No abstract

RESUMENEl trauma cerebral es un problema de salud pública significativo. La relación neuroinmunológica se altera con el trauma, lo que puede desencadenar una respuesta inmunológica innata local y sistémica que pone en riesgo la evolución favorable del paciente. El objetivo de esta revisión es describir las reacciones inmunológicas que se han observado en pacientes con lesión cerebral por trauma y relacionarlas con intervenciones anestésicas que pudieran modularlas.

Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant disease that represents approximately 5-10% of all patients with breast cancer. This syndrome is mainly associated to high risk pathogenic alleles in BRCA1/2 genes, but only for 25% of HBOC cases. More than 25 genes have been associated with familial breast and/or ovarian cancer and still more are expected to emerge. In the Mexican population there have been some efforts to analyze this syndrome, but they are limited to BRCA genes. This work aims to find new pathogenic alleles in exonic and splice sites in a panel of 143 cancer-predisposing genes in 309 Mexican cancer patients with suspicion of HBOC and 27 non-cancer patients with a severe family history of cancer, using massive parallel sequencing technology. In the group of cancer patients 14.6% (45/309) had pathogenic variants, 23.9% (74/309) harbored variants with unknown clinical significance (VUS) and 61.5% (109/309) were negative. The genes most frequently affected with pathogenic variants were BRCA2 24.4% (11/45), BRCA1 8.9% (4/45), MSR1 4.4% (2/45), ATM 4.4% (2/45), PDE11A 4.4% (2/45) and FANCI 4.4% (2/45). The non-cancer group had a 18.5% (5/27) of patients with pathogenic variants and 81.5% (22/27) were negative. In this group pathogenic variants were found in BRCA2, FANCF, PDE11A, POLH and WRN. Private or ultra-rare variants defined as VUS (ClinVar, deleterious in SIFT/Polyphen2, less than 0.001% in ExAC/1KG/ESP6500) were found in 53 genes. This study demonstrates that there is a higher contribution of pathogenic alleles in other susceptibility cancer genes (66.7%) than BRCA1/2 (33.3%), confirming that clinical sequencing of expanded gene panels will identify new, rare and private, variants and eventually will translate in better molecular diagnosis and personalized risk assessment in carriers. Clinical impact of the VUS identified here must be further evaluated. This work was supported by the National Autonomous University of Mexico, PAPIIT (IA204215). Citation Format: Felipe Vaca-Paniagua, Rosalía Quezada-Urban, Clara Díaz-Velásquez, Rina Gitler, Gabriela Torres-Mejia, Maria Patricia Rojo-Castillo, Max Sirota-Toporek, Andrea Figueroa-Morales, Oscar Moreno-García, Ivan Delgado-Enciso, Victor Hugo Garzón-Barrientos, Nayeli Lizbeth García-Esquivel, Ernesto Arturo Rojas-Jiménez, Héctor Gregorio-Martínez, Luis Ignacio Terrazas. Pathogenic germline variants in Mexican patients with hereditary breast and ovarian cancer syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4275. doi:10.1158/1538-7445.AM2017-4275

Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant disease that represents approximately 5-10% of all patients with breast cancer. This syndrome is mainly associated to high-risk pathogenic alleles in BRCA1 and BRCA2 genes, but only for 25% of HBOC cases. This work aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 31 non-cancer patients with a severe family history of cancer, using massive parallel sequencing. We found 15% (45/300) patients with pathogenic variants in the group of cancer patients; 12% (35/300) harbored variants with unknown clinical significance (VUS) and 73% (220/300) were negative. The non-cancer group had a 32% (10/31) of patients with pathogenic variants, 3% (1/31) had VUS and 65% (20/31) were negative. Moreover, the most recurrent mutation was the Mexican founder deletion of exons 9-12 in BRCA1, found in 5 of 16 cancer patients with alterations in this gene. Private or rare VUS variants with potential impact at protein level were found in 22 genes, being CHEK2 the one with most VUS (6/39). Noteworthy, our results show for the first time in the Mexican population an equal contribution of pathogenic alleles in other susceptibility cancer genes (50%) as in BRCA1/2 (50%). This highlights the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to broader gene panels. Further studies need to be conducted to define the clinical impact of the pathogenic alleles and VUS identified. Citation Format: Felipe Vaca-Paniagua, Rosalía Quezada-Urban, Clara E. Díaz-Velásquez, Rina Gitler, María P. Rojo-Castillo, Max Sirota-Toporek, Andrea Figueroa-Morales, Oscar Moreno-García, Lizbeth García Esquivel, Gabriela Torres-Mejía, Michael Dean, Ivan Delgado-Enciso, Héctor Ochoa-Díaz-López, Fernando Rodriguez-León, Virginia Jan, Victor H. Hugo Garzón-Barrientos, Pablo Ruiz-Flores, Perla K. Espino-Silva, Jorge Haro-Santa Cruz, Héctor Martínez-Gregorio, Ernesto Rojas-Jiménez, Rosa M. Álvarez-Gómez, Luis A. Herrera, Isabelle Romieu, Luis I. Terrazas, Yolanda I. Chirino, Cecilia Frecha, Javier Oliver, Sandra Perdomo. Comprehensive analysis of germline variants in Mexican patients with hereditary breast and ovarian cancer susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1240.

Breast cancer is the neoplastic disease with the highest incidence and mortality worldwide and nearly 10% of the cases are due to inherited pathogenic alleles in cancer predisposing genes such as BRCA1 and BRCA2. However, the spectrum of inherited breast cancer susceptibility not caused by BRCA1/2 pathogenic alleles has not been explored in the Mexican population. In this work we evaluated the presence of germline pathogenic alleles in the coding sequence and splice sites of 143 cancer susceptibility genes in 69 Mexican female patients with cancer that were selected for family cancer history. Inclusion criteria followed the guidelines of the National Comprehensive Cancer Network for Genetic/Familial High-Risk Assessment of Breast and Ovarian Cancer. Data from international databases of normal populations and cancer patients, as well as annotation information and technical parameters were used to define pathogenic variants. The genes with the highest frequency of pathogenic alleles (stopgain/loss, frameshift indels) were BRCA1 (8.7%, 6/69), BRCA2 (2.9%, 2/69), FANCC (2.9%), MSR1 (2.9%), FANCL (1.4%, 1/69), SDHB (1.4%) and TSC2 (1.4%). New or rare missense variants with unknown clinical significance (VUS), but defined as pathogenic in ClinVar or by algorithms assessing evolutionary conservation and deleterious structural changes at protein level, were found in single patients in the genes AIP, ANTXR1, APC, ATR, CD96, CYP21A2, ERCC3, ERCC6, FANCA, FANCB, FANCE, LIG4, LYST, MSH6, MSR1, MTAP, PDE11A, PDGFRA, PMS2, POLE, PTCH1, RAD50, RHBDF2, RUNX1 and WRN. These patients did not have pathogenic alleles, suggesting a potential contribution of these VUS to disease susceptibility. This work contributes to identify new susceptibility alleles that can predispose to hereditary breast cancer in the Mexican population. Further studies need to be conducted to define the clinical impact of the VUS identified here, which together with international efforts will better define genetic susceptibility to breast cancer. This work was supported by the National Autonomous University of Mexico, PAPIIT (IA204215). Citation Format: Felipe Vaca-Paniagua, Rosalía Quezada-Urban, Clara Estela Díaz-Velásquez, Rina Gitler, María Patricia Rojo-Castillo, Max Sirota-Toporek, Andrea Figueroa-Morales, Oscar Moreno-García, Fernando Mainero-Ratchelous, Lizzette Sabrina De Hoyos-Arévalo, Ivan Delgado-Enciso, Victor Hugo Garzón-Barrientos, Luis Ignacio Terrazas. Identification of germline pathogenic alleles in 143 cancer predisposing genes in Mexican patients with hereditary breast cancer by massive parallel sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2545.