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La transgénèse permet d’introduire dans une cellule un caractère d’intérêt biologique et un seul, en une seule étape. À l’opposé, les croisements classiques donnent des individus ayant hérité d’un des parents un des caractères agronomiques d’intérêt. Chez les plantes par exemple, il faut plusieurs générations de croisements par les méthodes classiques, pour arriver à introduire un nouveau gène contrôlant un caractère agronomique (par exemple un gène de résistance à une maladie issue d’une mêm...

3100 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in multiple tumors. Larotrectinib is a highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor, approved to treat adult and pediatric patients (pts) with TRK fusion cancer. In an integrated analysis of 206 pts with non-primary CNS TRK fusion cancer, larotrectinib demonstrated an investigator-assessed objective response rate (ORR) of 75%; median progression-free survival (PFS) was 35.4 months (mo; Hong et al, ASCO 2021). We report updated efficacy and safety data based on central review assessments in an expanded dataset. Methods: Data were pooled from three clinical trials (NCT02576431, NCT02122913, and NCT02637687) of pts with non-primary CNS TRK fusion cancer treated with larotrectinib. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. ORR was assessed by independent review committee (IRC) per RECIST v1.1. Data cut-off was July 20, 2021. Results: As of data cut-off, 244 of 269 larotrectinib-treated pts were evaluable for efficacy by IRC. There were 25 different tumor types. The most common were soft tissue sarcoma (STS [43%], including infantile fibrosarcoma [18%] and other STS [25%]), thyroid (11%), lung (10%), salivary gland (9%), and colorectal (7% [colon, n = 18; rectal, n = 1]). Ninety-four (35%) pts were aged < 18 years; 175 (65%) were ≥18 years. Pts had gene fusions involving NTRK1 (46%), NTRK2 (3%), or NTRK3 (51%). A total of 27%, 28%, and 45% of pts had 0, 1, and ≥2 prior lines of systemic therapy, respectively. The ORR was 69% (95% confidence interval [CI] 63–75): 64 (26%) complete response (CR), including 13 (5%) pathological CR, 104 (43%) partial response,41 (17%) stable disease, 20 (8%) progressive disease, and 15 (6%) not determined. Median time to response was 1.8 mo (range 0.9–16.2). Median duration of response (DoR) was 32.9 mo (95% CI 27.3–41.7); median follow-up was 28.3 mo. Median PFS was 29.4 mo (95% CI 19.3–34.3); median follow-up was 29.3 mo. At a median follow-up of 32.2 mo, median overall survival (OS) was not reached; the 48-mo OS rate was 64% (95% CI 55–73). Treatment duration ranged from 0.1 to 67.9 months. Treatment-related adverse events (TRAEs) were mainly Grade 1–2; 50 (20%) pts had Grade 3–4 TRAEs. Five (2%) pts discontinued treatment due to TRAEs. To exclude the possible confounding effect of ongoing enrollment on median DoR, we conducted an exploratory analysis in the subset of 164 pts who were analyzed as of July 2019. The ORR was 74% (95% CI 67–81) and median DoR was 34.5 mo (95% CI 27.6–43.3); median follow-up was 34.1 mo. Conclusions: With longer follow-up, larotrectinib continued to demonstrate rapid and durable responses, extended survival benefit, and a favorable safety profile. These results highlight the importance of testing for NTRK gene fusions in cancer pts. Clinical trial information: NCT02576431, NCT02122913, NCT02637687.

Supplemental material, sj-pdf-1-tam-10.1177_1758835920975613 for A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors by Anna Forsythe, Wei Zhang, Uwe Phillip Strauss, Marc Fellous, Maesumeh Korei and Karen Keating in Therapeutic Advances in Medical Oncology

Supplemental material, sj-pdf-1-tam-10.1177_1758835920975613 for A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors by Anna Forsythe, Wei Zhang, Uwe Phillip Strauss, Marc Fellous, Maesumeh Korei and Karen Keating in Therapeutic Advances in Medical Oncology

Supplemental material, sj-pdf-1-tam-10.1177_1758835920975613 for A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors by Anna Forsythe, Wei Zhang, Uwe Phillip Strauss, Marc Fellous, Maesumeh Korei and Karen Keating in Therapeutic Advances in Medical Oncology

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Primary ovarian insufficiency (POI) results in an early loss of ovarian function, and remains idiopathic in about 80% of cases. Here, we have performed a complete genetic study of a consanguineous family with two POI cases. Linkage analysis and homozygosity mapping identified 12 homozygous regions with linkage, totalling 84 Mb. Whole-exome sequencing of the two patients and a non-affected sister allowed us to detect a homozygous causal variant in the MCM9 gene. The variant c.1483GT [p.E495*], confirmed using Sanger sequencing, introduced a premature stop codon in coding exon 8 and is expected to lead to the loss of a functional protein. MCM9 belongs to a complex required for DNA repair by homologous recombination, and its impairment in mouse is known to induce meiotic recombination defects and oocyte degeneration. A previous study recently described two consanguineous families in which homozygous mutations of MCM9 were responsible for POI and short stature. Interestingly, the affected sisters in the family described here had a normal height. Altogether, our results provide the confirmation of the implication of MCM9 variants in POI and expand their phenotypic spectrum.

