Épidémiologie génétique des cancers

Publications de l’équipe

Année de publication : 2015

Paolo Peterlongo, Irene Catucci, Mara Colombo, Laura Caleca, Eliseos Mucaki, Massimo Bogliolo, Maria Marin, Francesca Damiola, Loris Bernard, Valeria Pensotti, Sara Volorio, Valentina Dall'Olio, Alfons Meindl, Claus Bartram, Christian Sutter, Harald Surowy, Valérie Sornin, Marie-Gabrielle Dondon, Séverine Eon-Marchais, Dominique Stoppa-Lyonnet, Nadine Andrieu, Olga M Sinilnikova, , Gillian Mitchell, Paul A James, Ella Thompson, , , Marina Marchetti, Cristina Verzeroli, Carmen Tartari, Gabriele Lorenzo Capone, Anna Laura Putignano, Maurizio Genuardi, Veronica Medici, Isabella Marchi, Massimo Federico, Silvia Tognazzo, Laura Matricardi, Simona Agata, Riccardo Dolcetti, Lara Della Puppa, Giulia Cini, Viviana Gismondi, Valeria Viassolo, Chiara Perfumo, Maria Antonietta Mencarelli, Margherita Baldassarri, Bernard Peissel, Gaia Roversi, Valentina Silvestri, Piera Rizzolo, Francesca Spina, Caterina Vivanet, Maria Grazia Tibiletti, Maria Adelaide Caligo, Gaetana Gambino, Stefania Tommasi, Brunella Pilato, Carlo Tondini, Chiara Corna, Bernardo Bonanni, Monica Barile, Ana Osorio, Javier Benitez, Luisa Balestrino, Laura Ottini, Siranoush Manoukian, Marco A Pierotti, Alessandra Renieri, Liliana Varesco, Fergus J Couch, Xianshu Wang, Peter Devilee, Florentine S Hilbers, Christi J van Asperen, Alessandra Viel, Marco Montagna, Laura Cortesi, Orland Diez, Judith Balmaña, Jan Hauke, Rita K Schmutzler, Laura Papi, Miguel Angel Pujana, Conxi Lázaro, Anna Falanga, Kenneth Offit, Joseph Vijai, Ian Campbell, Barbara Burwinkel, Anders Kvist, Hans Ehrencrona, Sylvie Mazoyer, Sara Pizzamiglio, Paolo Verderio, Jordi Surralles, Peter K Rogan, Paolo Radice (2015 Jul 2)

FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor.

Human molecular genetics : 5345-55 : DOI : 10.1093/hmg/ddv251 En savoir plus

Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.

Julie Lecarpentier, Catherine Noguès, Emmanuelle Mouret-Fourme, Bruno Buecher, Marion Gauthier-Villars, Dominique Stoppa-Lyonnet, Valérie Bonadona, Jean-Pierre Fricker, Pascaline Berthet, Olivier Caron, Isabelle Coupier, Pascal Pujol, Laurence Faivre, Paul Gesta, François Eisinger, Véronique Mari, Laurence Gladieff, Alain Lortholary, Elisabeth Luporsi, Dominique Leroux, Laurence Venat-Bouvet, Christine M Maugard, Chrystelle Colas, Julie Tinat, Christine Lasset, Nadine Andrieu, (2015 Jan 24)

Breast Cancer Risk Associated with Estrogen Exposure and Truncating Mutation Location in BRCA1/2 Carriers.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology : 698-707 : DOI : 10.1158/1055-9965.EPI-14-0884 En savoir plus

Mutations in BRCA1/2 confer a high risk of breast cancer, 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. Therefore, we hypothesize that such a variation may exist for other factors related to estrogen exposure.


Année de publication : 2014

Daniel J Park, Kayoko Tao, Florence Le Calvez-Kelm, Tu Nguyen-Dumont, Nivonirina Robinot, Fleur Hammet, Fabrice Odefrey, Helen Tsimiklis, Zhi L Teo, Louise B Thingholm, Erin L Young, Catherine Voegele, Andrew Lonie, Bernard J Pope, Terrell C Roane, Russell Bell, Hao Hu, Shankaracharya, Chad D Huff, Jonathan Ellis, Jun Li, Igor V Makunin, Esther M John, Irene L Andrulis, Mary B Terry, Mary Daly, Saundra S Buys, Carrie Snyder, Henry T Lynch, Peter Devilee, Graham G Giles, John L Hopper, Bing-Jian Feng, Fabienne Lesueur, Sean V Tavtigian, Melissa C Southey, David E Goldgar (2014 May 2)

Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers.

Cancer discovery : 804-15 : DOI : 10.1158/2159-8290.CD-14-0212 En savoir plus

Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case-control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confidence interval (CI), 1.29-8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome-spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7-6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7-21; P = 0.0003).


