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In view of the use of oncogenetics as a lever for proposing new-targeted therapies whose indications are expanding, this article provides an overview of this discipline in the French overseas departments and regions (DROM). Contrary to the metropolitan departments, where the number of consultations exceeds 100 consultations per 100,000 inhabitants for most centres in 2019, the number of consultations in the DROMs remains insufficient to meet the national average of 117 per 100,000 inhabitants. The financial and structural support offered by the INCa and the DGOS since 2003 has contributed favourably to the deployment of this activity in metropolitan France. This activity, which seems to be suffering in the DROMs, probably requires particular attention in order to understand the difficulties encountered and thus to meet the INCa's objective as well as possible: to identify and support patients with mutations by providing them with appropriate care., (Copyright © 2023 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

The first International Workshop of the ATM and Cancer Risk group focusing on the role of Ataxia-Telangiectasia Mutated (ATM) gene in cancer was held on December 4 and 5, 2019 at Institut Curie in Paris, France. It was motivated by the fact that germline ATM pathogenic variants have been found to be associated with different cancer types. However, due to the lack of precise age-, sex-, and site-specific risk estimates, no consensus on management guidelines for variant carriers exists, and the clinical utility of ATM variant testing is uncertain. The meeting brought together epidemiologists, geneticists, biologists and clinicians to review current knowledge and on-going challenges related to ATM and cancer risk. This report summarizes the meeting sessions content that covered the latest results in family-based and population-based studies, the importance of accurate variant classification, the effect of radiation exposures for ATM variant carriers, and the characteristics of ATM-deficient tumors. The report concludes that ATM variant carriers outside of the context of Ataxia-Telangiectasia may benefit from effective cancer risk management and therapeutic strategies and that efforts to set up large-scale studies in the international framework to achieve this goal are necessary., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

During the past decade, health technology assessment bodies have faced new challenges in establishing the benefits of new drugs for individuals and health-care systems. A topic of increasing importance to the field of oncology is the so-called agnostic regulatory approval of targeted therapies for cancer (independent of tumour location and histology) granted on the basis of basket trials. Basket trials in oncology offer the advantage of simultaneously evaluating treatments for multiple tumours, even rare cancers, in a single clinical trial. To address the novel challenges introduced by these trials, an interdisciplinary panel was convened on behalf of the Transparency Committee of the French National Authority for Health to clarify an approach designed to guarantee a transparent, reproducible, and fair assessment of histology-agnostic treatments for reimbursement by the French National Health Insurance Fund. The requirements of this approach include the need for randomisation, clinically relevant endpoints, appropriate correction for multiple significance testing, characterisation of subgroup heterogeneity, and validation of underlying biomarker assays. A prospectively designated external control is encouraged when the implementation of a direct comparison is deemed infeasible. We also underline the importance of recording outcomes from basket trials in a registry for use as future external controls., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The implementation of the third Cancer Plan, which began in January 2014, was completed in 2019. With nearly 90% of the actions carried out, this Plan was marked by the collective mobilisation of all stakeholders to reduce the burden of cancer in our country. Real successes have been recorded. But the progress made must not make us forget the pain and suffering endured by those affected by this disease, their families, loved ones and caregivers. Cancer continues to be a life-changing experience for those who face it. In this fight, progress in medicine, research, the quality and safety of care, progress in social support, support in returning to work and to a normal life are all hopes for all patients and their loved ones. They have only been possible thanks to the mobilisation of everyone and the dedication of the care teams. Many battles have been fought over the years and the results obtained are the best encouragement to continue the efforts. We must now amplify and improve our collective action. The ambitious objective of massively reducing the burden of cancer in the lives of the French must mobilise us all for the next decade., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: High consumption of red and processed meat is commonly associated with increased cancer risk, particularly colorectal cancer. Antibodies against the red meat-derived carbohydrate N-glycolylneuraminic acid (Neu5Gc) exacerbate cancer in "human-like" mice. Human anti-Neu5Gc IgG and red meat are both independently proposed to increase cancer risk, yet how diet affects these antibodies is largely unknown., Methods: We used world global data to demonstrate that colorectal cancer incidence and mortality are associated with increased national meat consumption. In a well-defined large cohort, we used glycomics to measure daily Neu5Gc intake from red meat and dairy, and investigated serum as well as affinity-purified anti-Neu5Gc antibodies. Based on 24-h dietary records, daily Neu5Gc intake was calculated for 19,621 subjects aged ≥ 18 years of the NutriNet-Santé study. Serum and affinity-purified anti-Neu5Gc antibodies were evaluated by ELISA and glycan microarrays in representative 120 individuals, each with at least eighteen 24-h dietary records (aged 45-60, Q1-Q4; aged > 60, Q1 and Q4; 10 men/women per quartile)., Results: We found that high-Neu5Gc diet, gender, and age affect the specificity, levels, and repertoires of anti-Neu5Gc IgG immune responses, but not their affinity. Men consumed more Neu5Gc than women, mostly from red meat (p = 0.0015), and exhibited higher overall serum anti-Neu5Gc IgG levels by ELISA (3.94 ng/μl versus 2.22 ng/μl, respectively; p = 0.039). Detailed glycan microarray analysis against 56 different glycans revealed high Neu5Gc-specificity with increased anti-Neu5Gc IgG and altered repertoires, associated with higher consumption of Neu5Gc from red meat and cow dairy. Affinity purification of serum anti-Neu5Gc antibodies revealed increased levels and biased array repertoire patterns, without an increase in antibody affinity, in individuals consuming higher Neu5Gc levels. Furthermore, in a high-meat diet, antibody diversity patterns on glycan microarrays shifted towards Neu5Gcα3-linked glycans, increasing the α3/α6-glycans ratio score., Conclusions: We found a clear link between the levels and repertoire of serum anti-Neu5Gc IgG and Neu5Gc intake from red meat and dairy. These precise rational methodologies allowed to develop a Gcemic index to simplify the assessment of Neu5Gc in foods that could potentially be adapted for dietary recommendations to reduce cancer risk.

