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The prevalence and contribution of BRCA1/2 (BRCA) pathogenic variants (PVs) to the cancer burden in Latin America are not well understood. This study aims to address this disparity. BRCA analyses were performed on prospectively enrolled Latin American Clinical Cancer Genomics Community Research Network participants via a combination of methods: a Hispanic Mutation Panel (HISPANEL) on MassARRAY; semiconductor sequencing; and copy number variant (CNV) detection. BRCA PV probability was calculated using BRCAPRO. Among 1,627 participants (95.2% with cancer), we detected 236 (14.5%) BRCA PVs; 160 BRCA1 (31% CNVs); 76 BRCA2 PV frequency varied by country: 26% Brazil, 9% Colombia, 13% Peru, and 17% Mexico. Recurrent PVs (seen ≥3 times), some region-specific, represented 42.8% (101/236) of PVs. There was no ClinVar entry for 14% (17/125) of unique PVs, and 57% (111/196) of unique VUS. The area under the ROC curve for BRCAPRO was 0.76. In summary, we implemented a low-cost BRCA testing strategy and documented a significant burden of non-ClinVar reported BRCA PVs among Latin Americans. There are recurrent, population-specific PVs and CNVs, and we note that the BRCAPRO mutation probability model performs adequately. This study helps address the gap in our understanding of BRCA-associated cancer in Latin America.

Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.

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.

Denisse Arcos-Montoya,1 Talia Wegman-Ostrosky,2,3 Sonia Mejía-Pérez,4 Marisol De la Fuente-Granada,1 Ignacio Camacho-Arroyo,5 Alejandro García-Carrancá,6 Marco A Velasco-Velázquez,7 Joaquín Manjarrez-Marmolejo,8 Aliesha González-Arenas1 1Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, México; 2Dirección de Investigación, Instituto Nacional Cancerología, Ciudad de México, México; 3División de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México, México; 4Subdirección de Neurocirugía, Instituto Nacional de Neurología y Neurocirugía, Ciudad de México, México; 5Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, México; 6Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México e Instituto Nacional de Cancerología, Ciudad de México, México; 7Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, México; 8Laboratorio de Fisiología de la Formación Reticular, Instituto Nacional de Neurología y Neurocirugía, Ciudad de México, MéxicoCorrespondence: Aliesha González-ArenasDepartamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, 04510, MéxicoTel +52 5556 22 9209Email alieshag@iibiomedicas.unam.mxIntroduction: Astrocytomas are the most common and aggressive primary brain tumors, and they are classified according to the degree of malignancy on a scale of I to IV, in which grade I is the least malignant and grade IV the highest. Many factors are related to astrocytomas progression as progesterone receptor (PR), whose transcriptional activity could be regulated by phosphorylation by protein kinase C alpha (PKCα) at the residue Ser400. Our aim was to investigate if PR phosphorylation together with PKCα expression could be used as a prognostic factor for astrocytomas malignancy.Methods: By immunofluorescence, we detected the content of PKCα, PR and its phosphorylation at Ser400 in 46 biopsies from Mexican patients with different astrocytoma malignancy grades; by bioinformatic tools using TCGA data, we evaluated the expression of PR and PKCα mRNA according to astrocytoma malignancy grades. For all statistical analyses, significance was p< 0.05.Results: We detected a positive correlation between the tumor grade and the content of PKCα, PR and its phosphorylation at Ser400, as well as the intracellular colocalization of these proteins. Interestingly, using an in silico assay, we found that the PR and PKCα expression at mRNA level has an inverse ratio with astrocytomas tumor grade.Discussion: These results indicate that PR and its phosphorylation at Ser400 site, as well as PKCα and their colocalization, could be considered as possible malignancy biomarkers for astrocytomas grades I–IV.Keywords: astrocytoma, glioblastoma, progesterone receptor, protein kinase C alpha, biomarker