The Biomolecular Engineering Commission considers that the knowledge acquired in the last three years has provided significant information in reply to the points raised in its review dated 16 February 2001. The Commission has studied the potential environmental impacts associated with large-scale herbicidetolerantGMoilseed rape crops, making a distinction between direct and indirect impacts. Direct impacts stem from the intrinsic properties of herbicide-tolerant GM oilseed rape crops whereas indirect impacts result from practices associated with the farming of these crops. The Commission considers that, in the absence of the use of the herbicide in question in and outside of farmed land, there is no direct environmental risk (development of invasive crops per se) associated with the presence of a herbicide-tolerance gene in oilseed rape (or related species). Nevertheless, since the interest of these tolerant crops lies in the use of the herbicide in question, indirect effects, to varying extents, have been identified and must be taken into account: the use of the herbicide in question, applied to agricultural fields containing the herbicide-tolerant crop could lead to an increase in oilseed rape volunteer populations in crop rotations; the selective pressure exerted by non-specific herbicides (to which the crops have been rendered tolerant) may be very high in cases of continuous and uncontrolled use of these herbicides, and may result in the persistence of rare events such as the reproduction of fertile interspecies hybrids; the change to the range of herbicides used should be conveyed by more effective weed control and, like any change in farming practices, induce indirect effects on the agri-ecosystem, particularly in terms of changes to weeds and the associated animal life. Accordingly, the Biomolecular Engineering Commission recommends a global approach in terms of the large-scale farming of herbicide-tolerant crops that: accounts for the characteristics of the herbicide and its current and future use; accounts for herbicide-tolerant varieties belonging to other species, liable to be farmed in French agriculture in the short term; targets, if applicable, the selection of crop/herbicide combinations according to the constraints associated with French agriculture; coordinates the evaluations conducted on herbicide-tolerant crops and those conducted on herbicides; implements a biovigilance system and its associated resources whenever herbicide-tolerant crop farming is envisaged. Our report highlights the need for the management of any herbicide-tolerant GM oilseed rape crops. Such a management plan must account for the diverse cropping situations, including crop rotations and farming practices. Management should be based on the prior evaluation of situations encountered, the development of measures commensurate with the risks, and a validation of their efficacy through biovigilance. The Biomolecular Engineering Commission considers that the indirect environmental and agronomic impacts associated with current management practices employed for herbicide-tolerant oilseed rape crops can only be determined, in addition to the knowledge acquired, by continuing ongoing experimental studies initiated. Mathematical and computer models – by formalizing complex scenarios that incorporate the functioning of different oilseed rape populations (farmed, spontaneous, volunteer plants) under specific farming practices – enables the simulation of potential impacts and the identification of suitable management measures. Nevertheless, at the present time, the introduction of more extensive farming than that currently practised, or managed progressive introduction, would make it possible to progress in the study of impacts and develop and validate management procedures enabling the limitation of adverse impacts. In the specific case of imports, the Biomolecular Engineering Commission considers that herbicidetolerant GM oilseed rape seed imports for processing and animal feed does not represent additional risks for the environment compared to other oilseed rape varieties on the market. Due to the very low likelihood of the dispersal of tolerant oilseed rape crops from imported seed, the impact of the herbicides used on communication routes is considered to be negligible in the current context. However, in order to supplement the information available on environmental impacts and avert any changes to the current situation, the Commission recommends that a general monitoring plan be implemented in parallel to the introduction of seeds onto the market. Finally, the Biomolecular Engineering Commission considers that biovigilance systems adapted to the various risks should be in place before any farming of commercial herbicide-tolerant varieties is undertaken. The Biomolecular Engineering Commission considers its analysis to be valid for non-selective herbicidetolerant varieties of oilseed rape obtained both by transgenesis and by means of a technique other than transgenesis.

Discussion Session 2Discussion Session 2; Prendre la mesure d’une culture ouverte et responsable. 3. Colloque Sciences de la vie en société

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International audience; A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism.

National audience

International audience; A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism.

chap. 11; National audience

“Functional wasteland,” “Nonrecombining desert” and “Gene-poor chromosome” are only some examples of the different definitions given to the Y chromosome in the last decade. In comparison to the other chromosomes, the Y is poor in genes, being more than 50% of its sequence composed of repeated elements. Moreover, the Y genes are in continuous decay probably due to the lack of recombination of this chromosome. But the human Y chromosome, at the same time, plays a central role in human biology. The presence or absence of this chromosome determines gonadal sex. Thus, mammalian embryos with a Y chromosome develop testes, while those without it develop ovaries (Polani [38]). What is responsible for the male phenotype is the testis-determining SRY gene (Sinclair [52]) which remains the most distinguishing characteristic of this chromosome. In addition to SRY, the presence of other genes with important functions has been reported, including a region associated to Turner estigmata, a gene related to the development of gonadoblastoma and, most important, genes related to germ cell development and maintenance and then, related with male fertility (Lahn and Page [31]). This paper reviews the structure and the biological functions of this peculiar chromosome.

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During a study of deletions of Y-chromosomal DNA in infertile males, sY116, a Y-linked STS, showed different electrophoretic mobilities in three males, two infertile and one fertile. A study of this STS among 35 other normal males showed that this locus is polymorphic. sY116 has a polya-rich stretch whose instability appears to be the most likely cause of this polymorphism. The possible usefulness of sY116 polymorphism in the detection of subtle genome-wide instabilities in some types of cancer is discussed.

3 tables 3 graph.; National audience

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chap. 12; International audience

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Supplement; National audience

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chap. 18; National audience

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chap. 27; International audience