MUTYH-associated polyposis (MUTYH-associated polyposis, MAP) is an autosomal recessive inheritance disorder related to bi-allelic constitutional pathogenic variants of the MUTYH gene which was first described in 2002. In 2011, a group of French experts composed of clinicians and biologists, performed a summary of the available data on this condition and drew up recommendations concerning the indications and the modalities of molecular analysis of the MUTYH gene in index cases and their relatives, as well as the management of affected individuals. In view of recent developments, some recommendations have become obsolete, in particular with regard to the molecular analysis strategy since MUTYH gene has been recently included in a consensus panel of 14 genes predisposing to colorectal cancer. This led us to revise all the points of the previous expertise. We report here the revised version of this work which successively considers the phenotype and the tumor risks associated with this genotype, the differential diagnoses, the indication criteria and the strategy of the molecular analysis and the recommendations for the management of affected individuals. We also discuss the phenotype and the tumor risks associated with mono-allelic pathogenic variants of MUTYH gene., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Marine mussel production is of substantial economic interest in numerous coastal areas worldwide, making crucial the study of pathologies that affect them. Disseminated neoplasia (DN) has recently been suggested to be linked to blue mussel, Mytilus edulis, mortality outbreaks observed in France since 2014, although the evidence remains indirect. In order to improve DN detection and monitoring, we compared the sensitivity of four diagnostic tools, namely haemocytology, histology, flow cytometry, and genetics. Haemocytological examination gave the best results in sensitivity and had the advantage of being non-invasive, allowing disease progression to be followed in affected mussels. Using this approach, we showed that DN progression is usually slow, and we provide evidence of remission events. We observed a high diversity of forms and mitotic features of neoplastic cells located in the vesicular connective tissue but rarely in the haemolymph. Circulating cells occur as four main types but are homogenous in morphology and DNA content within a single individual. Polyploidy proved very high, from 8 N to 18 N. Genetic analysis of haemolymph DNA showed that a Mytilus trossulus genetic signal was associated with almost all the DN cases here diagnosed by haemocytological examination, regardless of the DN type. This result corroborates DN is a transmissible cancer that first originated in a M. trossulus host and subsequently crossed into M. edulis. No pre-neoplastic conditions were detectable. The prevalence of the disease was quite low, which, together with the low morbidity observed in the lab, suggest DN is unlikely to be the direct cause of mortality outbreaks in France., (Copyright © 2019. Published by Elsevier Inc.)

