Prédispositions génétiques aux cancers : actualités et perspectives en 2005

Les études conduites au cours des vingt dernières années ont constitué un apport majeur pour la compréhension de la transformation tumorale. Elles ont ouvert un domaine nouveau de la génétique : l’étude de la prédisposition au cancer. Aujourd’hui, les situations les plus simples de prédisposition ont été identifiées : il s’agit d’altérations monogéniques s’accompagnant d’un risque tumoral élevé et de phénotypes spécifiques. Une quarantaine de gènes ont été identifiés, qui font l’objet d’une recherche par le biais de tests génétiques : l’indication de ces tests et la prise en charge ultérieure des sujets à risque doivent être réfléchies de façon collégiale, et des recommandations de prise en charge établies. Toutefois, un vrai défi à relever concerne l’identification des facteurs de prédispositions associés à des risques plus faibles, ou ayant un impact sur la réponse des patients aux traitements.Studies performed during these last twenty years have had a major impact on the understanding of carcinogenesis. They have opened a new field : cancer genetic predisposition. At the present time, most of the cancer predispositions linked to the alteration of one gene, associated with a high risk of cancer and with a specific phenotype have been identified. About 40 genes have been identified and have led to genetic testing. The indication of genetic testing, the management of at risk patients need the establishment of guidelines. The next challenge is the identification of cancer predisposing genes associated with low risk or modifying the effect of treatment

L’innovation en cancérologie, un modèle pour les politiques de santé The contribution of cancer innovation to public health’s issues

The fight against cancer as previously the fight against infectious diseases has become a model for the public health system. In both situations the discovery of the causal agents and the development of technology have lead to new and efficient measures in prevention and treatmentLa lutte contre le cancer, comme l'avait été avant elle la lutte contre les maladies infectieuses, est maintenant devenue un modèle pour les politiques de santé. Comme pour elle, la découverte des causes, associée à l'innovation technologique, permet une prise en charge innovante et efficac

Contribution of germline BRCA1 and BRCA2 sequence alterations to breast cancer in Northern India

BACKGROUND: A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Indian women. We investigated the distribution and the nature of BRCA1 and BRCA2 germline mutations and polymorphisms in a cohort of 204 Indian breast cancer patients and 140 age-matched controls. METHOD: Cases were selected with regard to early onset disease (≤40 years) and family history of breast and ovarian cancer. Two hundred four breast cancer cases along with 140 age-matched controls were analyzed for mutations. All coding regions and exon-intron boundaries of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis followed by direct sequencing of detected variants. RESULTS: In total, 18 genetic alterations were identified. Three deleterious frame-shift mutations (185delAG in exon 2; 4184del4 and 3596del4 in exon 11) were identified in BRCA1, along with one missense mutation (K1667R), one 5'UTR alteration (22C>G), three intronic variants (IVS10-12delG, IVS13+2T>C, IVS7+38T>C) and one silent substitution (5154C>T). Similarly three pathogenic protein-truncating mutations (6376insAA in exon 11, 8576insC in exon19, and 9999delA in exon 27) along with one missense mutation (A2951T), four intronic alterations (IVS2+90T>A, IVS7+75A>T, IVS8+56C>T, IVS25+58insG) and one silent substitution (1593A>G) were identified in BRCA2. Four previously reported polymorphisms (K1183R, S1613G, and M1652I in BRCA1, and 7470A>G in BRCA2) were detected in both controls and breast cancer patients. Rare BRCA1/2 sequence alterations were observed in 15 out of 105 (14.2%) early-onset cases without family history and 11.7% (4/34) breast cancer cases with family history. Of these, six were pathogenic protein truncating mutations. In addition, several variants of uncertain clinical significance were identified. Among these are two missense variants, one alteration of a consensus splice donor sequence, and a variant that potentially disrupts translational initiation. CONCLUSION: BRCA1 and BRCA2 mutations appear to account for a lower proportion of breast cancer patients at increased risk of harboring such mutations in Northern India (6/204, 2.9%) than has been reported in other populations. However, given the limited extent of reported family history among these patients, the observed mutation frequency is not dissimilar from that reported in other cohorts of early onset breast cancer patients. Several of the identified mutations are unique and novel to Indian patients

Predominance of null mutations in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a PI 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the PI 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T

Transactional sex among young women in rural South Africa: prevalence, mediators and association with HIV infection.