Summary Background Li-Fraumeni syndrome, caused primarily by pathogenic or likely pathogenic germline TP53 variants, is a rare, variably penetrant, cancer predisposition syndrome with very high risks of cancer starting in childhood, including the risk of multiple primary malignancies over an individual's lifespan. We aimed to characterise and quantify cancer incidence, patterns, and genotype–phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants. Methods This observational cohort study was done in 480 carriers of pathogenic or likely pathogenic germline TP53 variants enrolled in the National Cancer Institute's referral-based longitudinal Li-Fraumeni syndrome study between Aug 1, 2011, and March 24, 2020. Data on personal and family history of cancer were obtained through study questionnaires and validated by medical records. Variants were categorised on the basis of both loss-of-function (LOF) and dominant-negative effect (DNE) properties. Cancer incidence associated with Li-Fraumeni syndrome was compared with that of the general population using the Surveillance, Epidemiology, and End Results (SEER) 1975–2017 registry. Cancer incidence was evaluated with family-clustered Cox regression models and competing risk methods. This study is registered with ClinicalTrials.gov , NCT01443468 . Findings Individuals with Li-Fraumeni syndrome had a nearly 24 times higher incidence of any cancer than the general population (standardised incidence ratio 23·9; 95% CI 21·9–26·0), with the highest comparative incidence from childhood to 30 years of age. The overall cancer incidence remained 10·3 (95% CI 7·9–13·2) times higher than that of the general population after age 50 years. In women, when considering breast cancer as a competing risk, the probability of a first diagnosis of a non-breast cancer malignancy was substantially lower than that of any first cancer (24·4% [95% CI 19·6–30·5] vs 50·4% [43·5–56·5] by age 33·7 years). Overall, DNE_LOF and notDNE_LOF variants were associated with earlier age at first and second cancer compared with notDNE_notLOF and DNE_notLOF variants. The time interval from first to second cancer was shorter among carriers whose first cancer diagnoses were later in life. Multiple cancers were diagnosed within a short timeframe in some individuals, regardless of the order of cancer occurrence. Interpretation This study adds granularity to the understanding of cancer incidence and patterns in individuals with pathogenic or likely pathogenic germline TP53 variants. Integration of age range-specific cancer incidence estimates, cancer-free survival by functional variant group, the potential impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancies will be important for the development of strategies to optimise cancer screening and management for these individuals. Funding Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Institutes of Health.

Cancer is a complex group of diseases that constitute the second largest cause of mortality worldwide. The development of new drugs for treating this disease is a long and costly process, from the discovery of the molecule through testing in phase III clinical trials, a process during which most candidate molecules fail. The use of drugs currently employed for the management of other diseases (drug repurposing) represents an alternative for developing new medical treatments. Repurposing existing drugs is, in principle, cheaper and faster than developing new drugs. Antihypertensive drugs, primarily belonging to the pharmacological categories of angiotensin-converting enzyme inhibitors, angiotensin II receptors, direct aldosterone antagonists, β-blockers and calcium channel blockers, are commonly prescribed and have well-known safety profiles. Additionally, some of these drugs have exhibited pharmacological properties useful for the treatment of cancer, rendering them candidates for drug repurposing. In this review, we examine the preclinical and clinical evidence for utilizing antihypertensive agents in the treatment of cancer.

PURPOSE Previous studies have shown an approximately two-fold elevation in the relative risk of urinary bladder cancer (UBC) among people with a family history that could not be entirely explained by shared environmental exposures, thus suggesting a genetic component in its predisposition. Multiple genome-wide association studies and recent gene panel sequencing studies identified several genetic loci that are associated with UBC risk; however, the list of UBC-associated variants and genes is incomplete. MATERIALS AND METHODS We exome sequenced eight patients from three multiplex UBC pedigrees and a group of 77 unrelated familial UBC cases matched to 241 cancer-free controls. In addition, we examined pathogenic germline variation in 444 candidate genes in 392 The Cancer Genome Atlas UBC cases. RESULTS In the pedigrees, segregating variants were family-specific although the identified genes clustered in common pathways, most notably DNA repair ( MLH1 and MSH2) and cellular metabolism ( IDH1 and ME1). In the familial UBC group, the proportion of pathogenic and likely pathogenic variants was significantly higher in cases compared with controls ( P = .003). Pathogenic and likely pathogenic variant load was also significantly increased in genes involved in cilia biogenesis ( P = .001). In addition, a pathogenic variant in CHEK2 (NM_007194.4:c.1100del; p.T367Mfs*15) was over-represented in cases (variant frequency = 2.6%; 95% CI, 0.71 to 6.52) compared with controls (variant frequency = 0.21%; 95% CI, 0.01 to 1.15), but was not statistically significant. CONCLUSION These results point to a complex polygenic predisposition to UBC. Despite heterogeneity, the genes cluster in several biologically relevant pathways and processes, for example, DNA repair, cilia biogenesis, and cellular metabolism. Larger studies are required to determine the importance of CHEK2 in UBC etiology.

