Deep DNA sequencing of MGMT, TP53 and AGT in Mexican astrocytoma patients identifies an excess of genetic variants in women and a predictive biomarker.

PURPOSE: Astrocytomas are a type of malignant brain tumor with an unfavorable clinical course. The impact of AGT and MGMT somatic variants in the prognosis of astrocytoma is unknown, and it is controversial for TP53. Moreover, there is a lack of knowledge regarding the molecular characteristics of astrocytomas in Mexican patients. METHODS: We studied 48 Mexican patients, men and women, with astrocytoma (discovery cohort). We performed DNA deep sequencing in tumor samples, targeting AGT, MGMT and TP53, and we studied MGMT gene promoter methylation status. Then we compared our findings to a cohort which included data from patients with astrocytoma from The Cancer Genome Atlas (validation cohort). RESULTS: In the discovery cohort, we found a higher number of somatic variants in AGT and MGMT than in the validation cohort (10.4% vs < 1%, p < 0.001), and, in both cohorts, we observed only women carried variants AGT variants. We also found that the presence of either MGMT variant or promoter methylation was associated to better survival and response to chemotherapy, and, in conjunction with TP53 variants, to progression-free survival. CONCLUSIONS: The occurrence of AGT variants only in women expands our knowledge about the molecular differences in astrocytoma between men and women. The increased prevalence of AGT and MGMT variants in the discovery cohort also points towards possible distinctions in the molecular landscape of astrocytoma among populations. Our findings warrant further study.

Landscape of Germline Genetic Variants in AGT, MGMT, and TP53 in Mexican Adult Patients with Astrocytoma.

Astrocytoma is the most common type of primary brain tumor. The risk factors for astrocytoma are poorly understood; however, germline genetic variants account for 25% of the risk of developing gliomas. In this study, we assessed the risk of astrocytoma associated with variants in AGT, known by its role in angiogenesis, TP53, a well-known tumor suppressor and the DNA repair gene MGMT in a Mexican population. A case-control study was performed in 49 adult Mexican patients with grade II-IV astrocytoma. Sequencing of exons and untranslated regions of AGT, MGMT, and TP53 from was carried in an Ion Torrent platform. Individuals with Mexican Ancestry from the 1000 Genomes Project were used as controls. Variants found in our cohort were then assessed in a The Cancer Genome Atlas astrocytoma pan-ethnic validation cohort. Variants rs1926723 located in AGT (OR 2.74, 1.40-5.36 95% CI), rs7896488 in MGMT (OR 3.43, 1.17-10.10 95% CI), and rs4968187 in TP53 (OR 2.48, 1.26-4.88 95% CI) were significantly associated with the risk of astrocytoma after multiple-testing correction. This is the first study where the AGT rs1926723 variant, TP53 rs4968187, and MGMT rs7896488 were found to be associated with the risk of developing an astrocytoma.

[The woman in neurosurgery at the national institute of neurology and neurosurgery]. / La mujer en neurocirugía en el Instituto Nacional de Neurología y Neurocirugía (INNN).

Women have always had a hard time in the history of medicine; Dr. Isabel Blackwell was the first woman in history to practice medicine. Dr. Diana Beck became the world´s first female neurosurgeon. The first Latin American female neurosurgeon was Dr. María Cristina García Sancho y Álvarez-Tostado. All of these women had to face a large number of social, cultural, and economic obstacles in their path; however, this situation has changed gradually. Dr. Ana Lilia Siordia Karam was the first neurosurgeon to graduate from INNN. Nineteen years later the second female neurosurgeon at this institute was Dr. María Petra Herrera Guerrero. During their time at this institute they endured a lot of difficulties, especially with most of their coworkers; however, some coworkers treated them with respect and no gender distinction. Nowadays, four of the 25 total neurosurgery residents at INNN are women, and even though some of them have had to endure acts of gender discrimination, the general situation has changed. With work and respect, women have managed to have a larger role in the surgical field. We hope that in the near future a gender discrimination-free environment will be achieved in medicine and its specialties.

Subtemporal approach for the resection of a midbrain cavernous malformation: evaluation of safe surgical corridors.

Brainstem cavernous malformation management is complex due to its critical location and deleterious effect when bleeding. Therefore, every case should be thoroughly analyzed preoperatively. We present the case of a female patient with a midbrain cavernous malformation. A comprehensive anatomical and clinical analysis of the surgical corridors is done to decide the safest route. A subtemporal approach was done and the lateral mesencephalic sulcus and vein were important anatomical landmarks to guide the safe entry zone. Nuances of technique and surgical pearls related to the safe entry zones of the midbrain are discussed and illustrated in this operative video. The video can be found here: https://youtu.be/vYA-IgiT2lU.

Angiotensinogen rs5050 germline genetic variant as potential biomarker of poor prognosis in astrocytoma.

INTRODUCTION: Renin-angiotensin system (RAS) in brain cancer represents a scarcely explored field in neuro-oncology. Recently, some pre- and clinical studies have reported that RAS components play a relevant role in the development and behavior of gliomas. The angiotensinogen (AGT) rs5050 genetic variant has been identified as a crucial regulator of the transcription of AGT mRNA, which makes it a logical and promising target of research. The aim of this study was to determine the relationship between the AGT rs5050 genetic variant in blood with prognosis in astrocytoma. METHODS: A prospective pilot study was performed on forty-eight astrocytoma patients, who received the standard-of-care treatment. Blood samples were taken prior to surgery and DNA was sequenced using Ion Torrent next-generation sequencing and analyzed by Ion Reporter software. Descriptive, bivariate, multivariate, and survival analyses were performed using SPSS v21, STATA 12 and GraphPad Prism 7. RESULTS: Median follow-up was 41 months (range 1-48). Survival analysis showed a significant difference between the rs5050 genotypes (p = .05). We found lower survival rates in individuals with the GG-genotype of rs5050 AGT compared to patients with the TT- and TG-genotype (2 months vs. 11.5 months, respectively [p = .01]). In bivariate and multivariate analyses, GG-genotype was negatively associated with survival. CONCLUSIONS: In patients with astrocytoma, AGT rs5050 GG-genotype was associated with poor prognosis. We propose this germline genetic variant as a complementary biomarker, which can be detected practically and safely in blood samples or saliva.