In oncology, the expanding use of multi-gene panels to explore familial cancer predisposition and tumor genome analysis has led to increased secondary findings discoveries (SFs) and has given rise to important medical, ethical, and legal issues. The American College of Medical Genetics and Genomics published a policy statement for managing SFs for a list of genes, including 25 cancer-related genes. Currently, there are few recommendations in Europe. From June 2016 to May 2017, the French Society of Predictive and Personalized Medicine (SFMPP) established a working group of 47 experts to elaborate guidelines for managing information given on the SFs for genes related to cancers. A subgroup of ethicists, lawyers, patients' representatives, and psychologists provided ethical reflection, information guidelines, and materials (written consent form and video). A subgroup with medical expertise, including oncologists and clinical and molecular geneticists, provided independent evaluation and classification of 60 genes. The main criteria were the "actionability" of the genes (available screening or prevention strategies), the risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into three classes: for class 1 genes (n = 36), delivering the information on SFs was recommended; for class 2 genes (n = 5), delivering the information remained questionable because of insufficient data from the literature and/or level of evidence; and for class 3 genes (n = 19), delivering the information on SFs was not recommended. These guidelines for managing SFs for cancer-predisposing genes provide new insights for clinicians and laboratories to standardize clinical practices.

Background: Experimental evidence has suggested that vitamin D may be protective against tobacco-related cancers through the inhibition of the formation of tumors induced by tobacco carcinogens. To our knowledge, only one previous epidemiologic study investigated the association between vitamin D status and tobacco-related cancer risk, and no study has focused on vitamin D-related gene polymorphisms., Objective: Our objective was to prospectively study the association between plasma 25-hydroxyvitamin D [25(OH)D] concentrations, vitamin D-related gene polymorphisms, and risk of tobacco-related cancers., Design: A total of 209 tobacco-related cancers were diagnosed within the SU.VI.MAX (Supplémentation en vitamines et minéraux antioxydants) cohort (1994-2007) and were matched with 418 controls as part of a nested case-control study. Tobacco-related cancers (i.e., cancers for which tobacco is one of the risk factors) included several sites in the respiratory, digestive, reproductive, and urinary systems. Total plasma 25(OH)D was assessed with the use of an electrochemoluminescent assay. Polymorphisms were determined with the use of a TaqMan assay. Conditional logistic regression models were computed., Results: A 25(OH)D concentration ≥30 ng/mL was associated with reduced risk of tobacco-related cancers (OR for ≥30 compared with <30 ng/mL: 0.59; 95% CI 0.35, 0.99; P = 0.046). This association was observed in former and current smokers (OR for ≥30 compared with <30 ng/mL: 0.43; 95% CI: 0.23, 0.84; P = 0.01) but not in never smokers (P = 0.8). The vitamin D receptor (VDR) FokI AA genotype and retinoid X receptor (RXR) rs7861779 TT genotype were associated with increased risk of tobacco-related cancers [OR for homozygous mutant type (MT) compared with wild type (WT): 1.87; 95% CI: 1.08, 3.23; P-trend = 0.02; OR for heterozygous type (HT) plus MT compared with WT: 1.60; 95% CI: 1.07, 2.38; P = 0.02]., Conclusions: In this prospective study, high vitamin D status [25(OH)D concentration ≥30 ng/mL] was associated with decreased risk of tobacco-related cancers, especially in smokers. These results, which are supported by mechanistic plausibility, suggest that vitamin D may contribute to the prevention of tobacco-induced cancers in smokers and deserve additional investigation. The SU.VI.MAX trial was registered at clinicaltrials.gov as NCT00272428., (© 2015 American Society for Nutrition.)

