Invitae (United States)

Este estudio explora, desde un enfoque cualitativo y socio-crítico, las experiencias pedagógicas que los docentes del sistema público ecuatoriano implementan para fortalecer la cultura de legalidad en el aula. Mediante entrevistas semiestructuradas y grupos focales con 28 docentes y 12 directivos de instituciones educativas urbanas y rurales de tres provincias (Pichincha, Guayas y Chimborazo), se analizó cómo las prácticas docentes, la gestión escolar y la formación en valores contribuyen al desarrollo de la gobernanza democrática. Los resultados evidencian que, si bien existe un compromiso ético con la formación ciudadana, persisten tensiones entre el marco normativo educativo que promueve la participación y la justicia social y las limitaciones institucionales, como la burocracia, la falta de recursos y la desconfianza en las instituciones estatales. Las prácticas más efectivas integran el diálogo crítico, la reflexión ética y la participación estudiantil, alineadas con los principios de la pedagogía crítica. Se concluye que la cultura de legalidad en la escuela no puede reducirse a la transmisión de normas, sino que debe construirse desde la experiencia vivida y la transformación colectiva del entorno escolar.

5049 Background: Men with advanced prostate cancer (PrCa) and pathogenic germline variants (PGV) in homologous recombination repair (HRR) or mismatch repair (MMR) genes are eligible for targeted therapies, namely poly (ADP-ribose) polymerase inhibitors (PARPi), platinum chemotherapy, or immune checkpoint inhibitors (ICI). The influence of these PGV on uptake of targeted therapies is understudied and necessary to identify and intervene upon possible disparities. We describe PrCa targeted treatment patterns in men with advanced PrCa. Methods: Germline genetic testing (GGT) (Labcorp) and insurance claims data (Komodo Healthcare MapTM) were assembled for advanced PrCa (defined by ICD10/CPT codes) patients diagnosed from 2015-2024 with ≥ 1 year of claims pre-diagnosis. Treatment uptake by GGT result were compared with Χ 2 tests (negative/variant of uncertain significance (VUS), vs HRR/MMR PGV) and multivariable logistic regression (negative/VUS vs BRCA1/BRCA2 , other HRR/MMR PGV) (Table). Results: 11,545 men with advanced PrCa underwent GGT: 66% White, 50% commercial insurance, 27% PrCa family history, mean age at diagnosis: 65. 924 (8%) and 145 (1%) of men had ≥1 PGV in a HRR or MMR gene, respectively. 1,246 (11%) men received platinum chemotherapy, 332 (3%) received PARPi and 521 (5%) received ICI. Men with HRR PGV were more likely than men with VUS/negative results to receive platinum chemo (14% vs. 11%, p=0.001) and PARPi (16% HRR, 25% BRCA1/2 vs. 2%, p<0.001 for both) and men with MMR PGV were more likely to receive ICI (19% vs. 4%, p<0.001). Black men had lower odds of platinum chemo and ICI than White men, but higher odds of PARPi . Among men with HRR PGV, Black men and those with BRCA1/2 PGV were more likely to receive PARPi (Table). Conclusions: Less than 1 in 4 men with advanced PrCa and HRR/MMR PGV received appropriate targeted therapies. PARPi uptake among eligible patients was twice as high among Black men compared to White men, perhaps reflecting clinician perception of more aggressive disease; rates of platinum chemo and ICI were not similarly higher. These findings raise questions about appropriate receipt of targeted agents and future studies should qualitatively assess clinician prescribing patterns, including sequencing of therapies as approvals for first line PARPi expand. Multivariable analysis of factors associated (p<0.05) with targeted therapy uptake. Platinum chemoOR (CI) ICIOR (CI) PARPiOR (CI) PARPi (HRR PGV only)OR (CI) History of non-prostate cancer 12 (10-14) 12 (9-16) 1.4 (1-2) NS Positive GGT result (ref: negative/VUS) (ref: other HRR) BRCA1/BRCA2 NS NA 18 (14-24) 4 (3-6) Other HRR NS NA 5 (3-7) NA MMR NA 3 (2-5) NA NA Black race/ethnicity (ref: White) 0.7 (0.6-0.9) 0.4 (0.3-0.7) 1.9 (1-3) 2 (1-4) OR, odds ratio; CI, 95% confidence interval; NA, not applicable; NS, not significant. NS factors not shown: insurance, age at diagnosis, age2, family history of PrCa, geographic region.

