Regulators of genetic risk of breast cancer identified by integrative network analysis.

Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network comprising transcription factors and groups of putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via expression quantitative trait loci (eQTLs). We identified 36 overlapping regulons that were enriched for risk loci and formed a distinct cluster within the network, suggesting shared biology. The risk transcription factors driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to estrogen receptor (ER)(+) luminal A or luminal B and ER(-) basal-like cancers and to different luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation for determining the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.This work was funded by Cancer Research UK and the Breast Cancer Research Foundation. MAAC is funded by the National Research Council (CNPq) of Brazil. TEH held a fellowship from the US DOD Breast Cancer Research Program (W81XWH-11-1-0592) and is currently supported by an RAH Career Development Fellowship (Australia). TEH and WDT are funded by the NHMRC of Australia (NHMRC) (ID: 1008349 WDT; 1084416 WDT, TEH) and Cancer Australia/National Breast Cancer Foundation (ID 627229; WDT, TEH). BAJP is a Gibb Fellow of Cancer Research UK. We would like to acknowledge the support of The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345

Immunotherapy with checkpoint inhibitors for lung cancer: novel agents, biomarkers and paradigms

Despite recent advances, prognosis of patients with advanced lung cancer remains dismal. Owing to a better understanding of the interactions between immune system and tumor cells, immunotherapy has emerged as a promising therapeutic strategy. After the recent approval of nivolumab and the promising results with other immune checkpoint inhibitors, combination strategies are now subject of intensive research. Notwithstanding these successes, immunotherapy still holds significant drawbacks. As the target shifts from tumor cells to the tumor microenvironment, treatment paradigms are changing and several improvements are needed for optimal use in clinical practice. Robust biomarkers for patient selection and a reliable way of evaluating treatment response are high priorities. Herein we review current data on immune checkpoint inhibitors for lung cancer treatment

Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling

Hodgkin lymphoma (HL) is a malignancy of unknown pathogenesis. The malignant Hodgkin and Reed/Sternberg (HRS) cells derive from germinal center B cells (or rarely, T cells) but have a heterogeneous and largely uncharacterized phenotype. Using microarrays, we compared the gene expression profile of four HL cell lines with profiles of the main B cell subsets and B cell non-HLs to find out whether HRS cells, despite their described heterogeneity, show a distinct gene expression, to study their relationship to other normal and malignant B cells, and to identify genes aberrantly or overexpressed by HRS cells. The HL lines indeed clustered as a distinct entity, irrespective of their B or T cell derivation, and their gene expression was most similar to that of EBV-transformed B cells and cell lines derived from diffuse large cell lymphomas showing features of in vitro–activated B cells. Twenty-seven genes, most of which were previously unknown to be expressed by HRS cells, showed aberrant expression specifically in these cells, e.g., the transcription factors GATA-3, ABF1, EAR3, and Nrf3. For five genes, expression in primary HRS cells was confirmed. The newly identified HL-specific genes may play important roles in the pathogenesis of HL, potentially represent novel diagnostic markers, and can be considered for therapeutic targeting

¿Es posible el diagnóstico de la neoplasia folicular no invasiva con características nucleares de tipo de carcinoma papilar de tiroides (NIFTP) en nuestro medio?

