Recurrent somatic JAK3 mutations in NK-cell enteropathy.
Ontology highlight
ABSTRACT:
SUBMITTER: Xiao W
PROVIDER: S-EPMC6753620 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:INTRODUCTION:Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance. METHODS:We identified patients who had SRMs (4cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC. Patients were selected from 3 publicly available cohorts, The Cancer Genome Atlas (n = 110), University of Tokyo (n = 37), The International Cancer Genome Consortium (n = 31), and from our own institutional prospective database (n = 25). Among this cohort we analyzed mutations present in at least 5% of tumors, assessing for the enrichment of mutations and progression-free survival using the composite endpoint of recurrence or death of disease. Analysis was adjusted for multiple testing. A Cox regression model was used to assess clinical variables with significant mutations. RESULTS:In total, 203 patients were available for analysis. Median follow-up was 43.1 months among survivors. Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C, and MTOR were present in more than 5% of tumors. Twenty-three patients (11.3%) had recurrence or died of their disease. Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P 0.033. CONCLUSIONS:We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality. The strongest association was seen in those with KDM5C mutations. Use of these genomic biomarkers may improve stratification of patients with SRMs and for those who may be appropriate for active surveillance. Prospective evaluation of these markers is needed.
| S-EPMC5984192 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) has transformed the treatment of metastatic cancer but is hindered by variable response rates. A key unmet need is the identification of biomarkers that predict treatment response. To address this, we analyzed six whole exome sequencing cohorts with matched disease outcomes to identify genes and pathways predictive of ICB response. To increase detection power, we focus on genes and pathways that are significantly mutated following correction for epigenetic, replication timing, and sequence-based covariates. Using this technique, we identify several genes (BCLAF1, KRAS, BRAF, and TP53) and pathways (MAPK signaling, p53 associated, and immunomodulatory) as predictors of ICB response and develop the Cancer Immunotherapy Response CLassifiEr (CIRCLE). Compared to tumor mutational burden alone, CIRCLE led to superior prediction of ICB response with a 10.5% increase in sensitivity and a 11% increase in specificity. We envision that CIRCLE and more broadly the analysis of recurrently mutated cancer genes will pave the way for better prognostic tools for cancer immunotherapy.
| S-EPMC9270330 | biostudies-literature
Project description:Many recent publications highlight the large role of the pivotal eukaryotic nuclear export protein exportin-1 (XPO1) in the oncogenesis of several malignancies, and there is emerging evidence that XPO1 inhibition is a key target against cancer. The clinical validation of the pharmacological inhibition of XPO1 was recently achieved with the development of the selective inhibitor of nuclear export compounds, displaying an interesting anti-tumor activity in patients with massive pre-treated hematological malignancies. Recent reports have shown molecular alterations in the gene encoding XPO1 and showed a mutation hotspot (E571K) in the following two hematological malignancies with similar phenotypes and natural histories: primary mediastinal diffuse large B cell lymphoma and classical Hodgkin's lymphoma. Emerging evidence suggests that the mutant XPO1 E571K plays a role in carcinogenesis, and this variant is quantifiable in tumor and plasma cell-free DNA of patients using highly sensitive molecular biology techniques, such as digital PCR and next-generation sequencing. Therefore, it was proposed that the XPO1 E571K variant may serve as a minimal residual disease tool in this setting. To clarify and summarize the recent findings on the role of XPO1 in B cell hematological malignancies, we conducted a literature search to present the major publications establishing the landscape of XPO1 molecular alterations, their impact on the XPO1 protein, their interest as biomarkers, and investigations into the development of new XPO1-targeted therapies in B cell hematological malignancies.
| S-EPMC5307790 | biostudies-literature
Project description:Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma, yet it remains only partially characterized at the genomic level. To improve our understanding of the genetic underpinnings of this incurable and clinically heterogeneous disease, whole-exome sequencing was performed on tumor/normal pairs from a discovery cohort of 24 patients with FL. Using these data and mutations identified in other B-cell malignancies, 1716 genes were sequenced in 113 FL tumor samples from 105 primarily treatment-naive individuals. We identified 39 genes that were mutated significantly above background mutation rates. CREBBP mutations were associated with inferior PFS. In contrast, mutations in previously unreported HVCN1, a voltage-gated proton channel-encoding gene and B-cell receptor signaling modulator, were associated with improved PFS. In total, 47 (44.8%) patients harbor mutations in the interconnected B-cell receptor (BCR) and CXCR4 signaling pathways. Histone gene mutations were more frequent than previously reported (identified in 43.8% of patients) and often co-occurred (17.1% of patients). A novel, recurrent hotspot was identified at a posttranslationally modified residue in the histone H2B family. This study expands the number of mutated genes described in several known signaling pathways and complexes involved in lymphoma pathogenesis (BCR, Notch, SWitch/sucrose nonfermentable (SWI/SNF), vacuolar ATPases) and identified novel recurrent mutations (EGR1/2, POU2AF1, BTK, ZNF608, HVCN1) that require further investigation in the context of FL biology, prognosis, and treatment.
