The pathology of familial breast cancer: Morphological aspects

A small proportion of breast cancers are due to a heritable predisposition. Recently, two predisposition genes, BRCA1 and BRCA2, have been identified and cloned. The morphological features of tumours from patients harbouring mutations in the BRCA1 and BRCA2 genes differ from each other and from sporadic breast cancers. Both are of higher grade than are sporadic cases. An excess of medullary/atypical medullary carcinoma has been reported in patients with BRCA1 mutations. Multifactorial analysis, however, shows that the only features independently associated with BRCA1 mutations are a high mitotic count, pushing tumour margins and a lymphocytic infiltrate. For BRCA2 mutation, an association with tubular/lobular carcinoma has been suggested, but not substantiated in a larger Breast Cancer Linkage Consortium study. In multifactorial analysis, the independent features were a lack of tubule formation and pushing tumour margins only. The morphological analysis has implications for clinical management of patients

From Oncogenetic Pedigrees to Family Profiles: A Necessary Step to Enable Statistics

International audienceBackground: Cancer has always been a major domain requiring progress in statistics, methodology and bio-informatics. Oncogenetic, focusing on the relationship between genetics and cancer, is particularly concerned with “big data” issues, which includes genealogical pedigrees: their special structure – made of relations between members and possible clinical annotations - is too complex to be directly used for statistical purpose. This article describes a way to condense pedigrees so that they can be handled more easily and compared together.Method: our approach aggregates the genealogical and clinical information of pedigrees containing many generations. Condensed pedigrees, called “subtrees”, are composed of basic 2 or 3-generation pedigrees: for one whole pedigree, a subtree is calculated by the mean of all basic pedigrees it contains. These subtrees can then be grouped together for different subsets of families (for example breast/ovarian cancer families with or without BRCA mutation carrier). Such a grouping named “profile”, besides its reduced structure, is particularly interesting because for each studied characteristic, means and standard deviations are available. Moreover, distances between each subtree and various profiles can be calculated and used as a discriminant index.Results: Subtrees and profiles were validated using a subset of 454 families (22.348 members) with a Lynch syndrome: in 84, at least one member carried an MMR deleterious mutation. Two profiles were computed depending on the presence or the absence of MMR mutation in the families. An ROC analysis showed that distances between each family subtree and both profiles were significant predictors for MMR mutations.Conclusion: Subtrees and profiles show interesting discriminant properties to study pedigree data. This method seems suitable to search for population differences between monogenic cancer risk models and multigenic ones

Immunohistochemical expression of RARalpha, RARbeta, and Cx43 in breast tumor cell lines after treatment with lycopene and correlation with RT-QPCR

International audienceLe lycopène, le principal caroténoïde présent dans les tomates, est un puissant antioxydant associé à la prévention de maladies dégénératives telles que le cancer du sein. Cet effet pourrait être dû à l'interaction entre les récepteurs du lycopène et de l'acide rétinoïque ainsi qu'à la stimulation de la communication par jonction lacunaire et de la synthèse de la connexine 43. L'expression des protéines RARalpha, RARbeta et Cx43 a été analysée par immunohistochimie dans deux lignées cellulaires de cancer du sein. , MCF-7 et MDA-MB-231, et dans une lignée cellulaire de dystrophie fibrokystique, MCF-10a, après une exposition de 48 heures à 10 μM de lycopène. Une analyse PCR quantitative en temps réel a ensuite été effectuée pour mesurer l'expression de l'ARNm. L'expression de RARalpha et de Cx43 a été augmentée aux niveaux d'ARNm et de protéines dans deux lignées de cellules mammaires

Immunolocalization of BRCA1 protein in tumor breast tissue: prescreening of BRCA1 mutation in Tunisian patients with hereditary breast cancer?

BRCA1 is a tumor suppressor gene which is inactivated by mutation in familial breast and ovarian cancers. Over 300 different disease causing germ-line mutations have been described; 60% are unique to an individual family. This diversity and the large size of the gene lead us to search for a prescreening method for BRCA1 mutations. Since BRCA1 is a nuclear protein in normal cells, but reported by some authors to be cytoplasmic in breast tumor cells of patients with BRCA1 mutation, we evaluated immunohistochemistry as a prescreening technique to identify BRCA1 mutations in patients with familial presentation of breast cancer. Using a monoclonal antibody against the carboxy-terminal region of BRCA1, we performed immunohistochemistry on 18 tumor samples from patients with hereditary breast cancer. Cytoplasmic staining of BRCA1 was observed in 10 cases. Of the 18 tumors, 12 (66%) showed either BRCA mutation or BRCA1 accumulation or both, indicating that BRCA1 function might be lost in breast tumor cells not only through mutation, but also via abnormal cytoplasmic location. The immunohistochemical test used in this study would not be efficient as a pre-screening method of deleterious mutations, but it appeared useful to investigate tumor physiology

DNA repair gene ERCC2 polymorphisms and associations with breast and ovarian cancer risk

International audienceBreast and ovarian cancers increased in the last decades. Except rare cases with a genetic predisposition and high penetrance, these pathologies are viewed as a polygenic disease. In this concept, association studies look for genetic variations such as polymorphisms in low penetrance genes, i.e. genes in interaction with environmental factors. DNA repair systems that protect the genome from deleterious endogenous and exogenous damages have been shown to have significantly reduced. In particular, enzymes of the nucleotide excision repair pathway are suspected to be implicated in cancer. In this study, 2 functional polymorphisms in a DNA repair gene ERCC2 were analyzed. The population included 911 breast cancer cases, 51 ovarian cancer cases and 1000 controls. The genotyping of 2 SNP (Single Nucleotide Polymorphism) was carried out on the population with the MGB (Minor Groove Binder) probe technique which consists of the use of the allelic discrimination with the Taqman(R) method. This study enabled us to show an increase in risk of breast cancer with no oral contraceptive users and with women exhibiting a waist-to-hip ratio (WHR) > 0.85 for Asn homozygous for ERCC2 3/2

DNA repair gene ERCC2, XPC, XRCC1, XRCC3 polymorphisms and associations with bladder cancer risk in a French cohort

International audienceIn polygenic diseases, association studies look for genetic variation such as polymorphisms in low penetrance genes, i.e. genes in interaction with environmental factors. DNA repair systems that protect the genome from deleterious endogenous and exogenous damage have been shown to significantly reduce activity. In particular, enzymes of the nucleotide excision repair pathway are suspected to be implicated in cancer. In this study bladder cancer which is viewed as a polygenic disease was investigated. The functional polymorphisms of four DNA repair genes, excision repair cross-complementing group 2 (ERCC2), Xeroderma Pigmentosum group C (XPC), and Xray repair cross-complementing groups 1 and 3 (XRCC1 and XRCC3) were analyzed. The studied population included 51 bladder cancer cases and 45 controls. The genotyping of six SNP (single nucleotide polymorphism) was carried out on these populations with the MGB (Minor Groove Binder) probe technique which uses allelic discrimination with the Taqman(R) method. The Gln allele of the XPC 939 polymorphism was found to be associated with an increase in bladder cancer risk