TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer.

Metaplastic breast cancers (MBCs) are characterized by complex genomes, which seem to vary according to their histologic subtype. TERT promoter hotspot mutations and gene amplification are rare in common forms of breast cancer, but present in a subset of phyllodes tumors. Here, we sought to determine the frequency of genetic alterations affecting TERT in a cohort of 60 MBCs with distinct predominant metaplastic components (squamous, 23%; spindle, 27%; osseous, 8%; chondroid, 42%), and to compare the repertoire of genetic alterations of MBCs according to the presence of TERT promoter hotspot mutations or gene amplification. Forty-four MBCs were subjected to: whole-exome sequencing (WES; n = 27) or targeted sequencing of 341-468 cancer-related genes (n = 17); 16 MBCs were subjected to Sanger sequencing of the TERT promoter, TP53 and selected exons of PIK3CA, HRAS, and BRAF. TERT promoter hotspot mutations (n = 9) and TERT gene amplification (n = 1) were found in 10 of the 60 MBCs analyzed, respectively. These TERT alterations were less frequently found in MBCs with predominant chondroid differentiation than in other MBC subtypes (p = 0.01, Fisher's exact test) and were mutually exclusive with TP53 mutations (p < 0.001, CoMEt). In addition, a comparative analysis of the MBCs subjected to WES or targeted cancer gene sequencing (n = 44) revealed that MBCs harboring TERT promoter hotspot mutations or gene amplification (n = 6) more frequently harbored PIK3CA than TERT wild-type MBCs (n = 38; p = 0.001; Fisher's exact test). In conclusion, TERT somatic genetic alterations are found in a subset of TP53 wild-type MBCs with squamous/spindle differentiation, highlighting the genetic diversity of these cancers

Identification of a perinuclear positioning element in human subtelomeres that requires A-type lamins and CTCF

The localization of genes within the nuclear space is of paramount importance for proper genome functions. However, very little is known on the cis-acting elements determining subnuclear positioning of chromosome segments. We show here that the D4Z4 human subtelomeric repeat localizes a telomere at the nuclear periphery. This perinuclear activity lies within an 80 bp sequence included within a region known to interact with CTCF and A-type Lamins. We further show that a reduced level of either CTCF or A-type Lamins suppresses the perinuclear activities of D4Z4 and that an array of multimerized D4Z4 sequence, which has lost its ability to bind CTCF and A-type Lamins, is not localized at the periphery. Overall, these findings reveal the existence of an 80 bp D4Z4 sequence that is sufficient to position an adjacent telomere to the nuclear periphery in a CTCF and A-type lamins-dependent manner. Strikingly, this sequence includes a 30 bp GA-rich motif, which binds CTCF and is present at several locations in the human genome

Academic literacy study at the School of Veterinary Sciences of the National University of La Plata

Cuando nos referimos a alfabetización académica, hacemos referencia a los conocimientos necesarios para aprender en la universidad. Habiéndose realizado una evaluación diagnóstica en el curso de Patología General Veterinaria, se estudió esta problemática en los cursos de segundo año de la carrera de Medicina Veterinaria de la Facultad de Ciencias Veterinarias de la UNLP. Los objetivos del estudio incluyeron conocer qué importancia se da en los cursos de segundo año a la lectura y a la escritura, indagar en las ideas de los docentes al respecto, analizar las actividades de lectoescritura propuestas a los estudiantes y conocer las dificultades que éstos enfrentan ante la lectura y escritura de textos académicos. Para ello se analizaron las planificaciones y evaluaciones curriculares de cada curso, relatos de clases y textos escritos por estudiantes. Se realizaron observaciones de clase y se encuestó a docentes y estudiantes de segundo año. Los resultados muestran qué actividades de lectura y escritura están presentes, tanto en el curriculum práctico como en el formal, hallándose las actividades de escritura preponderantemente en la instancia de evaluación. Las encuestas docentes revelan ideas en transición entre la postura que no reconoce responsabilidad de la universidad en la alfabetización académica y la que sí lo hace. Las encuestas a estudiantes revelaron múltiples dificultades en la lectura, mientras que el análisis de sus escritos mostró dificultades en la escritura. El conocimiento de la situación actual permitirá diseñar proyectos de intervención tendientes a mejorarla, facilitando el proceso de incorporación de los estudiantes a la cultura académica.Academic literacy refers to the knowledge required for learning in college. Taken into account a previous diagnostic study in the Veterinary General Pathology course, in the present work we performed an evaluation of the academic literacy in the remaining courses of second year of the Veterinary Medicine Career, School of Veterinary Sciences, UNLP. Our objectives were to know the relevance given in the courses to reading and writing, to inquire into the teacher conceptions about the academic literacy, to analyze the literacy activities proposed, and to know the challenges they should go through during reading and writing academic texts. Here we analyze planning and evaluation of each course, class descriptions and texts written by students. Class observations and surveys directed to teachers and second-year students were made. The results showed that reading and writing activities are present in the practical curriculum as in the formal one. The writing activities are predominantly present in the evaluations. Surveys directed to teachers reveal teachers that recognize responsibility of the university in the academic literacy and teachers who do not. In addition, surveys directed to students revealed many difficulties in reading, while the analysis of writing showed some difficulties. Knowledge of the current situation will allow designing intervention projects aimed to facilitating the process of incorporation of students to the academic culture.Facultad de Ciencias Veterinaria

