Methylation marks in blood DNA reveal breast cancer risk in patients fulfilling hereditary disease criteria.

Less than 15-20% of patients who meet the criteria for hereditary breast and ovarian cancer (HBOC) carry pathogenic coding genetic mutations, implying that other molecular mechanisms may contribute to the increased risk of this condition. DNA methylation in peripheral blood has been suggested as a potential epigenetic marker for the risk of breast cancer (BC). We aimed to discover methylation marks in peripheral blood associated with BC in 231 pre-treatment BC patients meeting HBOC criteria, testing negative for coding pathogenic variants, and 156 healthy controls, through methylation analysis by targeted bisulfite sequencing on 18 tumor suppressor gene promoters (330 CpG sites). We found i) hypermethylation in EPCAM (17 CpG sites; p = 0.017) and RAD51C (27 CpG sites; p = 0.048); ii) hypermethylation in 36 CpG-specific sites (FDR q < 0.05) in the BC patients; iii) four specific CpG sites were associated with a higher risk of BC (FDR q < 0.01, Bonferroni p < 0.001): cg89786999-FANCI (OR = 1.65; 95% CI:1.2-2.2), cg23652916-PALB2 (OR = 2.83; 95% CI:1.7-4.7), cg47630224-MSH2 (OR = 4.17; 95% CI:2.1-8.5), and cg47596828-EPCAM (OR = 1.84; 95% CI:1.5-2.3). Validation of cg47630224-MSH2 methylation in one Australian cohort showed an association with 3-fold increased BC risk (AUC: 0.929; 95% CI: 0.904-0.955). Our findings suggest that four DNA methylation CpG sites may be associated with a higher risk of BC, potentially serving as biomarkers in patients without detectable coding mutations.

Novel Blood Biomarkers for Response Prediction and Monitoring of Stereotactic Ablative Radiotherapy and Immunotherapy in Metastatic Oligoprogressive Lung Cancer.

Up to 80% of patients under immune checkpoint inhibitors (ICI) face resistance. In this context, stereotactic ablative radiotherapy (SABR) can induce an immune or abscopal response. However, its molecular determinants remain unknown. We present early results of a translational study assessing biomarkers of response to combined ICI and SABR (I-SABR) in liquid biopsy from oligoprogressive patients in a prospective observational multicenter study. Cohort A includes metastatic patients in oligoprogression to ICI maintaining the same ICI due to clinical benefit and who receive concomitant SABR. B is a comparative group of oligometastatic patients receiving only SABR. Blood samples are extracted at baseline (T1), after the first (T2) and last (T3) fraction, two months post-SABR (T4) and at further progression (TP). Response is evaluated by iRECIST and defined by the objective response rate (ORR)-complete and partial responses. We assess peripheral blood mononuclear cells (PBMCs), circulating cell-free DNA (cfDNA) and small RNA from extracellular vesicles. Twenty-seven patients could be analyzed (cohort A: n = 19; B: n = 8). Most were males with non-small cell lung cancer and one progressing lesion. With a median follow-up of 6 months, the last ORR was 63% (26% complete and 37% partial response). A decrease in cfDNA from T2 to T3 correlated with a good response. At T2, CD8+PD1+ and CD8+PDL1+ cells were increased in non-responders and responders, respectively. At T2, 27 microRNAs were differentially expressed. These are potential biomarkers of response to I-SABR in oligoprogressive disease.

Fluorometric Quantification of Total Cell-Free DNA as a Prognostic Biomarker in Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Blockade.

The present study aimed to investigate the potential of basal cell-free fluorometric DNA (cfDNA) quantification as a prognostic biomarker in advanced non-small cell lung cancer (NSCLC) patients treated with an Immune Checkpoint Blockade (ICB). A discovery and validation cohort of 61 and 31 advanced lung cancer patients treated with ICB were included in this study. Quantification of cfDNA concentration was performed before the start of the treatment and patients were followed up for a median of 34 (30-40) months. The prognostic predicted value of cfDNA was evaluated based on ROC, and Cox regression was conducted via univariate and multivariate analyses to estimate the hazard ratio. We observed that a cfDNA cut-off of 0.55 ng/µL before the ICB determines the overall survival of patients with a log rank p-value of 3.3 × 10-4. That represents median survivals of 3.8 vs. 17.5 months. Similar results were obtained in the validation cohort being the log rank p-value 3.8 × 10-2 with median survivals of 5.9 vs. 24.3. The univariate and multivariate analysis revealed that the cut-off of 0.55 ng/µL before ICB treatment was an independent predictive factor and was significantly associated with a better survival outcome. High cfDNA concentrations identify patients with advanced NSCLC who do not benefit from the ICB. The determination of cfDNA is a simple test that could select a group of patients in whom new therapeutic strategies are needed.

