Explore the vast range of titles available.

Small intestine neuroendocrine tumors (SI-NETs) are the most common malignancy of the small bowel. Several clinical trials target PI3K/Akt/mTOR signaling; however, it is unknown whether these or other genes are genetically altered in these tumors. To address the underlying genetics, we analyzed 48 SI-NETs by massively parallel exome sequencing. We detected an average of 0.1 somatic single nucleotide variants (SNVs) per 106 nucleotides (range, 0-0.59), mostly transitions (C>T and A>G), which suggests that SI-NETs are stable cancers. 197 protein-altering somatic SNVs affected a preponderance of cancer genes, including FGFR2, MEN1, HOOK3, EZH2, MLF1, CARD11, VHL, NONO, and SMAD1. Integrative analysis of SNVs and somatic copy number variations identified recurrently altered mechanisms of carcinogenesis: chromatin remodeling, DNA damage, apoptosis, RAS signaling, and axon guidance. Candidate therapeutically relevant alterations were found in 35 patients, including SRC, SMAD family genes, AURKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of AKT1 or AKT2 was the most common event in the 16 patients with alterations of PI3K/Akt/mTOR signaling. We conclude that sequencing-based analysis may provide provisional grouping of SI-NETs by therapeutic targets or deregulated pathways.

In endometrial cancer, occult high-risk subtypes (rooted in histomorphologically low-risk disease) with insensitivity to adjuvant therapies impede improvements in therapeutic efficacy. Therefore, we aimed to assess the ability of molecular high-risk (MHR) and low-risk (MLR) ECPPF ( E 2F1 , C CNA2 , P OLE , P PP2R1A , F BXW7 ) stratification to profile recurrence in early, low-risk endometrioid endometrial cancer (EEC) and insensitivity to platinum-based chemotherapy or radiotherapy (or both) in high-risk EEC. Using The Cancer Genome Atlas endometrial cancer database, we identified 192 EEC cases with available DNA sequencing and RNA expression data. Molecular parameters were integrated with clinicopathologic risk factors and adverse surveillance events. MHR was defined as high (-H) CCNA2 or E2F1 log 2 expression (≥2.75), PPP2R1A mutations (-mu), or FBXW7 mu; MLR was defined as low (-L) CCNA2 and E2F1 log 2 expression (<2.75). We assessed 164 cases, plus another 28 with POLE mu for favorable-outcomes comparisons. MHR and MLR had significantly different progression-free survival (PFS) rates ( P < .001), independent of traditional risk factors (eg, TP53 mu), except for stage IV disease. PFS of CCNA2 -L/ E2F1 -L paralleled that of POLE mu. ECPPF status stratified responses to adjuvant therapy in stage III-IV EEC ( P < .01) and profiled stage I, grade 1–2 cases with risk of recurrence ( P < .001). MHR was associated with CTNNB1 mu-linked treatment failures ( P < .001). Expression of homologous recombination repair (HR) and cell cycle genes was significantly elevated in CCNA2 -H/ E2F1 -H compared with CCNA2 -L/ E2F1 -L ( P <1.0E-10), suggesting that HR deficiencies may underlie the favorable PFS in MLR. HRmu were detected in 20.7%. No treatment failures were observed in high-grade or advanced EEC with HRmu ( P = .02). Favorable PFS in clinically high-risk EEC was associated with HRmu and MLR ECPPF ( P < .001). In summary, MLR ECPPF and HRmu were associated with therapeutic efficacy in EEC. MHR ECPPF was associated with low-risk, early-stage recurrences and insensitivity to adjuvant therapies.