Année de publication : 2013

Francesca Damiola, Maroulio Pertesi, Javier Oliver, Florence Le Calvez-Kelm, Catherine Voegele, Erin L Young, Nivonirina Robinot, Nathalie Forey, Geoffroy Durand, Maxime P Vallée, Kayoko Tao, Terrell C Roane, Gareth J Williams, John L Hopper, Melissa C Southey, Irene L Andrulis, Esther M John, David E Goldgar, Fabienne Lesueur, Sean V Tavtigian (2013 Oct 21)

Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study.

Breast cancer research : BCR : R58 : DOI : 10.1186/bcr3669 En savoir plus

The MRE11A-RAD50-Nibrin (MRN) complex plays several critical roles related to repair of DNA double-strand breaks. Inherited mutations in the three components predispose to genetic instability disorders and the MRN genes have been implicated in breast cancer susceptibility, but the underlying data are not entirely convincing. Here, we address two related questions: (1) are some rare MRN variants intermediate-risk breast cancer susceptibility alleles, and if so (2) do the MRN genes follow a BRCA1/BRCA2 pattern wherein most susceptibility alleles are protein-truncating variants, or do they follow an ATM/CHEK2 pattern wherein half or more of the susceptibility alleles are missense substitutions?

Elena Bonora, Cosmeri Rizzato, Chiara Diquigiovanni, Tiphaine Oudot-Mellakh, Daniele Campa, Manuela Vargiolu, Mickaël Guedj, , James D McKay, Giovanni Romeo, Federico Canzian, Fabienne Lesueur (2013 Apr 29)

The FOXE1 locus is a major genetic determinant for familial nonmedullary thyroid carcinoma.

International journal of cancer : 2098-107 : DOI : 10.1002/ijc.28543 En savoir plus

Thyroid cancer is the most common endocrine malignancy and nonmedullary thyroid carcinoma (NMTC) represents 90% of all cases. NMTC risk in first-degree relatives of affected cases is elevated fivefold to ninefold. Familial NMTC (FNMTC) accounts for about 3-7% of all thyroid tumors and is a more aggressive clinical entity than its sporadic counterparts. Linkage analysis on high-risk families performed a decade ago mapped several susceptibility loci, but did not lead to the identification of high-penetrance causal germline mutations. More recently, a genome-wide association study (GWAS) identified common single nucleotide polymorphisms (SNPs) affecting the risk of sporadic NMTC. We sought to verify if the newly identified genetic risk factors for NMTC are relevant for FNMTC as well. We genotyped 23 SNPs at 11 candidate loci in 672 subjects belonging to 133 pedigrees with at least two NMTC cases. Statistical analysis was performed using family-based association tests, modified quasi-likelihood score and logistic-normal models. SNPs at 9q22.33 near FOXE1 showed convincing evidence of association with NMTC risk in these high-risk families. The other tested loci resulted negative. These findings confirm the importance of the SNPs identified by recent GWAS on sporadic NMTC on FNMTC as well. However, the proposed FOXE1 causal variants do not show the strongest association signal. Moreover, mutation screening of the FOXE1 coding sequence in the FNMTC cases did not identify rarer causal variants, suggesting that other yet unidentified variants at this locus are involved in FNMTC etiology.


Année de publication : 2012

Anouk Pijpe, Nadine Andrieu, Douglas F Easton, Ausrele Kesminiene, Elisabeth Cardis, Catherine Noguès, Marion Gauthier-Villars, Christine Lasset, Jean-Pierre Fricker, Susan Peock, Debra Frost, D Gareth Evans, Rosalind A Eeles, Joan Paterson, Peggy Manders, Christi J van Asperen, Margreet G E M Ausems, Hanne Meijers-Heijboer, Isabelle Thierry-Chef, Michael Hauptmann, David Goldgar, Matti A Rookus, Flora E van Leeuwen, , , (2012 Sep 8)

Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK).

BMJ (Clinical research ed.) : e5660 : DOI : 10.1136/bmj.e5660 En savoir plus

To estimate the risk of breast cancer associated with diagnostic radiation in carriers of BRCA1/2 mutations.

Julie Lecarpentier, Catherine Noguès, Emmanuelle Mouret-Fourme, Marion Gauthier-Villars, Christine Lasset, Jean-Pierre Fricker, Olivier Caron, Dominique Stoppa-Lyonnet, Pascaline Berthet, Laurence Faivre, Valérie Bonadona, Bruno Buecher, Isabelle Coupier, Laurence Gladieff, Paul Gesta, François Eisinger, Marc Frénay, Elisabeth Luporsi, Alain Lortholary, Chrystelle Colas, Catherine Dugast, Michel Longy, Pascal Pujol, Julie Tinat, , Rosette Lidereau, Nadine Andrieu (2012 Feb 22)

Variation in breast cancer risk associated with factors related to pregnancies according to truncating mutation location, in the French National BRCA1 and BRCA2 mutations carrier cohort (GENEPSO).

Breast cancer research : BCR : R99 : DOI : 10.1186/bcr3218 En savoir plus

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.