10571 Background: Germline and somatic pathogenic variants inform eligibility for poly (ADP-ribose) polymerase inhibitors (PARPi) in breast, ovarian, prostate and pancreatic (BOPP) cancers. The role of BRCA1/BRCA2 in BOPP cancers is well-established, but the significance of other homologous recombination repair (HRR) genes is evolving. Integrating germline and somatic data provides a comprehensive understanding of oncogenesis and informs therapeutic decisions and risk assessment. For example, patients with “two hits” (germline and somatic alteration in the same HRR gene) often exhibit exceptional responses to PARPi. Methods: Patients with BOPP cancers receiving standard of care germline genetic testing (GGT) (Labcorp Genetics, formerly Invitae) and comprehensive genomic profiling (CGP) (Omniseq Insight, Labcorp) between 2021-2024 were analyzed. CGP data was queried to determine if the germline pathogenic variant (PGV) 1) was detected in the tumor, 2) had suggestive loss-of-heterozygosity (LOH) with a variant allele fraction (VAF) of ≥ 0.6, 3) had a second hit in the same gene, or 4) had somatic mutation(s) in other HRR gene(s). These were compared between BRCA1/BRCA2 and other HRR PGVs using Fisher’s exact test with significance set at <0.05. Results: 607 patients with BOPP cancers underwent GGT and CGP; 57 (9.4%) had ≥ 1 PGV in an HRR gene. The PGV+ cohort was 51% White; mean age at GGT was 62 years (26-88). Breast cancer was the most common cancer (27), followed by ovarian (15), pancreatic (12) and prostate (4); 20 (35%) patients had a BRCA1/BRCA2 PGV and 37 (65%) patients had other HRR PGV, primarily CHEK2, ATM, PALB2 (Table). Most (88%) PGV were detected by CGP, with 100% of BRCA2 PGV identified. However, 8 (12%) of PGV+ patients would have been missed by CGP testing alone. VAF ≥ 0.6 and/or 2nd hits in the same gene were significantly more likely in those with BRCA1/2 PGV vs. other HRR. Rates of additional mutations in other HRR genes were not significantly different (p>0.05) between the groups (Table). Conclusions: BRCA1/2 PGV were frequently identified as suspected drivers of BOPP cancers compared to other HRR genes. However, one-third of patients with other HRR variants exhibited features suggestive of driving cancer pathogenesis. These findings may qualify indicated patients for targeted therapies or trials and highlight the synergistic value of combined germline and somatic testing. Tumor characteristics of patients with HRR PGV. Genes Total PGV+ patients N (%) PGV detected by CGP N (%) VAF ≥ 0.6 N (%) 2nd hit, same gene N (%) VAF ≥ 0.6 OR 2nd hit N (%) 2nd mutation, different HRR gene BRCA1/2 20 17 (85) 12 (71) a 2 (12) 14 (82) b 6 (35) BRCA1 11 8 (73) 7 (88) 0 (0) 7 (88) 2 (25) BRCA2 9 9 (100) 5 (56) 2 (22) 7 (78) 4 (44) Other HRR c 37 33 (89) 9 (27) a 4 (12) 11 (33) b 9 (27) a p=0.011; b p=0.005; c CHEK2 (14), ATM (7), PALB2 (5), BRIP1 (2), RAD51C (2); BARD1 , BLM, FANCA, FANCA/CHEK2, FANCM , NBN, RAD50 (1 each).

