Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention.

BACKGROUND & AIMS: Lynch syndrome (LS) carriers develop mismatch repair-deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers in LS carriers. METHODS: We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 detected mutated neoAgs that were validated in vitro using ELISpot and tetramer assays. RESULTS: Mutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced precancers, and 20% of precancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced precancers, and 107 in precancers. No neoAgs were detected in PWOMP. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced precancers, and 29% of precancers. We observed increased levels of naïve CD8+ and memory CD4+ T cells in mismatch repair-deficient cancers and precancers via transcriptomics analysis. CONCLUSIONS: Shared frameshift-neoAgs are generated within unstable microsatellite loci at initial stages of LS carcinogenesis and can induce T-cell responses, generating opportunities for vaccine development, targeting LS precancers and early-stage cancers.

Targeted next-generation sequencing of endometrial cancer and matched circulating tumor DNA: identification of plasma-based, tumor-associated mutations in early stage patients.

There is currently no blood-based marker in routine use for endometrial cancer patients. Such a marker could potentially be used for early detection, but it could also help to track tumor recurrence following hysterectomy. This is important, as extra-vaginal recurrence of endometrial endometrioid adenocarcinoma is usually incurable. This proof-of-principle study was designed to determine if tumor-associated mutations could be detected in cell-free DNA from the peripheral blood of early and late stage endometrial endometrioid carcinoma patients. Approximately 90% of endometrioid carcinomas have at least one mutation in the genes CTNNB1, KRAS, PTEN, or PIK3CA. Using a custom panel targeting 30 hotspot amplicons in these four genes, next-generation sequencing was performed on cell-free DNA extracted from plasma obtained from a peripheral blood draw at the time of hysterectomy and the matching tumor DNA from 48 patients with endometrioid endometrial carcinomas. At least one mutation in the tumor was detected in 45/48 (94%) of patients. Fifteen of 45 patients (33%) had a mutation in the plasma that matched a mutation in the tumor. These same mutations were not detected in the matched negative control buffy coat. Presence of a plasma mutation was significantly associated with advanced stage at hysterectomy, deep myometrial invasion, lymphatic/vascular invasion, and primary tumor size. Detecting a plasma-based mutation was independent of the amount of cell-free DNA isolated from the plasma. Overall, 18% of early stage patients had a mutation detected in the plasma. These results demonstrate that mutations in genes relevant to endometrial cancer can be identified in the peripheral blood of patients at the time of surgery. Future studies can help to determine the post-operative time course of mutation clearance from the peripheral blood and if mutation re-emergence is predictive of recurrence.

Advances in vaccine development for cancer prevention and treatment in Lynch Syndrome.

Lynch Syndrome (LS) is one of the most common hereditary cancer syndromes, and is caused by mutations in one of the four DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6 and PMS2. Tumors developed by LS carriers display high levels of microsatellite instability, which leads to the accumulation of large numbers of mutations, among which frameshift insertion/deletions (indels) within microsatellite (MS) loci are the most common. As a result, MMR-deficient (MMRd) cells generate increased rates of tumor-specific neoantigens (neoAgs) that can be recognized by the immune system to activate cancer cell killing. In this context, LS is an ideal disease to leverage immune-interception strategies. Therefore, the identification of these neoAgs is an ongoing effort for the development of LS cancer preventive vaccines. In this review, we summarize the computational methods used for in silico neoAg prediction, including their challenges, and the experimental techniques used for in vitro validation of their immunogenicity. In addition, we outline results from past and on-going vaccine clinical trials and highlight avenues for improvement and future directions.

Infarto pulmonar: signos que no debemos dejar pasar en TC de tórax sin contraste / Pulmonary infarction: the signs that we must not miss in chest CT without contrast

Resumen El infarto pulmonar (IP) resulta de la oclusión de las arterias pulmonares distales que generan isquemia, hemorragia y finalmente necrosis del parénquima pulmonar, siendo la causa más frecuente la embolia pulmonar (EP). El diagnóstico oportuno de IP permite el inicio precoz del tratamiento y el respectivo manejo de sostén, disminuyendo así la morbimortalidad asociada. El objetivo de esta revisión es remarcar la importancia de identificar aquellos signos, que en la tomografía computada (TC) sin contraste son altamente sensibles y específicos para el diagnóstico de IP. La TC de alta resolución constituye el método que más información aporta, pudiendo observar signos clásicos de IP como la opacidad en forma de cuña, opacidad con radiolucencia central y el signo del vaso nutricio; así como signos con alto valor predictivo negativo para IP, como la opacidad consolidativa con broncograma aéreo, sugestivo de otras patologías, ya sean infecciosas o tumorales.

Abstract Pulmonary infarction (PI) results from occlusion of the distal pulmonary arteries leading to ischemia, hemorrhage, and necrosis of the pulmonary parenchyma. The most common cause of pulmonary infarction is pulmonary embolism (PE). Early diagnosis of PI allows early initiation of treatment and supportive care, thus reducing the associated morbidity and mortality. This review aims to highlight the importance of identifying signs that are highly sensitive and specific for the diagnosis of PE even without IV contrast. High-resolution computed tomography (CT) is the method that provides the most information, as it observes classic signs of PI such as wedge-shaped opacity, central lucencies in peripheral consolidation, and the feeding vessel sign, as well as signs with high negative predictive value such as consolidating opacity with air bronchogram that are suggestive of other pathologies, whether infectious or tumoural.