Année de publication : 2010

Dominique Stoppa-Lyonnet, Bruno Buecher, Claude Houdayer, Antoie de Pauw, Marion Gauthier-Villars, Anne de la Rochefordière, Pascale This, Bernard Asselain, Nadine Andrieu (2010 Aug 10)

[Implications of genetic risk factors in breast cancer: culprit genes and associated malignancies].

Bulletin de l'Académie nationale de médecine : 2063-83; discussion 2084-5 En savoir plus

Our understanding of hereditary forms of breast cancer has made enormous advances over the past 15 years, based on epidemiological and molecular genetic studies, and the development of a vast number of informative genetic markers. These studies have involved women with both familial and sporadic forms of breast cancer. Genetic susceptibility to breast cancer can involve several modes of inheritance: Mendelian inheritance, mostly involving autosomal dominant mutations with high penetrance and a high risk of malignancy (the BRCA1, BRCA2, TP53, PTEN and STK11 genes); dominant mutations associated with a lower risk (ATM, BRIP1, PALB2, etc), and multigenic patterns involving common susceptibility variants, i.e., polymorphisms located within predisposing gene loci (FGFR2, TNRC9, MAP3K1, LSP1, etc.) or intergenic regions. Other predisposing factors remain to be discovered, as genetic factors associated with a high breast cancer risk (BRCA1, BRCA2, TP53, PTEN STK11, etc) are only found in about 20% of genetically screened breast cancer families. So far, only the first class of genes have found clinical applications, guiding the choice of medical or surgical treatment. More refined individual risk profiles will benefit from genome-wide polymorphic DNA variant studies anda better understanding of the impact of non genetic factors, such as the obstetrical and gynaecological history, and mutagen exposure.


Année de publication : 2006

Nadine Andrieu, David E Goldgar, Douglas F Easton, Matti Rookus, Richard Brohet, Antonis C Antoniou, Susan Peock, Gareth Evans, Diana Eccles, Fiona Douglas, Catherine Noguès, Marion Gauthier-Villars, Agnès Chompret, Flora E Van Leeuwen, Irma Kluijt, Javier Benitez, Brita Arver, Edith Olah, Jenny Chang-Claude, , , , (2006 Apr 20)

Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS).

Journal of the National Cancer Institute : 535-44 En savoir plus

Multiparity, young age at first childbirth, and breast-feeding are associated with a reduced risk of breast cancer in the general population. The breast cancer predisposition gene, BRCA1, regulates normal cell differentiation. Because mammary gland cells divide and differentiate during pregnancy, reproductive factors may influence breast cancer risk in BRCA1/2 mutation carriers differently than they do in noncarriers.


Année de publication : 2005

Nadine Andrieu, Eve Cavaciuti, Anthony Laugé, Katia Ossian, Nicolas Janin, Janet Hall, Dominique Stoppa-Lyonnet (2005 Sep 27)

Ataxia-telangiectasia genes and breast cancer risk in a French family study.

The Journal of dairy research : 73-80 En savoir plus

Ataxia-telangiectasia (AT) is a rare autosomal recessive early childhood disorder, characterized by progressive neuronal degeneration, immunological deficiency, radiosensitivity and an increased risk of cancer caused in most cases by mutations in the AT-mutated gene (ATM). Epidemiological studies on AT families have shown that AT heterozygous women have an increased risk of developing breast cancer (BC). The ATM protein plays a central role in the recognition and repair of DNA double-strand breaks and the subsequent activation of cell-cycle checkpoints. Whilst AT is a rare disease, 0.5-1 % of the general population are estimated to be AT mutation carriers, thus any increases in the risks of cancer associated with ATM carrier status are of public health relevance. The main results of our published studies on the risk of BC in 34 French AT families according to heterozygote status, type of ATM mutation and exogenous factors are summarized here. The risk of BC was higher in ATM heterozygous (HetATM) women and did not differ significantly according to the type of ATM mutation (missense vs truncating) carried by the AT family members but appeared associated with the position of some truncating mutations in certain binding domains of the ATM protein. The effect of exogenous factors, such as reproductive life factors and exposure to ionizing radiation, on the risk of BC according to ATM heterozygote status was assessed. There was no evidence for interaction (except for age at first full-term pregnancy). These findings does not appear to justify a separate screening program from that already available to other women with a first-degree relative affected by BC, as their risks have similar amplitude. Chest X-rays did not appear to be a risk factor for BC in our study population. More powerful studies, using data sets pooled from international sources are being set up to confirm these observations.

Nadine Andrieu, Marie-Gabrielle Dondon, Alisa M Goldstein (2005 Sep 15)

Increased power to detect gene-environment interaction using siblings controls.

Annals of epidemiology : 705-11 En savoir plus

Interest is increasing in studying gene-environment (G x E) interaction in disease etiology. Study designs using related controls as a more appropriate control group for evaluating G x E interactions have been proposed but often assume unrealistic numbers of available relative controls. To evaluate a more realistic design, we studied the relative efficiency of a 1:0.5 case-sibling-control design compared with a classical 1:1 case-unrelated-control design and examined the effect of the analysis strategy.