Background Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study. Methods Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons. Results Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided P = 3 × 10-4). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including BRCA1/2, FH, PALB2, PMS2, and CDKN2A. A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (NF1, SUFU, TSC1, PTCH2), Wilms tumor (WT1, REST), non-Hodgkin lymphoma (PMS2), and soft tissue sarcomas (SDHB, DICER1, TP53, ERCC4, FGFR3) compared with other pediatric cancers. Conclusion In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.

PURPOSE Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS cohorts. MATERIALS AND METHODS Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort. RESULTS We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants ( ATM, CDKN1C) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with FOXO1 fusion–negative RMS patients versus the patients with FOXO1 fusion–positive RMS. We identified pathogenic germline variants in CSGs previously ( TP53, NF1, DICER1, mismatch repair genes), rarely ( BRCA2, CBL, CHEK2, SMARCA4), or never ( FGFR4) reported in RMS. Numerous genes ( TP53, BRCA2, mismatch repair) were on the ACMG Secondary Findings 2.0 list. CONCLUSION In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines.

In recent years, multiple biomarkers have emerged in the field of neuro-oncology, with useful applications in improving diagnostic accuracy, establishing patient’s prognosis and predictive response to available medical therapy. The most frequently associated biomarkers, and their respective alterations, include, IDH1/2 mutation, 1p/19q codeletion, ATRX loss, TP53 mutation, MGMT promoter methylation, BRAF and H3 mutations. In this chapter, we review these biomarkers, but also other less understood ones involved in the diagnosis, prognosis and the treatment of gliomas, such as ABC transporters, AGT mutations, G-CIMP mutation, PTEN mutation, among others. We also include two algorithms for molecular-based decision-making for pediatric and adult gliomas and tables with comprehensive information of biomarkers in gliomas.

Young women with breast cancer represent 15% of cancer cases in Latin America. Genomic studies have found that early-onset breast-cancer cases exhibit a higher genetic susceptibility and a specific genomic signature as compared to their older counterparts. The aim of this study was to describe clinically relevant germline mutations in a cohort of young women with breast cancer. To achieve this, we analyzed hereditary-cancer genes from whole-exome sequencing data in 108 unrelated women with an extreme phenotype of breast cancer (≤40 years of age), diagnosed and treated at the National Cancer Institute of Mexico; 11% of the patients carried a pathogenic variant. BRCA2 comprised 46% of the mutations, followed by BRCA1 with 23%; PALB2 with 15%; and TP53 and RAD51C with 8 % each. This article describes a novel pathogenic mutation in RAD51C c.519dupT. The median age at diagnosis was 35 years overall; however, it was six years younger in patients with mutations. Age at diagnosis (OR=0.82, CI 95% 0.71-0.94; P= 0.008) and first-degree family history of cancer (OR=8.26, CI95% 1.35-50; P= 0.022) were the only epidemiological variables associated with mutational status. We found no differences in disease-free survival (p=0.403) or overall survival (p=0.735) among mutational status subgroups.

