Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 ...BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.
The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed ...whole-exome sequencing (WES) on 36 PCNSL patients and targeted MYD88 sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified MYD88 mutation in 67% (42 of 63) of patients, CDKN2A biallelic loss in 44% (16 of 36), and CD79b mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, CDKN2A), with few areas of amplification. CD79b mutations were associated with improved progression-free and overall survival. We did not identify amplification at the PD-1/PD-L1 loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified MYD88 mutation and CDKN2A loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of PD-L1 amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions.
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Glioneuronal tumors constitute a histologically diverse group of primary central nervous system neoplasms that are typically slow-growing and managed conservatively. Genetic alterations associated ...with glioneuronal tumors include
mutations and oncogenic fusions. To further characterize this group of tumors, we collected a cohort of 26 glioneuronal tumors and performed in-depth genomic analysis. We identified mutations in
(34%) and oncogenic fusions (30%), consistent with previously published reports. In addition, we discovered novel oncogenic fusions involving members of the
gene family in a subset of our cohort. One-patient with
exon 13 fused to
exon 11 initially underwent a subtotal resection for a 4th ventricular glioneuronal tumor but ultimately required additional therapy due to progressive, symptomatic disease. Given the patient's targetable fusion, the patient was enrolled on a clinical trial with entrectinib, a pan-Trk, ROS1, and
(anaplastic lymphoma kinase) inhibitor. The patient was treated for 11 months and during this time volumetric analysis of the lesion demonstrated a maximum reduction of 60% in the contrast-enhancing tumor compared to his pre-treatment magnetic resonance imaging study. The radiologic response was associated with resolution of his clinical symptoms and was maintained for 11 months on treatment. This report of a
fusion in glioneuronal tumors highlights its clinical importance as a novel, targetable alteration.
Declines in reproductive performance among older age classes have been reported in many bird and mammal species, and are commonly presented as demonstrating reproductive senescence. However, no ...declines in performance could be demonstrated in studies of several bird species. We measured reproductive performance in Common Terns (Sterna hirundo) of known age (2–28 yr) during a 19-yr period at a site in Buzzards Bay, Massachusetts, USA. We measured 6 components of reproductive performance and used generalized additive mixed models (GAMMs) in a Bayesian framework to analyze dependence of each measure on parental age, while controlling for variations among years and indices of individual quality. Four measures of performance improved (earlier laying date, higher values of clutch size, fledging success, and productivity) with age, most rapidly between ages 2 and 10 yr; egg mass and hatching success varied only slightly with age. No measure of performance showed reversals among the older age classes; fledging success and productivity continued to increase through at least age 22 yr. These findings are consistent with results from an earlier study of the same species. Continued increase in reproductive performance through the oldest age classes is not incompatible with “reproductive senescence” (decline in physiological or other functions required for successful reproduction) if either reproductive effort or efficiency continue to increase. Studies within our population have yielded no evidence for age-related increase in reproductive effort, but 3 studies have suggested that older Common Terns can raise chicks more successfully than younger birds without increasing reproductive effort, probably by more efficient foraging and chick provisioning. Our findings suggest that Common Terns offset reproductive senescence by continuing to improve efficiency through at least age 22 yr. Age-related changes in efficiency should be investigated in other species with similar life-history traits. LAY SUMMARY We studied Common Terns (Sterna hirundo) at a breeding colony in Massachusetts from 1970 until 2003: we banded chicks when they hatched so that we could determine their age when they returned to breed at the same site in subsequent years. The terns' breeding success continued to improve with age throughout their lives and was still increasing among birds that were 22 years old. Common Terns continually improve their skills at finding fish and provisioning their chicks, even after 20 years of practice.
Abstract
Although lung adenocarcinomas frequently metastasize to the brain, treatment options for lung adenocarcinoma brain metastases are limited. We discovered novel candidate drivers of ...progression by using case-control analyses to compare whole-exome sequencing data from a cohort of 73 lung adenocarcinoma brain metastases to a control cohort of 503 primary lung adenocarcinomas. We identified 3 genomic regions with significantly more frequent amplifications in brain metastases compared to the control cohort: MYC (12% vs 6%), YAP1 (7% vs 0.8%) and MMP13 (10% vs 0.6%). We also identified CDKN2A/B as a region deleted at a significantly greater frequency in brain metastases compared to primary lung adenocarcinomas (27% vs 13%, respectively). We confirmed frequent amplifications of MYC and YAP1/MMP13 in an independent validation cohort of 105 lung adenocarcinoma brain metastasis samples using fluorescence in situ hybridization. We further validated that MYC, YAP1 and MMP13 can drive brain metastases in a patient-derived xenograft mouse model. We found a higher incidence of metastases to the brain in mice receiving intracardiac injections of tumor cells expressing the candidate drivers compared to tumor cells expressing LacZ as a control. These results indicate that somatic alterations can drive lung adenocarcinomas to metastasize to the brain. The candidate brain metastasis drivers that we identified may serve as therapeutic targets in patients with lung adenocarcinomas who develop this devastating complication.
Glioblastomas are malignant neoplasms composed of diverse cell populations. This intratumoral diversity has an underlying architecture, with a hierarchical relationship through clonal evolution from ...a common ancestor. Therapies are limited by emergence of resistant subclones from this phylogenetic reservoir. To characterize this clonal ancestral origin of recurrent tumors, we determined phylogenetic relationships using whole exome sequencing of pre-treatment IDH1/2 wild-type glioblastoma specimens, matched to post-treatment autopsy samples (
= 9) and metastatic extracranial post-treatment autopsy samples (
= 3). We identified "truncal" genetic events common to the evolutionary ancestry of the initial specimen and later recurrences, thereby inferring the identity of the precursor cell population. Mutations were identified in a subset of cases in known glioblastoma genes such as
(
= 3),
(
= 4) and
(
= 5). However, by phylogenetic analysis, there were no protein-coding mutations as recurrent truncal events across the majority of cases. In contrast, whole copy-loss of chromosome 10 (12 of 12 cases), copy-loss of chromosome 9p21 (11 of 12 cases) and copy-gain in chromosome 7 (10 of 12 cases) were identified as shared events in the majority of cases. Strikingly, mutations in the
promoter were also identified as shared events in all evaluated pairs (9 of 9). Thus, we define four truncal non-coding genomic alterations that represent early genomic events in gliomagenesis, that identify the persistent cellular reservoir from which glioblastoma recurrences emerge. Therapies to target these key early genomic events are needed. These findings offer an evolutionary explanation for why precision therapies that target protein-coding mutations lack efficacy in GBM.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and ...FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.
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