Preclinical models in head and neck squamous cell carcinoma.

Head and neck cancer is the sixth most frequent cancer type. Drug resistance and toxicity are common challenges of the existing therapies, making the development of reliable preclinical models essential for the study of the involved molecular mechanisms as well as for eventual intervention approaches that improve the clinical outcome. Preclinical models of head and neck squamous cell carcinoma have been traditionally based on cell lines and murine models. In this review, we will go over the most frequently used preclinical models, from immortalised-cell and primary tumour cultures in monolayer or 3D, to the currently available animal models. We will scrutinise their efficiency in mimicking the molecular and cellular complexity of head and neck squamous cell carcinoma. Finally, the challenges and the opportunities of other envisaged putative approaches, as well as the potential of the preclinical models to further develop personalised therapies will be discussed.

Gut Microbiota and Therapy in Metastatic Melanoma: Focus on MAPK Pathway Inhibition.

Gut microbiome (GM) and its either pro-tumorigenic or anti-tumorigenic role is intriguing and constitutes an evolving landscape in translational oncology. It has been suggested that these microorganisms may be involved in carcinogenesis, cancer treatment response and resistance, as well as predisposition to adverse effects. In melanoma patients, one of the most immunogenic cancers, immune checkpoint inhibitors (ICI) and MAPK-targeted therapy-BRAF/MEK inhibitors-have revolutionized prognosis, and the study of the microbiome as a modulating factor is thus appealing. Although BRAF/MEK inhibitors constitute one of the main backbones of treatment in melanoma, little is known about their impact on GM and how this might correlate with immune re-induction. On the contrary, ICI and their relationship to GM has become an interesting field of research due to the already-known impact of immunotherapy in modulating the immune system. Immune reprogramming in the tumor microenvironment has been established as one of the main targets of microbiome, since it can induce immunosuppressive phenotypes, promote inflammatory responses or conduct anti-tumor responses. As a result, ongoing clinical trials are evaluating the role of fecal microbiota transplant (FMT), as well as the impact of using dietary supplements, antibiotics and probiotics in the prediction of response to therapy. In this review, we provide an overview of GM's link to cancer, its relationship with the immune system and how this may impact response to treatments in melanoma patients. We also discuss insights about novel therapeutic approaches including FMT, changes in diet and use of probiotics, prebiotics and symbiotics. Finally, we hypothesize on the possible pathways through which GM may impact anti-tumor efficacy in melanoma patients treated with targeted therapy, an appealing subject of which little is known.

Association of Circular RNA and Long Non-Coding RNA Dysregulation with the Clinical Response to Immune Checkpoint Blockade in Cutaneous Metastatic Melanoma.

Cutaneous melanoma (CM) is the most lethal form of skin cancer if it becomes metastatic, where treatment options and survival chances decrease dramatically. Immunotherapy treatments based on the immunologic checkpoint inhibitors programmed death cell protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) constituted a main breakthrough in the treatment of metastatic CM, particularly for the achievement of long-term benefits. Even though it is a very promising therapy, resistance to primary immune checkpoint blockade (ICB) arises in about 70% of CM patients treated with a CTLA-4 inhibitor, and 40-65% of CM patients administered with a PD-1-targeting treatment. Some long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are implicated in triggering pro- and anti-tumorigenic responses to various cancer treatments. The relationship between lncRNAs, circRNAs and ICB immunotherapy has not been explored in cutaneous metastatic melanoma (CMM). The aim of this pilot study is to evaluate the potential role of circRNA and lncRNA expression variability as pre-treatment predictor of the clinical response to immunotherapy in CMM patients. RNA-seq from 12 formalin-fixed paraffin-embedded (FFPE) samples from the metastatic biopsies of CMM patients treated with nivolumab was used to identify response-associated transcripts. Our findings indicate that specific lncRNAs and circRNAs, probably acting as competitive endogenous RNAs (ceRNAs), are involved in the regulatory networks of the immune response against metastatic melanoma that these patients have under treatment with nivolumab. Moreover, we established a risk score that yields predictions of the overall survival (OS) and progression-free survival (PFS) of CMM patients with high accuracy. This proof-of-principle work provides a possible insight into the function of ceRNAs, contributing to efforts to decipher the complex molecular mechanisms of ICB cancer treatment response.