Gliomas are the most common primary intrinsic tumor in the brain and are classified as low- or high-grade according to the World Health Organization (WHO). Patients with high-grade gliomas (HGG) who undergo surgical resection with adjuvant therapy have a mean overall survival of 15 months and 100% recurrence. The renin-angiotensin system (RAS), the primary regulator of cardiovascular circulation, exhibits local action and works as a paracrine system. In the context of this local regulation, the expression of RAS peptides and receptors has been detected in different kinds of tumors, including gliomas. The dysregulation of RAS components plays a significant role in the proliferation, angiogenesis, and invasion of these tumors, and therefore in their outcomes. The study and potential application of RAS peptides and receptors as biomarkers in gliomas could bring advantages against the limitations of current tumoral markers and should be considered in the future. The targeting of RAS components by RAS blockers has shown potential of being protective against cancer and improving immunotherapy. In gliomas, RAS blockers have shown a broad spectrum for beneficial effects and are being considered for use in treatment protocols. This review aims to summarize the background behind how RAS plays a role in gliomagenesis and explore the evidence that could lead to their use as biomarkers and treatment adjuvants.

Background Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8–5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982). Methods We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS). Results In the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers. Conclusion The 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls. Electronic supplementary material The online version of this article (10.1186/s13073-018-0607-5) contains supplementary material, which is available to authorized users.

The deletion of exons 9 to 12 of BRCA1 (9-12 del BRCA1) is considered a founder mutation in the Mexican population. We evaluate the usefulness of the target detection of 9-12 del BRCA1 as the first molecular diagnostic strategy in patients with Hereditary Breast and Ovarian Cancer (HBOC). We performed the genetic assessment of 637 patients with suspected HBOC. The region corresponding to the breakpoints for the 9-12 del BRCA1 was amplified by polymerase chain reaction (PCR). An analysis of the clinical data of the carriers and non-carriers was done, searching for characteristics that correlated with the deletion. The 9-12 del BRCA1 was detected in 5% of patients with suspected HBOC (30/637). In patients diagnosed with ovarian cancer, 13 of 30 were 9-12 del BRCA1 carriers, which represents 43%. We found a significant association between the 9-12 del BRCA1 carriers with triple negative breast cancer and high-grade papillary serous ovarian cancer. We concluded that the detection of the 9-12 del BRCA1 is useful as a first molecular diagnostic strategy in the Mexican population. In particular, it shortens the gap in genetic assessment in patients with triple negative breast cancer and ovarian cancer.

Background: Epigenetic aberrations lead to chemotherapy resistance; hence, their reversal by inhibitors of DNA methylation and histone deacetylases may overcome it. Patients and methods: Phase II, single-arm study of hydralazine and magnesium valproate added to the same schedule of chemotherapy on which patients were progressing. Schedules comprised cisplatin, carboplatin, paclitaxel, vinorelbine, gemcitabine, pemetrexed, topotecan, doxorubicin, cyclophosphamide, and anastrozole. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow, acetylators, and magnesium valproate at 40 mg/kg, beginning a week before chemotherapy. Response, toxicity, DNA methylation, histone deacetylase activity, plasma valproic acid, and hydralazine levels were evaluated. Results: Seventeen patients were evaluable for toxicity and 15 for response. Primary sites included cervix (3), breast (3), lung (1), testis (1), and ovarian (7) carcinomas. A clinical benefit was observed in 12 (80%) patients: four PR, and eight SD. The most significant toxicity was hematologic. Reduction in global DNA methylation, histone deacetylase activity, and promoter demethylation were observed. Conclusions: The clinical benefit noted with the epigenetic agents hydralazine and valproate in this selected patient population progressing to chemotherapy’ and re-challenged with the same chemotherapy schedule after initiating hydralazine and valproate’ lends support to the epigenetic-driven tumor-cell chemoresistance hypothesis (ClinicalTrials.gov Identifier: NCT00404508).

