the test within the past 3 years - and a range of possible contributing factors was investigated using logistic regression. Of 1186 women with an intact uterus who completed the questionnaire, 89.1% said they had had a Pap smear within the past 3 years. On multivariate analysis, the 10.9% who had not were significantly more likely to live alone (1.76 [1.13-2.74]), to have no children (2.17 [1.31-3.62]), to have never used contraception (5.35 [2.98-9.62]), to have less knowledge about Pap smear screening (3.40 [1.55-7.49]), and to be unvaccinated against hepatitis B (0.55 [0.35-0.87]). Despite high overall compliance with Pap smear screening recommendations among women who consulted general practitioners, several factors were significantly associated with a low uptake of the service. Considering these factors may help to refine messages aimed at cervical cancer prevention.
    Revue d Épidémiologie et de Santé Publique 09/2013; 61(5). DOI:10.1016/j.respe.2013.04.009 · 0.66 Impact Factor
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    ABSTRACT: HPV vaccination is recommended in France for girls aged 14 and for those aged 15-23 before sexual debut or who have become sexually active within the previous year. The first aim was to describe vaccination practice among 14-23-year-old girls visiting a general practitioner. A second objective was to investigate factors associated with starting vaccination among girls aged 14-18, in particular the regular practice of Pap-smear screening (PSS) by their mothers. A cross-sectional study was conducted from June to August 2009. A total of 87 general practitioners from the large Rhône-Alpes region contributed data on 502 girls/women who came for consultation. 231 (46.0%) of these girls/women had begun the process of HPV vaccination (68.2%, 56.9% and 18.7% of the 14-16, 17-20 and 21-23-year-olds respectively) of whom 139 (60.2%) had received all three doses. 92 girls/women (39.8%) had received only one or two doses at the time of study. However, in 71 (30.7%) cases, the gap between the last dose received and the time of study was within the between-dose interval recommended in the vaccination schedule. GPs reported that 16 (11.5%) had mentioned side effects following injections. Having a mother who practised regular PSS (Odds Ratio 6.2 [1.5-25.8]), having never lived with a partner (4.6 [1.6-13.5]) and vaccination against hepatitis B (3.2 [1.6-6.1]) were found to be independently correlated with the initiation of HPV vaccination among girls/women aged 14-18 years. Two years after the start of the programme, only half of girls/women aged 14-23 years had begun the process of HPV vaccination. HPV vaccination status was correlated with PSS in the mother, family status and hepatitis B vaccination. Such information may help to better target girls who are less likely to be vaccinated.
    Vaccine 09/2013; 31(45). DOI:10.1016/j.vaccine.2013.08.068 · 3.49 Impact Factor
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    ABSTRACT: Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with BRCA1/2 or MMR genes mutation. Genetic testing and consultations for familial high-risk individuals are exclusively funded and monitored by the INCa in France. All nationwide cancer genetics centers reported annually standardized parameters of activity from 2003 to 2011. The analysis included a total of 240,134 consultations and 134,652 genetic tests enabling to identify 32,494 mutation carriers. Referral for hereditary breast and ovarian cancer (HBOC) or colorectal cancer predisposition syndromes represented 59 % (141,639) and 23.2 % (55,698) consultations, respectively. From 2003 to 2011, we found a dramatic and steady increase of tests performed for BRCA1/2 (from 2,095 to 7,393 tests/year, P < 0.0001) but not for MMR genes (from 1,144 to 1,635/year, P = NS). The overall percentage of deleterious mutations identified in the probands tested was 13.8 and 20.9 % in HBOC and Lynch syndromes, respectively. Pooled analysis for BRCA1/2 and Lynch syndrome tests showed an inverse relationship between the percentage of mutation detected and the absolute number of tests performed over the time (overall Cochran-Armitage test for trend: P < 0.001). In families with BRCA1/2 or MMR identified mutations, there was an average number of 2.94 and 3.28 relatives performing targeted tests, respectively. This nationwide study shows a lack of referral and genetic testing in Lynch as compared to HBOC syndromes. Only a third of relatives of a proband with a predisposing mutation performed a targeted test. Enhanced information about benefit of genetic testing should be given to clinicians and patients for Lynch syndrome and relatives of a proband carrying an identified predisposing mutation.
    Breast Cancer Research and Treatment 08/2013; 141(1). DOI:10.1007/s10549-013-2669-9 · 4.20 Impact Factor
  • Journal of Clinical Oncology 04/2013; DOI:10.1200/JCO.2013.48.9765 · 17.88 Impact Factor
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    ABSTRACT: Germline alterations of the tumour suppressor TP53 gene are detected approximately in 25% of the families suggestive of Li-Fraumeni syndrome (LFS), characterised by a genetic predisposition to a wide tumour spectrum, including soft-tissue sarcomas, osteosarcomas, premenopausal breast cancers, brain tumours, adrenocortical tumours, plexus choroid tumours, leukaemia and lung cancer. The aim of this study was to determine the contribution of germline copy number variations (CNVs) to LFS in families without detectable TP53 mutation. Using a custom-designed high-resolution array CGH, we evaluated the presence of rare germline CNVs in 64 patients fulfilling the Chompret criteria for LFS, but without any detectable TP53 alteration. In 15 unrelated patients, we detected 20 new CNVs absent in 600 controls. Remarkably, in four patients who had developed each brain tumour, the detected CNV overlap the KDM1A, MTA3, TRRAP or SIRT3 genes encoding p53 partners involved in histone methylation or acetylation. Focused analysis of SIRT3 showed that the CNV encompassing SIRT3 leads to SIRT3 overexpression, and that in vitro SIRT3 overexpression prevents apoptosis, increases G2/M and results in a hypermethylation of numerous genes. This study supports the causal role of germline alterations of genes involved in chromatin remodelling in genetic predisposition to cancer and, in particular, to brain tumours.European Journal of Human Genetics advance online publication, 24 April 2013; doi:10.1038/ejhg.2013.68.
    European journal of human genetics: EJHG 04/2013; DOI:10.1038/ejhg.2013.68 · 4.23 Impact Factor

Publication Stats

4k Citations
1,281.41 Total Impact Points

Institutions

  • 2012–2015
    • Claude Bernard University Lyon 1
      • Laboratoire de biométrie et biologie evolutive (LBBE)
      Villeurbanne, Rhône-Alpes, France
  • 1988–2015
    • Centre Léon Bérard
      Lyons, Rhône-Alpes, France
  • 2013
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 2003–2013
    • French National Centre for Scientific Research
      • Laboratoire de Biométrie et Biologie Évolutive (LBBE)
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Cancer Research Center of Lyon
      Lyons, Rhône-Alpes, France
    • University of Nice-Sophia Antipolis
      Nice, Provence-Alpes-Côte d'Azur, France
  • 2007–2009
    • University of Lyon
      Lyons, Rhône-Alpes, France
  • 2005
    • International Agency for Research on Cancer
      Lyons, Rhône-Alpes, France