Background: Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed., Methods: The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01771458., Findings: Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8-11·6) in the experimental group and 11·3 months (8·1-11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7-3·8) in the experimental group versus 2·0 months (1·8-2·1) in the control group (hazard ratio 0·88, 95% CI 0·65-1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3-4 adverse events (p=0·30)., Interpretation: The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Biallelic mutations in ATM cause ataxia-telangiectasia (AT), a rare inherited disease with a high incidence of cancer. Precise estimates of the risk, presentation, and outcomes of cancer in patients with AT need to be addressed in large series., Patients and Methods: In this large retrospective cohort, 69 patients with cancers (24.5%) were identified among 279 patients with AT. Centralized review was performed on 60% of the lymphomas. Incidence rates were compared with the French population, and risk factors were analyzed., Results: Eight patients developed acute leukemias (including four T-cell acute lymphoblastic leukemias), 12 developed Hodgkin lymphoma (HL), 38 developed non-Hodgkin lymphoma (NHL), three developed T-cell prolymphocytic leukemia (T-PLL), and eight developed carcinoma at a median age of 8.3, 10.6, 9.7, 24.2, and 31.4 years, respectively (P < .001). The majority of NHLs were aggressive B-cell NHL. Epstein-Barr virus was associated with all of the HLs and 50% of the NHLs. Overall survival was shorter in patients with AT who developed cancer compared with those who did not develop cancer (15 v 24 years, respectively; P < .001). Survival was improved in patients who achieved a major response to treatment (3.46 v 0.87 years for major v minor responses, respectively; P = .011). Immunodeficiency was associated with increased risk of cancer. ATM mutation type was associated with a difference in survival in the entire cohort but not with cancer incidence or cancer survival., Conclusion: B-cell NHL, HL, and acute lymphoblastic leukemia occur at a high rate and earlier age than carcinomas in AT. T-PLLs are rarer than initially reported. Prognosis is poor, but patients may benefit from treatment with an improved survival., (© 2014 by American Society of Clinical Oncology.)

Drug approvals for molecularly stratified tumor subgroups make molecular testing mandatory and require that molecular diagnostics be performed nationwide. To this end, the French National Cancer Institute (INCa) and the French Ministry of Health have set up a national network of 28 regional molecular genetics centers. Selective molecular tests are performed in these facilities. They are free of charge for all patients in their region, irrespective of the type of establishment in which they are receiving treatment. A specific program has also been implemented to anticipate the launch of new targeted therapies and to accelerate the time-to-access to new drugs and experimental therapies. The initiative has been operational for 5 years and has been successful in meeting its initial aims of uniform nationwide test provision and fast implementation of molecular tests for new tumor biomarkers.

This study assessed the impact of the results of genetic testing for hereditary cancer from a multifactorial health psychology perspective, considering that emotional expression plays a key role in psychological adjustment. Measures of dispositional and transactional coping strategies, anxiety and alexithymia were filled out by 77 participants in a longitudinal study design. Statistical analyses were performed using general linear models and partial least squares path modelling, low-constraint methods that are particularly useful in the behavioural sciences. While anxiety levels prior to the result announcement were predictive of the distress experienced by noncarriers, considerable variability was observed for mutation carriers. Some subjects who had lower anxiety levels before the test displayed greater anxiety afterwards, but others seemed to anticipate the distress they would experience with the result that they showed a decrease in anxiety. The mutation carriers behaved as though their adaptive functioning were reshaped by the test result, independent of their disposition and previous emotional state, except in the case of alexithymia. Difficulty expressing emotions prior to genetic testing contributed to a similar difficulty after receiving the result, adding to the latter's emotional impact by promoting emotion-focused coping strategies and increasing distress., (© 2011 Taylor & Francis)

The present report presents the first evidence of disseminated neoplasia (DN) in cockles Cerastoderma edule from Arcachon Bay (France). Aneuploidy of neoplastic cells allowed the use of flow cytometry (FCM) to diagnose and stage DN. A 1year survey (2007) of the prevalence and intensity (% of aneuploid circulating cells in neoplastic cockles) was conducted. Prevalences ranged from 2.2% (June) to 13.6% (May), and disease intensity ranged from 18.7% (June) to 95.5% (September). These percentages were not correlated with seawater temperature, but rather showed unexplained oscillations over the year. Prevalence and intensity of DN were higher in cockles found at the surface of sediment compared to those buried normally (11.8% vs. 6.7% and 53.0% vs. 40.6%, respectively, p<0.05). DN could thus be one mechanism leading to unexplained presence of cockles at the surface of the sediment in Arcachon Bay. Ploidy characteristics of neoplastic cells were also investigated using FCM, revealing an unusual, broad continuum of ploidy distribution from 1.6 to 9.6n. Ploidy values were not in whole numbers in contrast to the rounded values reported in other studies. Ploidy varied according to DN intensity, with the ploidy distribution of neoplastic cells from lightly-diseased cockles being unimodal (3.7n median). In contrast, highly-diseased cockles showed a bimodal ploidy distribution (3.0n and 4.7n medians). This suggests that, in cockles from Arcachon Bay, mechanisms leading to aneuploidy are complex, developing during disease progression.