High IGKC-Expressing Intratumoral Plasma Cells Predict Response to Immune Checkpoint Blockade.

Resistance to Immune Checkpoint Blockade (ICB) constitutes the current limiting factor for the optimal implementation of this novel therapy, which otherwise demonstrates durable responses with acceptable toxicity scores. This limitation is exacerbated by a lack of robust biomarkers. In this study, we have dissected the basal TME composition at the gene expression and cellular levels that predict response to Nivolumab and prognosis. BCR, TCR and HLA profiling were employed for further characterization of the molecular variables associated with response. The findings were validated using a single-cell RNA-seq data of metastatic melanoma patients treated with ICB, and by multispectral immunofluorescence. Finally, machine learning was employed to construct a prediction algorithm that was validated across eight metastatic melanoma cohorts treated with ICB. Using this strategy, we have unmasked a major role played by basal intratumoral Plasma cells expressing high levels of IGKC in efficacy. IGKC, differentially expressed in good responders, was also identified within the Top response-related BCR clonotypes, together with IGK variants. These results were validated at gene, cellular and protein levels; CD138+ Plasma-like and Plasma cells were more abundant in good responders and correlated with the same RNA-seq-defined fraction. Finally, we generated a 15-gene prediction model that outperformed the current reference score in eight ICB-treated metastatic melanoma cohorts. The evidenced major contribution of basal intratumoral IGKC and Plasma cells in good response and outcome in ICB in metastatic melanoma is a groundbreaking finding in the field beyond the role of T lymphocytes.

Automatic Integration of Clinical and Genetic Data Using cBioPortal.

Precision medicine seeks to improve the prevention, diagnosis and treatment of patients based on genetic characteristics unique to each person. In oncology, therapeutic decisions have been established based on the genomic characteristics of each patient's tumor. Data integration is key for the successful implementation of precision medicine since it is necessary for both studying a large volume of data from different sources and working with an interdisciplinary and translational vision. In this work, a bioinformatic process was successfully implemented that allows the integration of patients' genomic data, from two molecular biology laboratories, with their clinical data provided by their electronic medical records. For this, the REDCap data capture software, the cBioPortal visualization and analysis software, and a computer tool developed to automate the processing and annotation of the information in REDCap were used to be included in cBioPortal, for the "Map of Tumor Genomic Actionability of Argentina" project.

Emerging noninvasive methylation biomarkers of cancer prognosis and drug response prediction.

Cancer is the second leading cause of death worldwide being responsible for 9.6 million deaths in 2018. Epigenetic alterations are key in directing the aberrant expression of tumor-associated genes that drive cellular malignant transformation and cancer progression. Among epigenetic alterations, DNA methylation is the most deeply studied one in relation to environmental exposure. Tissue biopsies have traditionally been the main procedure by which a small sample of body tissue is excised to confirm cancer diagnosis or to indicate the primary site when cancer has spread. In contrast, the analysis of circulating tumor-derived material, or tumor circulome, by means of liquid biopsy of peripheral blood, urine, saliva or sputum is a noninvasive, fast and reproducible alternative to tissue biopsy. Recently, the assessment of epigenetic alterations such as DNA methylation and hydroxymethylation in circulating free DNA has been proved possible. These marks can be associated to prognosis and response to a variety of treatments including chemotherapy, hormonotherapy or immunotherapy. Epigenetic biomarkers may offer some advantages over RNA or genetic biomarkers given their stability in bodily fluids and their high tissue-specificity. While many challenges are still ahead, the unique advantages of these types of biomarkers is urging the scientific community to persevere in their clinical validation and integration into reliable prediction models. This review aims at recapitulating the emerging noninvasive DNA methylated biomarkers of importance for prediction of prognosis and drug response in cancer.

The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes.