Neoantigen vaccines are under investigation for various cancers, including epidermal growth factor receptor (EGFR)-driven lung cancers1,2. We tracked the phylogenetic history of an EGFR mutant lung cancer treated with erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine (NPV) targeting ten somatic mutations, including EGFR exon 19 deletion (ex19del). The ex19del mutation was clonal, but is likely to have appeared after a whole-genome doubling (WGD) event. Following osimertinib and NPV treatment, loss of the ex19del mutation was identified in a progressing small-cell-transformed liver metastasis. Circulating tumour DNA analyses tracking 467 somatic variants revealed the presence of this EGFR wild-type clone before vaccination and its expansion during osimertinib/NPV therapy. Despite systemic T cell reactivity to the vaccine-targeted ex19del neoantigen, the NPV failed to halt disease progression. The liver metastasis lost vaccine-targeted neoantigens through chromosomal instability and exhibited a hostile microenvironment, characterized by limited immune infiltration, low CXCL9 and elevated M2 macrophage levels. Neoantigens arising post-WGD were more likely to be absent in the progressing liver metastasis than those occurring pre-WGD, suggesting that prioritizing pre-WGD neoantigens may improve vaccine design. Data from the TRACERx 421 cohort3 provide evidence that pre-WGD mutations better represent clonal variants, and owing to their presence at multiple copy numbers, are less likely to be lost in metastatic transition. These data highlight the power of phylogenetic disease tracking and functional T cell profiling to understand mechanisms of immune escape during combination therapies.

SummaryThe tumor suppressor CHEK2 encodes the serine/threonine protein kinase CHK2 which, upon DNA damage, is important for pausing the cell cycle, initiating DNA repair, and inducing apoptosis. CHK2 phosphorylation of the tumor suppressor BRCA1 is also important for mitotic spindle assembly and chromosomal stability. Consistent with its cell-cycle checkpoint role, both germline and somatic variants in CHEK2 have been linked to breast and other cancers. Over 90% of clinical germline CHEK2 missense variants are classified as variants of uncertain significance, complicating diagnosis of CHK2-dependent cancer. We therefore sought to test the functional impact of all possible missense variants in CHK2. Using a scalable multiplexed assay based on the ability of human CHK2 to complement DNA sensitivity of Saccharomyces cerevisiae cells lacking the CHEK2 ortholog, RAD53, we generated a systematic “missense variant effect map” for CHEK2 missense variation. The map reflects known biochemical features of CHK2 while offering new biological insights. It also provides strong evidence toward pathogenicity for some clinical missense variants and supporting evidence toward benignity for others. Overall, this comprehensive missense variant effect map contributes to understanding of both known and yet-to-be-observed CHK2 variants.

Como veremos a lo largo de este artículo, nos vamos a encontrar con sistemas legitimarios muy dispares: En algunos derechos forales la legítima de los ascendentes regulada en el derecho común no se contempla; así mismo encontraremos en varias legislaciones forales un derecho de alimentos de carácter sucesorio e incluso analizaremos un sistema con absoluta libertad de testar.

Pathogenic variants in the titin gene (TTN) are known to cause a wide range of cardiac and musculoskeletal disorders, with skeletal myopathy mostly attributed to biallelic variants. We identified monoallelic truncating variants (TTNtv), splice site or internal deletions in TTN in probands with mild, progressive axial and proximal weakness, with dilated cardiomyopathy frequently developing with age. These variants segregated in an autosomal dominant pattern in 7 out of 8 studied families. We investigated the impact of these variants on mRNA, protein levels, and skeletal muscle structure and function. Results reveal that nonsense-mediated decay likely prevents accumulation of harmful truncated protein in skeletal muscle in patients with TTNtvs. Splice variants and an out-of-frame deletion induce aberrant exon skipping, while an in-frame deletion produces shortened titin with intact N- and C-termini, resulting in disrupted sarcomeric structure. All variant types were associated with genome-wide changes in splicing patterns, which represent a hallmark of disease progression. Lastly, RNA-seq studies revealed that GDF11, a member of the TGF-β superfamily, is upregulated in diseased tissue, indicating that it might be a useful therapeutic target in skeletal muscle titinopathies.