Background Mucinous ovarian tumors represent a distinct histotype of epithelial ovarian cancer. The rarest (2-4 % of ovarian carcinomas) of the five major histotypes, their genomic landscape remains poorly described. We undertook hotspot sequencing of 50 genes commonly mutated in human cancer across 69 mucinous ovarian tumors. Our goals were to establish the overall frequency of cancer-hotspot mutations across a large cohort, especially those tumors previously thought to be “RAS-pathway alteration negative”, using highly-sensitive next-generation sequencing as well as further explore a small number of cases with apparent heterogeneity in RAS-pathway activating alterations. Methods Using the Ion Torrent PGM platform, we performed next generation sequencing analysis using the v2 Cancer Hotspot Panel. Regions of disparate ERBB2-amplification status were sequenced independently for two mucinous carcinoma (MC) cases, previously established as showing ERBB2 amplification/overexpression heterogeneity, to assess the hypothesis of subclonal populations containing either KRAS mutation or ERBB2 amplification independently or simultaneously. Results We detected mutations in KRAS , TP53 , CDKN2A , PIK3CA , PTEN , BRAF , FGFR2 , STK11 , CTNNB1 , SRC , SMAD4 , GNA11 and ERBB2. KRAS mutations remain the most frequently observed alteration among MC (64.9 %) and mucinous borderline tumors (MBOT) (92.3 %). TP53 mutation occurred more frequently in carcinomas than borderline tumors (56.8 % and 11.5 %, respectively), and combined IHC and mutation data suggest alterations occur in approximately 68 % of MC and as many as 20 % of MBOT. Proven and potential RAS-pathway activating changes were observed in all but one MC. Concurrent ERBB2 amplification and KRAS mutation were observed in a substantial number of cases (7/63 total), as was co-occurrence of KRAS and BRAF mutations (one case). Microdissection of ERBB2 -amplified regions of tumors harboring KRAS mutation suggests these alterations are occurring in the same cell populations, while consistency of KRAS allelic frequency in both ERBB2 amplified and non-amplified regions suggests this mutation occurred in advance of the amplification event. Conclusions Overall, the prevalence of RAS-alteration and striking co-occurrence of pathway “double-hits” supports a critical role for tumor progression in this ovarian malignancy. Given the spectrum of RAS-activating mutations, it is clear that targeting this pathway may be a viable therapeutic option for patients with recurrent or advanced stage mucinous ovarian carcinoma, however caution should be exercised in selecting one or more personalized therapeutics given the frequency of non-redundant RAS-activating alterations.

Background Multifocal micronodular pneumocyte hyperplasia as first manifestation of tuberous sclerosis complex has rarely been reported. Case presentation We report a case of a 50-year-old white, non-Hispanic or Latino, female with no prior history of tuberous sclerosis complex who presented with nonspecific symptoms. Chest computed tomography showed multiple bilateral ground-glass lung nodules, ranging from 4 to 7 mm. Wedge biopsies led to a histological differential diagnosis of atypical adenomatous hyperplasia and multifocal micronodular pneumocyte hyperplasia. Some of the lesions were then micro-dissected and molecular studies revealed a pathogenic TSC1 mutation and loss of heterozygosity of the TSC1 gene. In the absence of adenomatous hyperplasia driver mutations, these findings were consistent with the diagnosis of multifocal micronodular pneumocyte hyperplasia. Follow-up blood work revealed mosaicism for the TSC1 mutation, meeting diagnostic criteria for tuberous sclerosis complex. Conclusion Our report suggests that multifocal micronodular pneumocyte hyperplasia should be considered in the differential diagnosis of bilateral, small ground-glass nodules and molecular testing may be useful to confirm the diagnosis.

During the past decade, the age-adjusted mortality rate for endometrial cancer (EC) increased 1.9% annually with TP53 mutant ( TP53 -mu) EC disproportionally represented in advanced disease and deaths. Therefore, we aimed to assess pivotal molecular parameters that differentiate clinical outcomes in high- and low-risk EC. Using the Cancer Genome Atlas, we analyzed EC specimens with available DNA sequences and quantitative gene-specific RNA expression data. After polymerase ɛ ( POLE )-mutant specimens were excluded, differential gene-specific mutations and mRNA expressions were annotated and integrated. Consequent to TP53 -mu failure to induce p21, derepression of multiple oncogenes harboring promoter p21 repressive sites was observed, including CCNA2 and FOXM1 ( P < .001 compared with TP53 wild type [ TP53 -wt]). TP53 -wt EC with high CCNA2 expression ( CCNA2 -H) had a targeted transcriptomic profile similar to that of TP53 -mu EC, suggesting CCNA2 is a seminal determinant for both TP53 -wt and TP53 -mu EC. CCNA2 enhances E2F1 function, upregulating FOXM1 and CIP2A , as observed in TP53 -mu and CCNA2 -H TP53 -wt EC ( P < .001). CIP2A inhibits protein phosphatase 2A, leading to AKT inactivation of GSK3β and restricted oncoprotein degradation; PPP2R1A and FBXW7 mutations yield similar results. Upregulation of FOXM1 and failed degradation of FOXM1 is evidenced by marked upregulation of multiple homologous recombination genes ( P < .001). Integrating these molecular aberrations generated a molecular biomarker panel with significant prognostic discrimination ( P = 5.8×10 −7 ); adjusting for age, histology, grade, myometrial invasion, TP53 status, and stage, only CCNA2 -H/ E2F1 -H ( P = .0003), FBXW7 -mu/ PPP2R1A -mu ( P = .0002), and stage ( P = .017) were significant. The generated prognostic molecular classification system identifies dissimilar signaling aberrations potentially amenable to targetable therapeutic options.