Purpose: Preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND) practices for inherited predisposition to cancer are heterogeneous in industrialized countries. In France, permission to perform PGD/PND must be obtained from registered Multidisciplinary Prenatal Diagnosis Teams (MPDTs). The aim of this study was to determine French professionals' attitudes about the acceptability of PGD and PND for inherited predisposition to cancer., Methods: A cross-sectional survey was performed, involving self-administered questionnaires mailed to all registered cancer geneticists (CGs; n = 123) and MPDTs (n = 47) in France., Results: The response rates of CGs and MPDTs were 62% and 64%, respectively; 59% and 50% of the CGs had at least discussed PGD and PND, respectively, with their consultees during the previous year. When severe cancer is liable to occur in childhood with a high penetrance and no effective methods of prevention/treatment exist, high rates of acceptability of PGD/PND were recorded (> 80%). When cancer is liable to occur before the age of 50 years but not in childhood and some form of prevention/treatment is available that preserves quality of life, PGD was rated as acceptable by one MPDT (3.3%) and 10 CGs (13.2%), and PND was rated acceptable by nine CGs (11.8%). Most respondents agreed that the acceptability of PND/PGD depends on patients' family history of cancer and their reproductive history., Conclusion: With the most severe forms of inherited cancer, no differences were observed between the acceptability to practitioners of PND and PGD, but with late-onset syndromes, there is still much uncertainty. Guidelines would help to standardize the practices of professionals handling these reproductive issues.

Organised since 1990 in France, cancer genetics has been strengthened since 2003 by the programme "Plan Cancer" which resulted in an improvement of the organisation of activities. The aim of this review is to present an update of the estimation of the needs of the population in this field for the next ten years, provided by a group of experts mandated by the French National Cancer Institute. Identification and management of major hereditary predispositions to cancer have a major impact on decrease in mortality and incidence. Sensitivity of criteria for the detection of BRCA1/2 mutations could be substantially improved by enlarging the indication for genetic testing to isolated cases of ovarian cancer occurring before 70 years and to familial cases occurring after this age limit. In the Lynch syndrome, the present criteria would have an excellent sensitivity for the detection of mutations in the mismatch repair (MMR) genes if the pre-screening of tumours on microsatellite instability (MSI) phenotype was effective, but these criteria are actually poorly applied. However, genetic testing should not be proposed to all the patients affected by tumours belonging to the spectrum of major predispositions and a fortiori to unaffected persons unless an affected relative has been identified as a carrier. The prescription of tests should continue to be strictly controlled and organised, in patients as well as in at-risk relatives. The enlargement of criteria and the improvement in the spreading of recommendations should result in an increase of genetic counselling activity and of the prescriptions of tests by a factor 2 to 4, and to a lesser extent in the clinical management of at risk persons. In a near future, it appears important to mandate experts on specific issues such as the determinants of the lack of effective application of tumour screening for MSI phenotype, the recommendations for the identification and the management of MYH-associated polyposis, or the predictive value of tumour characteristics for the identification of BRCA1/2 mutations. The expected increase in cancer genetics activity will need an optimal organisation to increase the throughput. Such measures will help in facing up to new predispositions that will probably be identified in common cancers.

Background: Since 2002, hereditary cancer gene testing has been funded at the national level in France. Here we report on the impact of this funding on the number of tests carried out and specify the genes/syndromes on which these tests focus., Methods: All French laboratory facilities funded had to submit a report on their activities to the French Health Ministry in March 2004., Results: Funding has led to an increase of >344% in the number of tests carried out between the years 2000 and 2003. For every 100,000 inhabitants, 16.02 cases with a familial cancer syndrome (index cases subjected to 'diagnostic genetic testing') and 4.44 relatives of an index case with a proven mutation were tested. The overall mutation detection rate was 15.2% in the case of breast cancer genes and 17.2% in that of mismatch repair genes., Conclusion: In France, the current mutation detection rate is high in comparison with the 10% benchmark level. A further increase can be expected to occur in the number of tests carried out in the future., ((c) 2008 S. Karger AG, Basel)

The French Cancer Plan 2003-2007 has made translational research central to its research programme, to ensure the care-research continuum and the quickest application possible for the most recent discoveries, for the patients' benefit. This is a new field of research, still little-known or ill-understood. A working group, composed of physicians and researchers from academic research and industrial research, sought to define translational research in cancerology and define the issues at stake in it. Translational research needs to develop in close connection with the patients in order to enable a bi-directional flow of knowledge from cognitive research toward medical applications and from observations made on patients toward cognitive research. Placed under the aegis of the French National Cancer Institute and Leem Research, the group has put forth a strategy for implementing translational research in cancerology in France to make it attractive, competitive and efficient and to foster the development of public-private partnerships.