In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemotherapy achieve a pathological complete response after treatment and more than 90% die due to metastasis formation. The diverse clinical responses and metastatic developments are attributed to extensive intrapatient genetic heterogeneity and tumor evolution acting on this neoplasm. In this work, we aimed to evaluate genomic alterations and tumor evolution in TNBC patients with aggressive disease. We sequenced the whole exome of 16 lesions from four patients who did not respond to therapy, and took several follow-up samples, including samples from tumors before and after treatment, as well as from the lymph nodes and skin metastases. We found substantial intrapatient genetic heterogeneity, with a variable tumor mutational composition. Early truncal events were MCL1 amplifications. Metastatic lesions had deletions in RB1 and PTEN, along with TERT, AKT2, and CCNE1 amplifications. Mutational signatures 06 and 12 were mainly detected in skin metastases and lymph nodes. According to phylogenetic analysis, the lymph node metastases occurred at an early stage of TNBC development. Finally, each patient had three to eight candidate driving mutations for targeted treatments. This study delves into the genomic complexity and the phylogenetic and evolutionary development of aggressive TNBC, supporting early metastatic development, and identifies specific genetic alterations associated with a response to targeted therapies.

Liquid Biopsy as a Tool for the Characterisation and Early Detection of the Field Cancerization Effect in Patients with Oral Cavity Carcinoma.

Oral squamous cell carcinoma (OSCC) constitutes approximately 25% of all head and neck cancer, for which the consumption of tobacco and alcohol are the main associated risk factors. The field cancerization effect of OSCC is one of the main reasons for the poor survival rates associated with this disease. Despite some advances, its ccharacterization and early diagnosis continue to challenge modern oncology, and the goal of improving the prognosis remains to be achieved. Among new early diagnostic tools for OSCC that have been proposed, liquid biopsy appears to be an ideal candidate, as studies have shown that the analysis of blood and saliva provides promising data for the early detection of relapses or second tumours.

La biopsia líquida en el diagnóstico y monitoreo de pacientes oncológicos: Oportunidades y retos en Latinoamérica / Liquid biopsy in the diagnosis and monitoring of cancer patients: opportunities and challenges in Latin America

Resumen En los últimos años el estudio de los ácidos nucleicos circulantes ha tenido grandes avances en el campo de la oncología, lo que ha permitido avanzar de forma importante en las aplicaciones clínicas de la biopsia líquida en diferentes áreas como el pronóstico, la estadificación, la predicción de recurrencia, la selección y monitorización de tratamientos, entre otros. Lo anterior se debe en gran parte al desarrollo de nuevas y mejores tecnologías, algunas de las cuales incluso han sido autorizadas para el diagnóstico y seguimiento clínico de ciertos tipos de cáncer. No obstante, la utilización de la biopsia líquida como herramienta de apoyo clínico sigue siendo objeto de estudio. Debido a la importancia que ha cobrado este avance tecnológico a nivel mundial, se realizó una revisión de literatura con el fin de establecer el estado actual del uso de biopsia líquida en oncología, así como sus aplicaciones clínicas actuales, con un énfasis en Latinoamérica.

Abstract In recent years, the study of circulating nucleic acids has made great progress in the field of oncology, allowing for significant advances in clinical applications of liquid biopsy in diverse areas such as prognosis, staging, recurrence prediction, selection and monitoring of treatments, among others. This advance is largely due to the development of new and better technologies, some of which have even been validated for the diagnosis and clinical follow-up of certain types of cancer. However, the use of liquid biopsy as an additional tool in clinical oncology remains under study. Given the worldwide importance of this technological advance, a literature review was conducted to establish the current status of the use of liquid biopsy in oncology, as well as its current clinical applications, with a particular focus on Latin America.

Comprehensive Genomic Profile of Heterogeneous Long Follow-Up Triple-Negative Breast Cancer and Its Clinical Characteristics Shows DNA Repair Deficiency Has Better Prognostic.

Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which promotes a clinical heterogeneity that further complicates treatment. We performed a detailed whole exome sequencing profile of 29 Mexican patients with long follow-up TNBC to identify genomic alterations associated with overall survival (OS), disease-free survival (DFS), and pathologic complete response (PCR), with the aim to define their role as molecular predictive factors of treatment response and prognosis. We detected 31 driver genes with pathogenic mutations in TP53 (53%), BRCA1/2 (27%), CDKN1B (9%), PIK3CA (9%), and PTEN (9%), and 16 operative mutational signatures. Moreover, tumors with mutations in BRCA1/2 showed a trend of sensitivity to platinum salts. We found an association between deficiency in DNA repair and surveillance genes and DFS. Across all analyzed tumors we consistently found a heterogeneous molecular complexity in terms of allelic composition and operative mutational processes, which hampered the definition of molecular traits with clinical utility. This work contributes to the elucidation of the global molecular alterations of TNBC by providing accurate genomic data that may help forthcoming studies to improve treatment and survival. This is the first study that integrates genomic alterations with a long follow-up of clinical variables in a Latin American population that is an underrepresented ethnicity in most of the genomic studies.