INTRODUCTION: Young adolescent women in sub-Saharan Africa are three to four times more likely to be HIV-positive than boys or men. One of the relationship dynamics that is likely to be associated with young women's increased vulnerability to HIV is transactional sex. There are a range of HIV-related risk behaviours that may drive this vulnerability. However, to date, limited epidemiological data exist on the role of transactional sex in increasing HIV acquisition, especially among young women in sub-Saharan Africa. Our paper presents data on the prevalence of self-reported engagement in transactional sex and explores whether transactional sex is associated with increased risk of HIV infection among a cohort of young, rural, sexually active South African women. We also explore whether this relationship is mediated through certain HIV-related risk behaviours. METHODS: We analyzed baseline data from a phase III trial of conditional cash transfers for HIV prevention of 693 sexually active, school-going young women aged 13-20 years in rural South Africa. We examined the association between young women's engagement in transactional sex and HIV infection. Transactional sex is defined as a non-commercial, non-marital sexual relationship whereby sex is exchanged for money and/or gifts. We explored whether this relationship is mediated by certain HIV-related risk behaviours. We used logistic and multinomial regression and report unadjusted and adjusted odds ratios with 95% CI. RESULTS: Overall, 14% (n=97) of sexually active young women reported engaging in transactional sex. Engagement in transactional sex was associated with an increased risk of being HIV-positive (aOR: 2.5, CI: 95% 1.19-5.25, p=0.01). The effect size of this association remained nearly unchanged when adjusted for certain other dimensions of HIV risk that might help explain the underlying pathways for this relationship. CONCLUSIONS: This study provides quantitative support demonstrating that transactional sex is associated with HIV infection in young women. Even though the specific variables tested do not mediate the relationship, a potential explanation for this association may be that the men with whom young women are having sex belong to networks of sexually connected individuals who are at a "high risk" for HIV infection. The results highlight the importance of structural intervention approaches that can alter the context of young women's HIV risk

Multifactorial Analysis of Differences Between Sporadic Breast Cancers and Cancers Involving BRCA1 and BRCA2 Mutations

Background: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. Methods: Specimens of tumor tissue (5-µm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. Results: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. Conclusions: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients. [J Natl Cancer Inst 1998;90:1138-45

Elevation patterns of plant diversity and recent altitudinal range shifts in Sinai’s high mountain flora

Questions: Is there evidence of recent altitudinal range shifts in a hyper-arid Middle Eastern desert mountain flora? How do the directions of shift for upper and lower altitudinal range limits of plants vary? Location: Hyper-arid mountain desert, St Katherine Protectorate, South Sinai, Egypt. Method: We tested for shifts in both upper and lower altitudinal range limits by comparing a 1970s dataset of recorded species’ limits with recent surveys using altitudinal transects across 36 sites. Altitudinal limits between 63 paired upper-limit and 22 paired lower-limit values from the 1970s and 2014 were compared using paired t-tests; binomial tests were used to indicate the dominant direction of change. The upper and lower limits of 22 species were considered together to allow assessment of overall altitudinal range-size changes. In order to avoid the potential effect of yearly environmental fluctuations on the distributions of annual species, subsets of upper and lower limit shifts were taken for perennials, and trees and shrubs. Results: Our results show significant overall upslope shifts in mean upper altitudinal limits and significant overall downslope shifts in mean lower altitudinal limits. A majority of assessed species expanded their altitudinal ranges, but the responses of individual species varied. Since perennial herbs/graminoids, and trees and shrubs, show strong patterns of change, we suggest there has been a long-term shift in altitudinal range in South Sinai’s mountain flora. Greater research effort needs to be focussed upon the drivers of range-shift responses in arid regions

European code against cancer 4th edition: 12 ways to reduce your cancer risk

This overview describes the principles of the 4th edition of the European Code against Cancer and provides an introduction to the 12 recommendations to reduce cancer risk. Among the 504.6 million inhabitants of the member states of the European Union (EU28), there are annually 2.64 million new cancer cases and 1.28 million deaths from cancer. It is estimated that this cancer burden could be reduced by up to one half if scientific knowledge on causes of cancer could be translated into successful prevention. The Code is a preventive tool aimed to reduce the cancer burden by informing people how to avoid or reduce carcinogenic exposures, adopt behaviours to reduce the cancer risk, or to participate in organised intervention programmes. The Code should also form a base to guide national health policies in cancer prevention. The 12 recommendations are: not smoking or using other tobacco products; avoiding second-hand smoke; being a healthy body weight; encouraging physical activity; having a healthy diet; limiting alcohol consumption, with not drinking alcohol being better for cancer prevention; avoiding too much exposure to ultraviolet radiation; avoiding cancer-causing agents at the workplace; reducing exposure to high levels of radon; encouraging breastfeeding; limiting the use of hormone replacement therapy; participating in organised vaccination programmes against hepatitis B for newborns and human papillomavirus for girls; and participating in organised screening programmes for bowel cancer, breast cancer, and cervical cancer