L'opposition contre les brevets de Myriad Genetics et leur révocation totale ou partielle en Europe : Premiers enseignements

Les procédures d'opposition contre les brevets de Myriad Genetics sur le gène BRCA1 ont débouché sur la révocation totale d'un premier brevet sur la méthode de diagnostic génétique du cancer du sein, décision de l'Office européen des brevets (OEB) du 18 mai 2004, puis sur la révocation de l'essentiel du second brevet qui portait sur le gène lui-même, le 21 janvier 2005. Ce brevet ne porte plus que sur quelques fragments du gène utilisés comme sondes, les revendications sur les applications diagnostiques ayant été supprimées. Enfin, le 25 janvier 2005, L'OEB a fortement réduit les revendications d'un troisième brevet qui portait sur des mutations particulières du gène. Au lieu des 34 mutations accordées initialement par l'OEB, ce brevet ne porte plus que sur une sonde étroitement définie pour détecter une seule mutation. Et l'usage de cette sonde n'est pas un point de passage obligé. Ces décisions mettent fin au monopole juridique revendiqué par Myriad Genetics sur le gène BRCA1 dans sa totalité et sur le diagnostic génétique du cancer du sein. Elles laissent le champ libre aux généticiens européens qui peuvent développer et mettre en oeuvre leurs méthodes de tests dans le cadre d'une organisation clinique et à caractère non lucratif.The proceedings instituted against three European patents held by the US company Myriad Genetics, on the BRCA1 gene and the breast cancer diagnosis gene, resulted in the total or partial revocation of these patents. These decisions put an end to the legal monopoly claimed by Myriad Genetics on the BRCA1 gene and on breast cancer gene tests, and left the field open to European geneticists to develop and implement their test methods within the framework of a clinical not-for-profit organization. The opposition procedure, through which any actor is allowed to challenge European patents, was used by geneticists doctors in Europe to refuse the emergence of an industrial monopoly on a medical service offered in a clinical context. The decision to revoke or strongly limit these patents was based on the European Patent Office's refusal to establish an invention priority on a sequence that had errors at the time the application was filed by the patent holder, in September 1994. The patent holder was granted an invention priority only on 24 March 1995, when it filed an application for a corrected sequence of the gene. But by then the BRCA1 gene sequence had already been divulged in a public data base, Genbank, from October 1994, notably by Myriad. Myriad Genetics' patents were thus victims of the patent race that prompted the firm to file multiple patent applications on insufficiently validated sequences, and of the conflict between diffusion in the public domain and the novelty requirement. Opposition to the patents, undertaken by a coalition of medical institutions, human genetic societies, two States, Holland and Austria, an environmental protection organization (Greenpeace), and the Swiss Labour Party, made it possible to preserve and develop the clinical economy of genetic tests in Europe. It resulted in amendments to intellectual property laws in France and thus extended the possibility of using compulsory licences for public health purposes to in vitro diagnosis

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

Screening of male breast cancer and of breast-ovarian cancer families for BRCA2 mutations using large bifluorescent amplicons

41 breast cancer or breast-ovarian cancer families, including 12 families with at least one affected first-degree male relative, were screened for mutations in the BRCA2 gene. Mutations had not been found in the BRCA1 gene of these families. Chemical cleavage of Mismatch was used to identify nucleotide changes within large PCR products (average size 1.2 kb) that carried strand-specific fluorescent end-labels. 15 amplicons were sufficient to scan 18 exons, including the large exon 11. The remaining 9 small exons were examined by Denaturing Gradient Gel Electrophoresis. The high sensitivity of this approach was documented by the detection, in these 41 patients, of all 9 exonic single nucleotide polymorphisms reported with heterozygosity >0.1. Truncating BRCA2 mutations were found in 7 of the 41 families. 3 of them were in the group of 12 families comprising cases of male breast cancer. Since the methods used here have no bias for particular types of mutations, these data confirm the high proportion of frameshifts among mutations in BRCA2. However, relevant single nucleotide substitutions were also found: one resulting in a stop codon and another one, present in a male patient, was the previously reported change Asp2723His, that affects a highly conserved region of the BRCA2 protein. This study indicates a BRCA2 contribution of 10% (95% CI 2.5–17.5) to our original cohort of 59 breast-ovarian cancer families, whereas the contribution of BRCA1 had been estimated at 46% (95% CI 33–59). © 2001 Cancer Research Campaign http://www.bjcancer.co

Genome Alteration Print (GAP): a tool to visualize and mine complex cancer genomic profiles obtained by SNP arrays

GAP, a method for analyzing complex cancer genome profiles from SNP arrays, performs well even with poor quality data and rearranged genome

Increased risk of breast cancer among female relatives of patients with ataxia-telangiectasia: a causal relationship?

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A new scoring system for the diagnosis of BRCA1/2 associated breast-ovarian cancer predisposition.

International audienceCriteria have been proposed for genetic testing of breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. Using simulations, this study evaluates the efficiency (sensitivity, positive predictive value [PPV] and specificity) of the various criteria used in France. The efficiency of the criteria published in 1998, which are largely used, is not optimal. We show that some extensions of these criteria provide an increase in sensitivity with a low decrease in specificity and PPV. The study shows that scoring systems (Manchester, Eisinger) have similar efficiency that may be improved. In this aim, we propose a new scoring system that takes into account unaffected individuals and kinship coefficients between family members. This system increases sensitivity without affecting PPV and specificity. Finally, we propose a two-step procedure with a large screening by the physician for recommending genetic counselling, followed by a more stringent selection by the geneticist for prescribing genetic testing. This procedure would result in an increase of genetic counselling activity but would allow the identification of almost 80% of mutation carriers among affected individuals, with a mutation detection rate of 15% and a specificity of 88%

germline mutations in women with familial breast cancer and a relative with haematological malignancy

International audienceBiallelic inactivation of the gene causes ataxia–telangiectasia (A–T), a complex neurological disease associated with a high risk of leukaemias and lymphomas. Mothers of A–T children, obligate heterozygote mutation carriers, have a breast cancer (BC) relative risk of about 3. The frequency of carriers in BC women with a BC family history has been estimated to be 2.70%. To further our clinical understanding of familial BC and examine whether haematological malignancies are predictive of germline mutation, we estimated the frequency of heterozygote mutation carriers in a series of 122 BC women with a family history of both BC and haematological malignancy and without mutation. The gene screening was performed with a new high throughput method, EMMA (enhanced mismatch mutation analysis). Amongst 28 different variants, eight mutations have been identified in eight patients: two mutations leading to a putative truncated protein and six being likely deleterious mutations. One of the truncating mutations was initially interpreted as a missense mutation, p.Asp2597Tyr, but is actually a splice mutation (c.7789G>T/p.Asp2597_Lys2643>LysfsX3). The estimated frequency of heterozygote mutation carriers in our series is 6.56% (95% CI: 2.16–10.95), a significantly higher figure than that observed in the general population, estimated to be between 0.3 and 0.6%. Although a trend towards an increased frequency of carriers was observed, it was not different from that observed in a population of familial BC women not selected for haematological malignancy as the frequency of carriers was 2.70%, a value situated in the confidence interval of our study