AR-V7 as a Biomarker for Resistance to Treatment with Abiraterone/Enzalutamide in Three Latin American Countries: A Hypothetical Cost-Saving Analysis.

BACKGROUND: Prostate cancer is the most incident and one of the deadliest male cancers in Latin America. Treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) includes androgen receptor signaling inhibitors such as abiraterone and enzalutamide, for which androgen receptor splice variant 7 (AR-V7) has emerged as a biomarker for primary resistance. Our study sought to analyze the potential economic impact of the use of AR-V7 detection as a treatment indicator in patients with mCRPC in three Latin American countries. MATERIALS AND METHODS: A hypothetical cost prediction model for the use of noninvasive circulating tumor cell-based AR-V7 testing as a treatment indicator for patients eligible for treatment with abiraterone/enzalutamide was conducted using available information on treatment and testing costs from Mexico, Argentina, and Colombia. RESULTS: At an estimated prevalence of AR-V7 positivity of 20%, the use of upfront AR-V7 genetic testing resulted in annual net savings of $9,801,669.97, $6,390,055.75, and $3,096,780.91 in Mexico, Argentina, and Colombia, respectively. A direct relationship between AR-V7 positivity prevalence and net savings was found. CONCLUSION: The use of a noninvasive AR-V7 detection assay as a treatment indicator tool in patients eligible for treatment with abiraterone or enzalutamide in Latin America could be a cost-effective approach for the management of these patients. Additional efforts are needed to accurately determine the incidence of castration-resistant prostate cancer cases and the prevalence of AR-V7 positivity in Latin America in order to predict the potential economic benefit of its clinical use. IMPLICATIONS FOR PRACTICE: In Latin America, prostate cancer is the most frequently diagnosed cancer in men, and the burden of this disease is expected to double in this region by 2030. Noninvasive detection of androgen receptor splice variant 7 (AR-V7) is being currently validated as a predictive biomarker for benefit with androgen receptor signaling inhibitor therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). This hypothetical cost-saving analysis shows that AR-V7 testing in peripheral blood of patients with CRPC eligible for treatment with abiraterone or enzalutamide might represent a cost-effective strategy to select patients who will benefit from AR-axis-directed treatment in three Latin American countries.

Predictors of Survival After Head and Neck Squamous Cell Carcinoma in South America: The InterCHANGE Study.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) incidence is high in South America, where recent data on survival are sparse. We investigated the main predictors of HNSCC survival in Brazil, Argentina, Uruguay, and Colombia. METHODS: Sociodemographic and lifestyle information was obtained from standardized interviews, and clinicopathologic data were extracted from medical records and pathologic reports. The Kaplan-Meier method and Cox regression were used for statistical analyses. RESULTS: Of 1,463 patients, 378 had a larynx cancer (LC), 78 hypopharynx cancer (HC), 599 oral cavity cancer (OC), and 408 oropharynx cancer (OPC). Most patients (55.5%) were diagnosed with stage IV disease, ranging from 47.6% for LC to 70.8% for OPC. Three-year survival rates were 56.0% for LC, 54.7% for OC, 48.0% for OPC, and 37.8% for HC. In multivariable models, patients with stage IV disease had approximately 7.6 (LC/HC), 11.7 (OC), and 3.5 (OPC) times higher mortality than patients with stage I disease. Current and former drinkers with LC or HC had approximately 2 times higher mortality than never-drinkers. In addition, older age at diagnosis was independently associated with worse survival for all sites. In a subset analysis of 198 patients with OPC with available human papillomavirus (HPV) type 16 data, those with HPV-unrelated OPC had a significantly worse 3-year survival compared with those with HPV-related OPC (44.6% v 75.6%, respectively), corresponding to a 3.4 times higher mortality. CONCLUSION: Late stage at diagnosis was the strongest predictor of lower HNSCC survival. Early cancer detection and reduction of harmful alcohol use are fundamental to decrease the high burden of HNSCC in South America.

Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach.