Upper Pleistocene sea level changes and human peopling at the northern margin of the Mediterranean Sea: the S-P-Heritage Project

none20openAndrea Zerboni, Irene M. Bollati, Luca Forti, Silvia Gazzo, Abdelkader Moussous, Giovanni Muttoni, Fabio Negrino, Olivier Notter, Manuela Pelfini, Alessandro Perego, Serena Perini, Luca Ragaini, Eleonora Regattieri, Elena Rossoni-Notter, Alessio Rovere, Deirdre Ryan, Marco Serradimigni, Elisabetta Starnini, Matteo Vacchi, Marta PappalardoZerboni, Andrea; Bollati, Irene M.; Forti, Luca; Gazzo, Silvia; Moussous, Abdelkader; Muttoni, Giovanni; Negrino, Fabio; Notter, Olivier; Pelfini, Manuela; Perego, Alessandro; Perini, Serena; Ragaini, Luca; Regattieri, Eleonora; Rossoni-Notter, Elena; Rovere, Alessio; Ryan, Deirdre; Serradimigni, Marco; Starnini, Elisabetta; Vacchi, Matteo; Pappalardo, Mart

Morphological and genomic characteristics of breast cancers occurring in individuals with Lynch Syndrome

PurposeLynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and endometrial cancers. Whether breast cancers developing in the context of Lynch syndrome are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphologic and genomic characteristics of breast cancers occurring in Lynch syndrome individuals.Experimental designA retrospective analysis of 20,110 patients with cancer who underwent multigene panel genetic testing was performed to identify individuals with a likely pathogenic/pathogenic germline variant in MLH1, MSH2, MSH6, or PMS2 who developed breast cancers. The histologic characteristics and IHC assessment of breast cancers for MMR proteins and programmed death-ligand 1 (PD-L1) expression were assessed on cases with available materials. DNA samples from paired tumors and blood were sequenced with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (≥468 key cancer genes). Microsatellite instability (MSI) status was assessed utilizing MSISensor. Mutational signatures were defined using SigMA.ResultsA total of 272 individuals with Lynch syndrome were identified, 13 (5%) of whom had primary breast cancers. The majority of breast cancers (92%) were hormone receptor-positive tumors. Five (42%) of 12 breast cancers displayed loss of MMR proteins by IHC. Four (36%) of 11 breast cancers subjected to tumor-normal sequencing showed dominant MSI mutational signatures, high tumor mutational burden, and indeterminate (27%) or high MSISensor scores (9%). One patient with metastatic MMRd breast cancer received anti-PD1 therapy and achieved a robust and durable response.ConclusionsA subset of breast cancers developing in individuals with Lynch syndrome are etiologically linked to MMRd and may benefit from anti-PD1/PD-L1 immunotherapy

Converging and evolving immuno-genomic routes toward immune escape in breast cancer

Abstract The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions