PALB2 germline mutations in a multi-gene panel testing cohort of 1905 breast-ovarian cancer patients in Argentina.

PURPOSE: PALB2 variants have been scarcely described in Argentinian and Latin-American reports. In this study, we describe molecular and clinical characteristics of PALB2 mutations found in multi-gene panels (MP) from breast-ovarian cancer (BOC) families in different institutions from Argentina. METHODS: We retrospectively identified PALB2 pathogenic (PV) and likely pathogenic (LPV) variants from a cohort of 1905 MP results, provided by one local lab (Heritas) and SITHER (Hereditary Tumor Information System) public database. All patients met hereditary BOC clinical criteria for testing, according to current guidelines. RESULTS: The frequency of PALB2 mutations is 2.78% (53/1905). Forty-eight (90.5%) are PV and five (9.5%) are LPV. Most of the 18 different mutations (89%) are nonsense and frameshift types and 2 variants are novel. One high-rate recurrent PV (Y551*) is present in 43% (23/53) of the unrelated index cases. From the 53 affected carriers, 94% have BC diagnosis with 14% of bilateral cases. BC phenotype is mainly invasive ductal (78%) with 62% of hormone-receptor positive and 22% of triple negative tumors. Self-reported ethnic background of the cohort is West European (66%) and native Latin-American (20%) which is representative of Buenos Aires and other big urban areas of the country. CONCLUSION: This is the first report describing molecular and clinical characteristics of PALB2 carriers in Argentina. Frequency of PALB2 PV in Argentinian HBOC families is higher than in other reported populations. Y551* is a recurrent mutation that seems to be responsible for almost 50% of PALB2 cases.

Cumulative incidence of subsequent malignancy after allo-HCT conditioned with or without low-dose total body irradiation.

Subsequent malignancies (SMs) present a significant burden of morbidity and are a common cause of late mortality in survivors of allogeneic hematopoietic cell transplant (allo-HCT). Previous studies have described total body irradiation (TBI) as a risk factor for the development of SMs in allo-HCT survivors. However, most studies of the association between TBI and SM have examined high-dose TBI regimens (typically ≥600 cGy), and thus little is known about the association between low-dose TBI regimens and risk of SMs. Our goal, therefore, was to compare the cumulative incidence of SMs in patients of Alberta, Canada, who received busulfan/fludarabine alone vs busulfan/fludarabine plus 400 cGy TBI. Of the 674 included patients, 49 developed a total of 56 malignancies at a median of 5.9 years' posttransplant. The cumulative incidence of SMs at 15 years' post-HCT in the entire cohort was 11.5% (95% confidence interval [CI], 8.5-15.6): 13.4% (95% CI, 9.1-19.3) in the no-TBI group and 10.8% (95% CI, 6.6-17.4) in the TBI group. In the multivariable model, TBI was not associated with SMs, whereas there was an association with number of pre-HCT cycles of chemotherapy. The standardized incidence ratio for the entire cohort, compared with the age-, sex-, and calendar year-matched general population, was 1.75. allo-HCT conditioning that includes low-dose TBI does not seem to increase risk of SMs compared with chemotherapy-alone conditioning.

Spectrum of BRCA1/2 variants in 940 patients from Argentina including novel, deleterious and recurrent germline mutations: impact on healthcare and clinical practice.

BRCA1/2 mutations in Latin America are scarcely documented and in serious need of knowledge about the spectrum of BRCA pathogenic variants, information which may alter clinical practice and subsequently improve patient outcome. In addition, the search for data on testing policies in different regions constitutes a fundamental strength for the present study, which analyzes BRCA1/2 gene sequences and large rearrangements in 940 probands with familial and/or personal history of breast/ovary cancer (BOC). In non-mutated DNA samples, Multiplex Ligation-dependent Probe Amplification assays (MLPA) were used for the analysis of large rearrangements. Our studies detected 179 deleterious mutations out of 940 (19.04%) probands, including 5 large rearrangements and 22 novel mutations. The recurrent mutations accounted for 15.08% of the total and only 2.87% of the probands analyzed, very different from a Hispanic panel previously described. IN CONCLUSION: a) this first comprehensive description of the spectrum in BRCA1/2 sheds light on the low frequency of recurrent mutations; b) this information is key in clinical practice to select adequate sequencing studies in our population, subsequently improve patient outcome and prevent damage associated to false normal reports resulting from the use of invalid population panels; c) panels of mutations from other populations should be cautiously validated before imported, even those of apparently similar origin, a concept to be considered beyond significance in Argentina.

Corrigendum: ADHD Rehabilitation through Video Gaming: A Systematic Review Using PRISMA Guidelines of the Current Findings and the Associated Risk of Bias.

[This corrects the article on p. 151 in vol. 6, PMID: 26557098.].

Lynch syndrome in South America: past, present and future.

After decades of unawareness about Lynch syndrome, the medical community in South America is increasingly interested and informed. The visits and support of mentors like H. T. Lynch had been crucial to this awakening. Several countries have at least one registry with skilled personnel in genetic counseling and research. However, this only represents a very restricted resource for the region. According to the GETH, there are 27 hereditary cancer care centers in South America (21 in Brazil, 3 in Argentina, 1 in Uruguay, 1 in Chile and 1 in Peru). These registries differ in fundamental aspects of function, capabilities and funding, but are able to conduct high quality clinical, research and educational activities due to the dedication and personal effort of their members, and organizational support. More support from the governments as well as the participation of the community would boost the initiatives of people leading these groups. Meantime, the collaboration among the South American registries and the involvement of registries and leaders from developed countries will allow to maximize the efficiency in caring for affected patients and their families. The aim of this article is to describe how the knowledge of LS began to be spread in South America, how the first registries were organized and to summarize the current state of progress. In addition, we will provide an update of the clinical and molecular findings in the region.

ADHD Rehabilitation through Video Gaming: A Systematic Review Using PRISMA Guidelines of the Current Findings and the Associated Risk of Bias.

Empirical research studies have highlighted the need to investigate whether video game can be useful as a tool within a neuropsychological rehabilitation program for attention deficit hyperactivity disorder (ADHD) patients. However, little is known about the possible gains that this kind of video game-based interventions can produce and even if these gains can be transferred to real life abilities. The present paper aims to uncover key information related to the use of video game in ADHD neuropsychological rehabilitation/intervention by focusing on its gains and its capability to transfer/generalize these gains to real life situation via a systematic review of the empirical literature. The PRISMA guidelines were adopted. Internet-based bibliographic searches were conducted via seven major electronic databases (i.e., PsycARTICLES, PsycINFO, Web of Science, Core Collection BIOSIS Citation Index, MEDLINE, SciELO Citation Index, and PubMed) to access studies examining the association between video game interventions in ADHD patients and behavioral and cognitive outcomes. A total of 14 empirical studies meeting the inclusion criteria were identified. The studies reported the attention, working memory, and the behavioral aspects as the main target of the intervention. Cognitive and behavioral gains were reported after the video game training (VGT). However, many bias related to the choice of outcome instruments, sampling and blindness of assessors, weaken the results power. Additional researches are important to clarify the effects and stability of the VGT programs, and an important effort should be made to construct better methods to assess improvements on everyday cognitive abilities and real world functioning.

Censo de recursos humanos y recursos moleculares para diagnóstico y evaluación de cáncer hereditario en Argentina / Survey of Human and Molecular resources for diagnosis and evaluation of hereditary cancer in Argentina

INTRODUCCION: El Instituto Nacional del Cáncer ha realizado un Censo de Recursos Humanos y Moleculares en Cáncer Hereditario. OBJETIVOS: Identificar y categorizar consultorios deasesoramiento genético oncológico y laboratorios que realizan estudiosmoleculares en Argentina para elaborar estrategias tendientes a mejorar la detección y manejo de los tumores de alto riesgo más frecuentes, como cáncer de mama y cáncer colorrectal hereditarios. METODOS: Se relevaron 187 instituciones públicas y privadas detodo el país y como recurso para el relevamiento se consultaron basesde datos nacionales. RESULTADOS: Se identificaron 44 consultorios de asesoramiento genético y 25 laboratorios. Dos tercios de las entidades incluidas fueron privadas y un tercio, públicas. Todas las prestaciones se concentraban en 9 de las 24 jurisdicciones. El 94% de las instituciones públicas ofrecían asesoramiento mediante profesionales especializados, mientras que el 43% de las instituciones privadas no tenían profesionales especializados a cargo dela consulta. En los laboratorios relevados se realizan determinacionespara 15 síndromes, 25 genes y 2 entidades no sindrómicas.CONCLUSIONES: Los recursos humanos y moleculares relevados son heterogéneos en su distribución geográfica y muestran una amplia variabilidad en las prestaciones proporcionadas.

INTRODUCTION: The National Cancer Institute of Argentina has developed a national Survey of Human and Molecular Hereditary Cancer Resources. OBJECTIVES: To identify and categorize cancer genetic counseling clinics andlaboratories performing molecular studies as the basis for public health strategies to improve detection and management of the most frequent hereditary cancers, like breast andcolorectal ones. METHODS: A total of 187 public and private institutions around the country were surveyed and as a resource for mapping national databases were consulted. RESULTS: A total of 44 genetic counseling clinics and 25 laboratories were identified. Two-thirds of the institutions are private and one-third, public. All services are concentrated in 9 of the 24 jurisdictions. While 94% of the public institutionsoffer counseling by specialized professionals, 43% of the private institutions do not have specialized professionals in charge of that area. Determinations for 15 syndromes,25 different genes and 2 non-syndromic entities are made. CONCLUSIONS: The surveyed human and molecular resources are heterogeneous in their distribution and show a wide variability in the services provided.

Whole-genomic survey of oligodendroglial tumors: correlation between allelic imbalances and gene expression profiles.

Malignant gliomas are the most common subtype of primary central nervous system (CNS) tumors. Their pathological classification, however, remains subjective, stimulating researchers to actively seek objective molecular markers to discover alternative and more reproducible tools for improved subtypification. Herein, we present a global survey of genomic alterations in oligodendroglial tumors (OT). Genetic and epigenetic alterations identified in this study are correlated with OT molecular groups we have recently reported: a neurogenic group composed of tumors with loss of heterozygosity (LOH) at 1p-19q, IDH1 mutations, and MGMT promoter methylation, showing good prognosis; an intermediate group, presenting TP53 mutations or LOH at 17p, IDH1 mutations, and GSTP1 promoter methylation; and a proliferative group, presenting major genetic alterations (LOH at 10q, EGFR amplification, and CDKN2A/ARF deletion) and poor prognosis. These results allowed us to refine our molecular characterization associated with prognosis, referring exclusively to oligodendroglial tumors.

Loss of heterozygosity at 1p-19q induces a global change in oligodendroglial tumor gene expression.

Oligodendroglial tumors presenting loss of heterozygosity (LOH) at 1p and 19q have been shown to be sensitive to chemotherapy, thus making 1p-19q status testing a key aspect in oligodendroglioma diagnosis and prognosis. Twenty-nine tumor samples (19 oligodendrogliomas, 10 oligoastrocytomas) were analyzed in order to obtain a molecular profile identifying those bearing 1p-19q LOH. Other genomic anomalies usually present in gliomas, such as EGFR amplification, CDKN2A/ARF deletion, 10q LOH and TP53 mutation, were also studied. Tumors with 1p-19q LOH overexpressed genes related to neurogenesis. Genes linked to immune response, proliferation and inflammation were overexpressed in the group with intact 1p-19q; this group could in turn be further divided in two subgroups: one overexpressing genes involved in immune response and inflammation that did not show major genetic aberrations other than the TP53 mutation and EGFR trisomy in a few cases, and another overexpressing genes related to immune response and proliferation that had a predominance of samples carrying several anomalies and presenting worse outcomes. This molecular signature was validated by analyzing a set of ten tumor samples (three oligodendrogliomas, seven oligoastrocytomas); all ten samples were correctly assigned. LOH at 1p-19q results in haploinsufficiency and copy number reduction of several genes, including NOTCH 2; this phenomenon produces a global change in gene expression inducing a pro-neural status that results in restrictions to cell migration and proliferation. Tumors without LOH at 1p-19q exhibit the opposite characteristics, explaining their more aggressive behavior.