It is known that cell-free DNA circulates in plasma/serum of patients with cancer and that part of this DNA circulates as nucleosomes that can be quantified by ELISA. We analyzed the effect of tumor and chemotherapy upon the levels of nucleosomes in vitro, in vivo and in cervical cancer patients. The levels of nucleosomes pre- and post-treatment were correlated with response in 11 patients receiving chemotherapy. Nucleosomes were determined in nude mice treated with or without cisplatin and carrying tumors generated with HeLa cells, and in the cell lysate and supernatant of HeLa cells exposed to cisplatin in culture. In addition, nucleosomes were determined at different time points in patients and in rats receiving chemotherapy. Nucleosomes were higher in patients that controls (1,760 vs. 601, p = 0.0001). After 24 hr of treatment with oxaliplatin and gemcitabine, the levels decreased in 6 patients of whom 5 had response. Nucleosome levels differed between mice xenografted and not xenografted (765 vs. 378, p = 0.001) and between xenografted treated with or without cisplatin (650 vs. 765, p = 0.010), but not in tumor-free animals treated and untreated with cisplatin (378 vs. 379, p = 0.99). In vitro, nucleosomes reached at peak 8 hr in cell lysates to decrease thereafter, whereas in supernatant, levels continued to increase up to 24 hr. Serial determination of nucleosomes in patients showed a rise within 6-12 hr and then a reduction to below the basal at 24 hr. In rats, nucleosomes had no major changes in those receiving oxaliplatin or the triple combination of cisplatin, gemcitabine and paclitaxel as compared to untreated controls. An overdose of this triple combination produced a transient elevation of almost 1,000 AU over the basal. Our results demonstrate that most of circulating nucleosomes originate from the tumor and that chemotherapy produces an early rise most likely due to tumor apoptosis and that nucleosomes are rapidly cleared from circulation. On the contrary, chemotherapy within the therapeutic range of doses has no effect on nucleosome levels in healthy mice and rats. This data suggests that the determination of circulating nucleosomes pre- and post-treatment could be a useful test to predict response to chemotherapy in cancer patients.

Introduction. Rhabdomyosarcoma (RMS) accounts for 5% of all pediatric cancer and is the most prevalent soft tissue tumor in childhood and adolescents. RMS is thought to arise from primitive mesenchymal stem cells directed towards myogenesis. Between 7-33% of RMS cases arise from a hereditary cancer syndrome, like LFS or NF1. We analyzed germline genetic variants in hereditary cancer genes in 122 children with RMS. Methodology. In 122 children with RMS and 1001 cancer-free adults, we examined germline exome data to determine the frequency of genetic variants in 51 cancer genes known to underlie syndromes associated with RMS. DNA was extracted from blood or buccal cells using standard methods. Exome enrichment was performed with NimbleGen SeqCap EZ Human Exome Library v3.0+UTR, on an Illumina HiSeq. Annotation of each exome variant was performed using a custom software pipeline. We evaluated all variants that passed quality controls with a population minor allele frequency (MAF) Results We compared the age, gender, histologic type and localization of the primary RMS of the patients with and without P/LP variants in the 51 genes. In the patients without P/LP variants, the mean age of diagnosis was 5 years and the most frequent site of diagnosis was head and neck. In the group with P/LP variants, the mean age of diagnosis was 10 years, and the most frequent site was pelvis. In the 51 genes that were analyzed we found 9 P and 12 LP variants in 15 genes: TP53, ATM, MSH6, PMS, DICER1, FANCA, RECQL4, PTEN, WRN, RB1, BUB1B, RET, APC, FANCM and TSC2; genes with 2 variants include WRN, PTEN, BUB1B, FANCA and RET. Most of the variations were stopgain, follow by missense, frameshift insertion and splicing genetic variations. Ten of this genes are associated with an autosomal dominant pattern of inheritance. In one 15-year-old female patient with an alveolar RMS in the paraspinal area we found P/LP variants in PTEN and PMS2. The frequency of P/LP variants in cases was 16% and 3% in controls. Conclusions. To our knowledge, this is the first study where multiple germline variation where analyses in children with RMS. We found P/LP variation in 16% of all the cases (pending orthogonal confirmation); the mean age of diagnosis was 10 years old and their primary tumor site was in the pelvis (50%). Identification of P/LP variation in genes underlying RMS-associated syndromes has implications for follow-up, screening and management of these patients and their families. We acknowledge the Children’s Oncology Group in helping to assemble the RMS cohort. Citation Format: Talia Wegman-Ostrosky, Rajesh Patidar, Sivasish Sindiri, Jack Shern, Douglas S. Hawkins, Daniel Catchpoole, Jun S. Wei, Stephen Skapek, Javed Khan, Douglas R. Stewart. Exome analysis of known hereditary cancer genes in 122 children with rhabdomyosarcoma [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 3003. doi:10.1158/1538-7445.AM2017-3003