Purpose: Hereditary Breast and Ovarian Cancer (HBOC) syndrome is responsible for ~5-10% of all diagnosed breast and ovarian cancers. Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among women in Latin America (LA). The main objective of this study was to develop a comprehensive understanding of the genomic epidemiology of HBOC throughout the establishment of The Latin American consortium for HBOC-LACAM, consisting of specialists from 5 countries in LA and the description of the genomic results from the first phase of the study. Methods: We have recruited 403 individuals that fulfilled the criteria for HBOC from 11 health institutions of Argentina, Colombia, Guatemala, Mexico and Peru. A pilot cohort of 222 individuals was analyzed by NGS gene panels. One hundred forty-three genes were selected on the basis of their putative role in susceptibility to different hereditary cancers. Libraries were sequenced in MiSeq (Illumina, Inc.) and PGM (Ion Torrent-Thermo Fisher Scientific) platforms. Results: The overall prevalence of pathogenic variants was 17% (38/222); the distribution spanned 14 genes and varied by country. The highest relative prevalence of pathogenic variants was found in patients from Argentina (25%, 14/57), followed by Mexico (18%, 12/68), Guatemala (16%, 3/19), and Colombia (13%, 10/78). Pathogenic variants were found in BRCA1 (20%) and BRCA2 (29%) genes. Pathogenic variants were found in other 12 genes, including high and moderate risk genes such as MSH2, MSH6, MUTYH, and PALB2. Additional pathogenic variants were found in HBOC unrelated genes such as DCLRE1C, WRN, PDE11A, and PDGFB. Conclusion: In this first phase of the project, we recruited 403 individuals and evaluated the germline genetic alterations in an initial cohort of 222 patients among 4 countries. Our data show for the first time in LA the distribution of pathogenic variants in a broad set of cancer susceptibility genes in HBOC. Even though we used extended gene panels, there was still a high proportion of patients without any detectable pathogenic variant, which emphasizes the larger, unexplored genetic nature of the disease in these populations.

Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility.

Hereditary breast and ovarian cancer syndrome (HBOC) represents 5⁻10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 high-risk patients with a severe family history of cancer, using massive parallel sequencing. We found pathogenic variants in 23 genes, including BRCA1/2. In the group of cancer patients 15% (46/300) had a pathogenic variant; 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had 22% (6/27) of patients with pathogenic variants, 4% (1/27) had VUS and 74% (20/27) were negative. The most recurrent mutations were the Mexican founder deletion of exons 9-12 and the variant p.G228fs in BRCA1, each found in 5 of 17 patients with alterations in this gene. Rare VUS with potential impact at the protein level were found in 21 genes. Our results show for the first time in the Mexican population a higher contribution of pathogenic alleles in other susceptibility cancer genes (54%) than in BRCA1/2 (46%), highlighting the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to include broader gene panels.

Cancer Genomic Resources and Present Needs in the Latin American Region.

In Latin America (LA), cancer is the second leading cause of death, and little is known about the capacities and needs for the development of research in the field of cancer genomics. In order to evaluate the current capacity for and development of cancer genomics in LA, we collected the available information on genomics, including the number of next-generation sequencing (NGS) platforms, the number of cancer research institutions and research groups, publications in the last 10 years, educational programs, and related national cancer control policies. Currently, there are 221 NGS platforms and 118 research groups in LA developing cancer genomics projects. A total of 272 articles in the field of cancer genetics/genomics were published by authors affiliated to Latin American institutions. Educational programs in genomics are scarce, almost exclusive of graduate programs, and only few are concerning cancer. Only 14 countries have national cancer control plans, but all of them consider secondary prevention strategies for early diagnosis, opportune treatment, and decreasing mortality, where genomic analyses could be implemented. Despite recent advances in introducing knowledge about cancer genomics and its application to LA, the region lacks development of integrated genomic research projects, improved use of NGS platforms, implementation of associated educational programs, and health policies that could have an impact on cancer care.

Isolation and characterization of a novel putative human polyomavirus.

The small double-stranded DNA polyomaviruses (PyVs) form a family of 73 species, whose natural hosts are primarily mammals and birds. So far, 13 PyVs have been isolated in humans, and some of them have clearly been associated with several diseases, including cancer. In this study, we describe the isolation of a novel PyV in human skin using a sensitive degenerate PCR protocol combined with next-generation sequencing. The new virus, named Lyon IARC PyV (LIPyV), has a circular genome of 5269 nucleotides. Phylogenetic analyses showed that LIPyV is related to the raccoon PyV identified in neuroglial tumours in free-ranging raccoons. Analysis of human specimens from cancer-free individuals showed that 9 skin swabs (9/445; 2.0%), 3 oral gargles (3/140; 2.1%), and one eyebrow hair sample (1/439; 0.2%) tested positive for LIPyV. Future biological and epidemiological studies are needed to confirm the human tropism and provide insights into its biological properties.