Cancer epidemiology has undergone marked development since the 1950s. One of the most spectacular and specific contributions was the demonstration of the massive effect of smoking on the occurrence of lung, larynx, and bladder cancer. Major chemical, physical, and biological carcinogenic agents have been identified in the working environment and in the overall environment. The chain of events from environmental exposures to cancer requires hundreds of polymorphic genes coding for proteins involved in the transport and metabolism of xenobiotics, or in repair, or in an immune or inflammatory response. The multifactorial and multistage characteristics of cancer create the theoretical conditions for statistical interactions that have been exceptionally detected. Over the last two decades, a considerable mass of data has been generated, mostly addressing the interactions between smoking and xenobiotic-metabolizing enzymes in smoking-related cancers. They were sometimes considered disappointing, but they actually brought a lot of information and raised many methodological issues. In parallel, the number of polymorphisms that can be considered candidate per function increased so much that multiple testing has become a major issue, and genome wide-screening approaches have more and more gained in interest. Facing the resulting complexity, some instruments are being set up: our studies are now equipped with carefully sampled biological collections, high-throughput genotyping systems are becoming available, work on statistical methodologies is ongoing, bioinformatics databases are growing larger and access to them is becoming simpler; international consortiums are being organized. The roles of environmental and genetic factors are being jointly elucidated. The basic rules of epidemiology, which are demanding with respect to sampling, with respect to the histological and molecular criteria for cancer classification, with respect to the evaluation of environmental exposures, their timeframes, quantification and covariables, with respect to study size and with respect to the rigor of multivariate analyses, are more pertinent than ever before.

Epidemiological studies have indicated that ataxia-telangiectasia (AT) heterozygotes in AT families have an increased risk of cancer, particularly of breast cancer (BC). However, in BC case-control studies, no significant differences were found in the frequency of ATM mutations between patients and controls. In such studies missense mutations were found more frequently than truncating mutations, suggesting that the cancer risk depends on mutation type. To investigate this possibility, we assessed the risk of BC according to the type and position of the ATM truncating mutation in extended AT families. DNA or RNA that had been isolated from blood or buccal cells of AT children and their relatives was screened for ATM germ-line mutations using restriction endonuclease fingerprinting, the protein truncation test, fluorescence-assisted mismatch analysis, and direct sequencing. The standardized incidence ratio of cancer associated with ATM heterozygosity status and type of mutation was estimated. We tested for genotype-phenotype correlations by simulations, permuting mutations among parental branches. No significant difference was found in the relative risk of breast cancer or any other type of cancer based on mutation type. However, the occurrence of BC may be associated with truncating mutations in certain binding domains of the ATM protein (e.g., P53/BRCA1, beta-adaptin, and FAT domains; P = 0.006). In this limited sample set, the presence of missense or truncating ATM mutations was not associated with different cancer risks. The risk of BC appeared to be associated with the alteration of binding domains rather than with the length of the predicted ATM protein.

The knowledge of the epidemiology of cancer in childhood is relevant of a strict methodology allowed by the activation of population-based specific registries, case-control and cohort studies. Descriptive epidemiology is a mean of survey and of public health, while analytic epidemiology contributes to define the role of genetic and environmental factors, along with their interaction. The collected data help indirectly to improve the care of the child with cancer and to a better understanding of the carcinogenesis.

Thanks to progress in molecular genetics, we now have new powerful tools allowing certain or highly presumptive prediction of disease course. The impact on medical practice has been disconcerting. These tools may be very helpful for many patients and families concerned by genetic diseases. For health professionals, the new knowledge must be handled with care to discern the true patient benefit. The patient-doctor relationship - from information delivery, with its known or unknown effects on the individual patient and his/her family and offspring, to the new prospects for gene therapy - must be conducted in a spirit of free exchange allowing responsible real life decision making. Living necessarily implies taking risks, but also trusting human capacity to establish mutual relationships on the basis of trust, fellowship and fraternity.

The rapid development of cancer genomics is due to important progresses in oncogenesis, human genome sequencing and emergence of new technologies in genome and transcriptome analysis. In this context, the aim of the French program 'Cartes d'Identites des Tumeurs--Molecular Portraits of Tumors' is to build a public data base containing a pan genome assessment of genome and transcriptome alterations in the major types of tumors as well as in relevant normal cells and experimental models. Data mining is done in the context of genome annotations and clinical and biological informations attached to the enrolled samples. The goal of the program is to define new tests useful for diagnostic procedures in clinical laboratories and new targets for biological treatments of tumors.

The aim of 'Atlas of Genetics and Cytogenetics in Oncology and Haematology' (http://www.infobiogen.fr/services/chromcancer) is to present summarized information on chromosome abnormalities in cancer, with extensions to genes involved in cancer and to cancer-prone diseases. Information is to be updated. This database is made for and by cytogeneticists, molecular biologists, clinicians in oncology and in haematology, and pathologists.

An epidemiological study of 842 polycythaemic patients (entered between 1980 and 1997 in the French investigational prospective protocols) is presented. The global incidence is approximately 0.8-1.5/100,000/year in the reference area (Ile-de-France and surrounding areas). It increases linearly with age until 80, which suggests that several mutational somatic events are necessary. There was a slight male excess (sex-ratio 1.2, after correction for the percentage of male and female French people still living at risk). We did observe a slight excess of PV in the population of Jewish ancestry. A surprising excess of former blood donors (20.7% of the PV cases, compared to 8% estimated in the reference population) was observed. Only a few cases of familial myeloproliferative diseases and occurence of leukemia in the family of our patients have been observed; even if slight, this excess is statistically significant. In contrast, no excess of carcinomas was observed either in the family or in the patients' antecedents. We did not find any excess of radiation exposure in our cases. When analysing the previous occupation of our patients a possible excess of physicians and of patients previously working in occupations using solvents and glues was found, but this finding needs confirmation.

The orientation of the medical activity toward preventive strategies knows currently an important development. This movement shows various logic, which are: on one hand a rational step, a strategic choice in favour of prevention, and on the other hand a choice by elimination, when the other forms of intervention establish insufficient efficiency. Prevention had to follow the path of validity to acquire pertinence. The gold-standard is randomised blinded trials and it is this kind of procedure that has been proposed in the BCPT (Breast cancer prevention trial). By comparison with a classic therapeutic trial the main differences of prevention trial lay in: criteria of inclusion, analyses of impact larger than the simple efficiency (quality of life), on the focus on the risk (especially genetic) and the legal context. One of the main points is the question of risks induced by an intervention on healthy persons. In this context, even the passage of an uncertainty to a "certainty" concerning induced risks can not always suffice to close the controversy. Physicians cannot in this case, refer to norms and to models since this type of intervention is new.

A complete family history was obtained for 501 patients with Wilms' tumor, treated in departments of pediatric oncology in whole France. The information was collected by self-questionnaire and/or by interview of parents. The proportion of bilateral cases is 4.6% and there are 12 patients (2.4%) with a positive family history of Wilms' tumor. The affected relatives are most often distant and no first degree relative was affected. Apart from the well-known associations with aniridia, hemihypertrophy, genitourinary anomalies, Beckwith-Wiedeemann, and Drash syndromes, there is also a significant excess of congenital heart defects (P = .008) which remains to be explained. Several findings support the bimutational hypothesis such as earlier diagnosis and increased parental age in bilateral cases. No particular anomalies and no increased frequency of childhood cancer were found in patients' relatives. The frequency of Wilms' tumor in relatives was estimated to be less than 0.4% in sibs, 0.06% in uncles and aunts, and 0.04% in first cousins. These figures are very different from those found in retinoblastoma and suggest that the mechanism may be more complex in Wilms' tumor. This conclusion is in agreement with molecular biology studies in tumors and linkage analysis in multiple case families which suggest that more than one locus is involved.

Authors have studied 758 sera from normal subjects in Marseille area. The genotype frequencie Hp 1 is 0,39, similar that of France in general. The phenotype repartition is 16% for Hp 1-1, 45% for Hp 2-1 and 39% for Hp 2-2. People with carcinoma have shown a increase of the frequencie of the phenotype Hp 2-2 and a decrease of the frequencie of genotype Hp 1, mostly in lung carcinoma (Hp 1 = 0,29) and in carcinoma of digestive track (Hp 1 = 0,19). However, a control group, which is constituted by people hospitalized in the Anti-Cancerous Center, has a Hp 1 frequencie of 0,29 a well as lung carcinoma, no explication was found.