Introduction: Astrocytomas are the most common and lethal brain tumors with a median survival of 15 months. Different biomarkers have arisen to classify and treat this type of tumors; one of these markers is MGMT. The methylation status of this gene is a prognostic and predictive factor. The MGMT (O-6-Methylguanine-DNA Methyltransferase) is involved in the cellular response to the effects of O6-methylguanine (O6-MeG) in DNA. Repairs alkylated guanine in DNA by transferring the alkyl group at the O-6 position to a cysteine residue in the enzyme. The dysregulation of this methylation is critical in the development of certain cancers. Objective: To identify germinal MGMT gene variations in patients with astrocytoma. Material and methods: 55 randomly selected Mexican patients diagnosed with astrocytoma between 2008-2014 were consented to perform the molecular analysis of the whole gene and 5´UTR and 3´UTR regions of MGMT at Ion Torrent platform. Each amplified region had a depth of minimum 1500x. Ion Reporter software was used to analyze the genetic variants and using Integrative Genomic Viewer we confirmed that each variant had a Phred higher than 25. Genotypic frequencies were compared with HapMapMex and Mexican ancestry population from the 1000 Genomes project. Results. In lymphocytes DNA, eight genetic variants were found, and two of them were statistically significant risk factors: rs7896488 alternative allele A with a frequency of 15% in patients with astrocytoma, and only 4% of the control group (OR=5.53, IC 1.96-15.59 p = 0.0007) and rs2308326 ancestral allele C, where 93% of the patients were carriers of allele C in contrast with 73% of controls (OR=5.39, IC 2.29-12.69 p = 0.000019). These variants are non-coding single nucleotide polymorphisms, rs7896488 is a 3' UTR genetic variant, while rs2308326 is an intronic variant. Conclusion: Our study found two new risk SNV for Astrocytoma in a Mexican population. Citation Format: Liliana Gomez-Flores-Ramos, Talia Wegman-Ostrosky. Novel MGMT variant association in Mexican patients with astrocytoma [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 3414. doi:10.1158/1538-7445.AM2017-3414

Introduction: Malignant tumors of the central nervous system contribute extremely to cancer mortality especially in the high risk age groups. In USA are the second and the fifth leading cause of cancer mortality in men and women aged 20 to 39 years respectively. Astrocytomas are the most common and lethal tumors of the CNS, being the most common grade IV (glioblastoma) (4.37 per 100,000 population). The prognosis of astrocytomas can be predicted by specific clinical factors allowing neurosurgeons and neuro-oncologists to define the best treatment for each patient. Some patients’ features like age, gender, performance status and tumor localization have been studied as potential prognostic factors. In Mexico there are few reports on demographic, clinical characteristics and prognostic factors in adults. Objective: To explore the clinical prognostic factors for adults affected with astrocytoma Methods: Using a historic cohort, we selected by simple randomization, 155 clinical files from patients with astrocytoma. The main outcome variable was overall survival time (OS). To identify clinical prognosis factors we used: bivariate analysis, Cox regression models, log rank test and Kaplan-Meier survival function. Results: The mean age at diagnosis was 45.7 years. Compared with other studies, our population was 15 years younger when diagnosed. Analysis by stage in grade II, III and IV also showed a younger age of presentation. The OS was 15 months, 9% (n = 14) presented a survival of 2 years and 3% of 3 years. Kaplan-Meier survival estimate showed that the variables grade, Karnofsky Performance Status (KPS)>70, the type of resection, chemotherapy, radiotherapy, alcohol consumption, familiar history of cancer and clinical presentation were significantly associated to survival time. Using proportional Hazard Model the variables: age, grade IV, resection, chemotherapy + radiotherapy and KPS where prognosis factors. Conclusion: Astrocytoma in our study was present in young adults. The OS was 15 months, 9% (n = 14) presented a survival of 2 years and 3% of 3 years. The variables alcoholism, family history of cancer and clinical presentation influenced significantly survival time, and showed a tendency in the mortality analyses. Citation Format: Talia Wegman-Ostrosky, Nancy Reynoso Noverón, Sonia Iliana Mejía-Pérez, Thalía Estefania Sánchez-Correa MD, Rosa María Álvarez, Bernardo Cacho, Luis A. Montalvo, Teresita Corona. Clinical prognostic factors in adult with astrocytoma: Historic cohort. [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 3420.