Introducción: La variante folicular encapsulada no invasiva del carcinoma papilar detiroides (CPT) se re-clasificó como neoplasia folicular de tiroides no invasiva concaracterísticas nucleares de tipo papilar (NIFTP). Estos tumores se consideran comoneoplasias de muy bajo potencial maligno, con riesgo casi nulo de recurrencia ymortalidad. Objetivos: i) valorar la prevalencia de NIFTP en pacientes con CPT, ii) evaluar laevolución de los mismos y, iii) determinar las alteraciones moleculares halladas en estetipo de neoplasia.Materiales y Métodos: Estudio multicéntrico retrospectivo, observacional,longitudinal, que incluyó a pacientes con diagnóstico de CPT mayores de 18 añospertenecientes a 11 centros asistenciales de Argentina, diagnosticados entre el 1 deenero de 2006 y el 31 de diciembre de 2016. El diagnóstico de NIFTP se efectuó segúnlos criterios referidos por Nikiforov en el año 2016 y fue confirmado por al menos dospatólogos. Se incluyeron 2677 muestras de pacientes con diagnóstico de carcinomapapilar de tiroides. De estos, 612 (22%) fueron carcinoma papilar variante folicular y33 (1,23%) reunieron criterios diagnósticos de NIFTP. Resultados: De las 2677 muestras analizadas, se diagnosticó NIFTP en 33 pacientes(1,23%), el total de pacientes evaluados habían sido tratados con tiroidectomía total y el51% recibió ablación con radioyodo (mediana 100 mCi). Ningún paciente presentómetástasis ganglionares, a distancia, o necesidad de re-intervención quirúrgica. Luegode un seguimiento promedio de 30,5 meses, la respuesta final se consideró excelente enel 82% y 3% presentó una respuesta indeterminada. En 5 casos (15%) no huboseguimiento para establecer respuesta. Se observaron mutaciones de RAS en 4 (17%) yde BRAF V600E en 3 (13%). Conclusiones: La prevalencia de NIFTP en esta serie se encuentra dentro de las másbajas reportadas. La respuesta excelente al tratamiento en la mayoría de pacientes conseguimiento confirma el carácter indolente de estos tumores. Los hallazgos molecularesdifieren de lo publicado, lo que podría deberse a particularidades geográficas y/o étnicas.Introduction: Non-invasive encapsulated follicular variant of papillary thyroid cancer was reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in 2016. These neoplasms have an extremely low potential of malignancy. Objectives: i) to assess the prevalence of NIFTP in patients with papillary thyroid carcinoma, ii) to evaluate their outcomes and iii) to determine their molecular profile. Materials and methods: Multicenter, descriptive, retrospective study. Patients from 11 referral centers with papillary thyroid cancer diagnosed from January 2006 to December 2016 were included. Diagnosis of NIFTP was based on criteria described by Nikiforov in 2016. At least two pathologists agreed on the diagnosis. Two thousand six hundred and seventy seven patients with papillary thyroid cancer were included; 612 (22%) of them were follicular variant papillary thyroid cancer, and 33 (1.23%) were classified as NIFTP. Results: Thirty three patients (1.23%) fulfilled diagnostic criteria for NIFTP. All patients underwent total thyroidectomy, and 51% were treated with radioiodine (median dose 100 mCi). No metastatic lymph nodes, distant metastases or recurrences were found. After a mean follow up of 30.5 months, 82% of patients had an excellent response, 3% had an indeterminate response and data was missing in the remaining 15%. RAS mutations were detected in 4 patients (17%) and BRAF V600E in 3 (13%). Discussion: The prevalence of NIFTP in our series is among the lowest reported. Excellent outcomes of patients underscore their low malignant potential. However, molecular findings differ from other series, which may be related to environmental or ethnic features of our population.Fil: Saban, Melina. Hospital Británico de Buenos Aires; ArgentinaFil: Orlandi, Ana Maria. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Deutsch, Susana I. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Pitoia, Fabián. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Lowenstein, Alicia Edita. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Calabrese, M. C.. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Cavallo, Andrea. Hospital de Alta Complejidad de Formosa; ArgentinaFil: Lotti, Alejandro. Hospital Británico de Buenos Aires; ArgentinaFil: Mosnteros Albi, M.. Hospital Dr. Arturo Oñativia - Salta Capital.; ArgentinaFil: Tolaba, N. Hospital Dr. Arturo Oñativia - Salta Capital.; ArgentinaFil: Nallar Dera, Marcelo. Hospital Dr. Arturo Oñativia - Salta Capital.; ArgentinaFil: Jaen, A.. Hospital Italiano; ArgentinaFil: Figurelli, Silvina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Carrizo, F.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Colobraro, A.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Garcia Tascon, G.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Saccoliti, M.. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital General de Agudos Carlos Durand.; ArgentinaFil: Paes de Lima, A.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Lencioni, María Julia. Hospital de Alta Complejidad de Formosa; ArgentinaFil: Califano, Ines. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Cabezon, C.. Hospital Italiano; ArgentinaFil: Abelleira, E.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Alcaraz, G.. Hospital Privado Universitario de Córdoba; ArgentinaFil: Brenta, Gabriela. Hospital Cesar Milstein; ArgentinaFil: Bielski, Laila. Sanatorio Guemes Sociedad Anonima.; ArgentinaFil: Castro Jozami, Lorena. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Corino, M.. Hospital Italiano; ArgentinaFil: Faure, Eduardo. Complejo Medico Policial Bartolome Churruca Andres Visca; ArgentinaFil: Frascaroli, G.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Gauna, Alicia Teresa. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Guerra, Jorgelina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Gutierrez, S.. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital General de Agudos Carlos Durand.; ArgentinaFil: Ilera, Veronica. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Iorcansky, S.. Hospital Italiano; ArgentinaFil: Martinez, Maria Paz. Hospital Alemán; ArgentinaFil: Moldes, Sofia. Complejo Medico Policial Bartolome Churruca Andres Visca; ArgentinaFil: Negueruela, M.. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Oneto, A.. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital General de Agudos Carlos Durand.; ArgentinaFil: Parisi, Carina. Hospital Italiano; ArgentinaFil: Reyes, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Rosemblit, Cinthia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Russo Picasso, Maria Fabiana. Hospital Italiano; ArgentinaFil: Salas, Monica Delia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Sartorio, Mariana Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Schnitman, M.. Hospital Italiano; ArgentinaFil: Sklate, Roxana. Hospital Tornu; ArgentinaFil: Croome, Silva. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Storani, Maria Elena. Municipalidad de Vicente Lopez (buenos Aires); ArgentinaFil: Vazquez, A.. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital General de Agudos Carlos Durand.; ArgentinaFil: Zund, Santiago. Centro de Educaciones Médicas e Investigación Clínica "Norberto Quirno"; ArgentinaFil: Zunino, A.. Gobierno de la Ciudad de Buenos Aires; Argentin