Abstract Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant CNS neoplasms that typically occur in children <2 years of age. These are characterized by high-grade histologic features and mutations of the INI1/SMARCB1 gene readily detected by loss of expression by immunohistochemistry. Among adults, the majority of AT/RTs occurs in the cerebral hemispheres. A small number of adult AT/RTs involving the sellar and suprasellar region reported in the literature suggest a distinct clinical course for this group. Here, we describe detailed clinical and genetic characterization of 5 adult patients with AT/RTs involving the sellar and suprasellar region, and provide a review of the available clinical and genetic features of 22 previously reported cases in order to help increase our understanding of this unusual entity.

Angiomatoid fibrous histiocytoma (AFH) is an uncommon soft-tissue neoplasm that arises mostly in the extremities of young people and generally carries a good prognosis. Intracranial location is unusual and frequently associated with myxoid change. EWSR1 gene fusions with members of the CREB family ( CREB1, ATF1 , and CREM ) are well-established events in AFH. These fusions have also been described in other neoplasms including intracranial myxoid mesenchymal tumor, and it is still uncertain whether the latter is a distinct entity or if it represents a myxoid variant of AFH. Here, we describe a rare falcine AFH presenting in a 50-year-old woman. The most striking feature of this tumor was its diffuse rhabdoid morphology with focal high mitotic activity, raising the consideration of rhabdoid meningioma (WHO grade III). The tumor cells were moderately positive for EMA and negative for progesterone receptor and SSTR2 prompting additional studies. Desmin was strongly positive and CD99 showed membranous immunoreactivity. BAP1, INI-1, and BRG1 expressions were retained. Next-generation sequencing analysis demonstrated an EWSR1 – ATF1 gene fusion, supporting the diagnosis of an unusual rhabdoid variant of AFH. After gross total resection of this tumor, the patient remains free of disease 5 months after the surgery without additional treatment.

The rapid evolution of mass spectrometry-based single-cell proteomics now enables the cataloging of several thousand proteins from single cells. We investigated whether we could discover cellular heterogeneity beyond proteome, encompassing post-translational modifications (PTM), protein-protein interaction, and variants. By optimizing the mass spectrometry data interpretation strategy to enable the detection of PTMs and variants, we have generated a high-definition dataset of single-cell and nuclear proteomic-states. The data demonstrate the heterogeneity of cell-states and signaling dependencies at the single-cell level and reveal epigenetic drug-induced changes in single nuclei. This approach enables the exploration of previously uncharted single-cell and organellar proteomes revealing molecular characteristics that are inaccessible through RNA profiling. This study explored single cells and single organelles to reveal unique molecular characteristics such as mutant peptides and modulation of diverse post-translational modifications that are inaccessible through DNA/RNA profiling.

Background RNA-seq is a well-established method for studying the transcriptome. Popular methods for library preparation in RNA-seq such as Illumina TruSeq® RNA v2 kit use a poly-A pulldown strategy. Such methods can cause loss of coverage at the 5′ end of genes, impacting the ability to detect fusions when used on degraded samples. The goal of this study was to quantify the effects RNA degradation has on fusion detection when using poly-A selected mRNA and to identify the variables involved in this process. Results Using both artificially and naturally degraded samples, we found that there is a reduced ability to detect fusions as the distance of the breakpoint from the 3′ end of the gene increases. The median transcript coverage decreases exponentially as a function of the distance from the 3′ end and there is a linear relationship between the coverage decay rate and the RNA integrity number (RIN). Based on these findings we developed plots that show the probability of detecting a gene fusion (“sensitivity”) as a function of the distance of the fusion breakpoint from the 3′ end. Conclusions This study developed a strategy to assess the impact that RNA degradation has on the ability to detect gene fusions by RNA-seq.