Background: Astrocytomas are the most common and lethal brain tumors. The median survival of patients is 15 months. The study of genetic alterations may help to understand the mechanisms of development and behavior of the disease and thus understand the risk factors and prognostic factors. AGT gene and its peptide derivatives, are involved in cell proliferation and neoangiogenesis and resistance to apoptosis, hence the pathogenesis of astrocytomas. Objective: To identify somatic and germinal AGT gene variations in from patients with astrocytoma. Material and methods: 155 randomly selected files from patients diagnosed with astrocytoma between 2008-2014 were revised to determined clinical prognosis factor in Mexican population. In 25 patients, the molecular analysis of the whole codification region, 5´UTR and 3´UTR of the gene AGT was done in tumors biopsy and blood. Each amplified region had a depth of minimum 1500x. IonReporter software was utilize to analyze the genetic variants and using Integrative Genomic Viewer we confirmed that each variant had a Phred higher than 25. Genotypic frequencies were compared with HapMapMex. Results The clinical variants associated with prognosis were age (OR 0.01 IC 95% 1.02-1.07, p = 0.000), Grade IV (OR 17.11, IC 95% 1.89-132.13 p = 0.011), location of tumor (OR 1.17, IC 1.2-6.3, p = 0.016), total resection (OR = .186, IC 95% .098-.622, p = 0.003, Karnofsky (OR = .05, IC 95% 0.024-0.24, p = 0.003), motor deficiency (OR = 3.5, IC = 1.1-10.5, p = 0.025). In blood were found 11 genetic variants. rs4049, rs2148582, rs699, rs4762 and rs1926723 were associated with risk of tumor in the codominant model. rs5050 (- A20C) was statistically associated with the prognosis (OR 10.8, IC 1.16-100.51 p = 0.036). These variant it is part of a haplotype related to low expression of angiotensinogen. In biopsies of 2 patients missense mutations were found p.Arg477His in one patient and Gly226Ala -Pro165Ser in another one. Conclusion: In 8% of the tumors samples new somatic mutations were found. The genetic variant rs5050 of AGT is a prognosis biomarker in patients with astrocytoma. Citation Format: Talia Wegman-Ostrosky, Ernesto Soto-Reyes, Silvia Vidal-Millan, Sonia Mejia, José Sánchez-Corona, Luis A. Herrera. AGT mutations as a prognosis factor in patients with astrocytoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 594. doi:10.1158/1538-7445.AM2015-594

ss Open Acce Meeting abstract Epigenetic therapy with hydralazine and valproate associated to cisplatin chemoradiation in FIGO stage IIIB. A phase II study Myrna Candelaria1, Lucely Cetina1, Alicia Garcia1, Talia Wegman-Ostrosky1, Elizabeth Robles1, Aurora Gonzalez-Fierro1, Carlos Lopez-Graniel2, Aaron Gonzalez2, David Cantu2, Lesbia Ribera3, Lucia Taja-Chayeb1, Catalina Trejo-Becerril1, Enrique Perez-Cardenas1, Carlos Perez-Plasencia1, Alma Chavez-Blanco1 and Alfonso Duenas-Gonzalez*1,4