| S-EPMC5270390 | biostudies-literature
Project description:Cardiac myxomas are benign tumors that commonly arise within the left atria. Familial cardiac myxomas are a part of Carney Complex (CNC), an autosomal dominant multiple neoplasia syndrome caused by germline mutations in PRKAR1A. Seven percent of cardiac myxomas are associated with CNC. To date, the genetic basis of isolated cardiac myxomas (ICM), however, has not been fully elucidated.We investigated the genetic profile of ICM using whole exome sequencing (WES). Suspected mutations were confirmed using targeted sanger sequencing. To further examine the presence of PRKAR1A mutations in ICM, we performed targeted sequencing in an additional 61 ICM specimens.87.5% (7/8) of ICM harbored mutations in PRKAR1A. Three of the 8 ICM harbored biallelic somatic mutations of PRKAR1A, including c.607_610del:p.Leu203fs (pathogenic) + c.C896G:p.Ser299X (pathogenic), c.952delT:p.Leu318fs (pathogenic) + c.769-2 A>G (pathogenic) and c.178-1 G>C (pathogenic) + c. 550+1 G>C (pathogenic). Four of 8 tumors harbored monoallelic PRKAR1A mutations, including c.523_524insG:p.Tyr175_Val176delinsX (pathogenic), c.C920A:p.Ser307X (pathogenic), c.30delG:p.Glu10fs (pathogenic) and c.C289T:p.Arg97X (pathogenic). No identical variants were observed across the 8 ICM samples. Interestingly, none of these variants have been previously described in familial cardiac myxomas. In order to confirm our findings, directed sequencing of 61 ICM specimens was subsequently performed. Sixty-four percent (39/61) of ICMs tumors contained inactivating PRKAR1A mutations.Our findings suggest that loss-of-function mutations of PRKAR1A may play a vital role in the formation of isolated cardiac myxomas.
| S-EPMC5732779 | biostudies-literature
Project description:We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1(P29S)) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1(P29S) showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.
| S-EPMC3432702 | biostudies-literature
Project description:In addition to somatic mutations, germline genetic predisposition to hematologic malignancies is currently emerging as an area attracting high research interest. In this study, we investigated genetic alterations in Korean acute lymphoblastic leukemia/lymphoma (ALL) patients using targeted gene panel sequencing. To this end, a gene panel consisting of 81 genes that are known to be associated with 23 predisposition syndromes was investigated. In addition to sequence variants, gene-level copy number variations (CNVs) were investigated as well. We identified 197 somatic sequence variants and 223 somatic CNVs. The IKZF1 alteration was found to have an adverse effect on overall survival (OS) and relapse-free survival (RFS) in childhood ALL. We found recurrent somatic alterations in Korean ALL patients similar to previous studies on both prevalence and prognostic impact. Six patients were found to be carriers of variants in six genes associated with primary immunodeficiency disorder (PID). Of the 81 genes associated with 23 predisposition syndromes, this study found only one predisposition germline mutation (TP53) (1.1%). Altogether, our study demonstrated a low probability of germline mutation predisposition to ALL in Korean ALL patients.
| S-EPMC8076247 | biostudies-literature
Project description:Aberrant regulation of gene expression in cancer can promote survival and proliferation of cancer cells. Here we integrate whole-genome sequencing data from The Cancer Genome Atlas (TCGA) for 436 patients from 8 cancer subtypes with ENCODE and other regulatory annotations to identify point mutations in regulatory regions. We find evidence for positive selection of mutations in transcription factor binding sites, consistent with these sites regulating important cancer cell functions. Using a new method that adjusts for sample- and genomic locus-specific mutation rates, we identify recurrently mutated sites across individuals with cancer. Mutated regulatory sites include known sites in the TERT promoter and many new sites, including a subset in proximity to cancer-related genes. In reporter assays, two new sites display decreased enhancer activity upon mutation. These data demonstrate that many regulatory regions contain mutations under selective pressure and suggest a greater role for regulatory mutations in cancer than previously appreciated.
| S-EPMC4485503 | biostudies-literature
Project description:Prostate cancer is a highly heritable molecularly and clinically heterogeneous disease. To discover germline events involved in prostate cancer predisposition, we develop a computational approach to nominate heritable facilitators of somatic genomic events in the context of the androgen receptor signaling. Here, we use a ranking score and benign prostate transcriptomes to identify a non-coding polymorphic regulatory element at 7p14.3 that associates with DNA repair and hormone-regulated transcript levels and with an early recurrent prostate cancer-specific somatic mutation in the Speckle-Type POZ protein (SPOP) gene. The locus shows allele-specific activity that is concomitantly modulated by androgen receptor and by CCAAT/enhancer-binding protein (C/EBP) beta (CEBPB). Deletion of this locus via CRISPR-Cas9 leads to deregulation of the genes predicted to interact with the 7p14.3 locus by Hi-C chromosome conformation capture data. This study suggests that a polymorphism at 7p14.3 may predispose to SPOP mutant prostate cancer subclass through a hormone-dependent DNA damage response.Prostate cancer is a heterogeneous disease, and many cases show somatic mutations of SPOP. Here, the authors show that a non-coding polymorphic regulatory element at 7p14.3 may predispose to SPOP mutant prostate cancer subclass through a hormone dependent DNA damage response.
| S-EPMC5491529 | biostudies-literature
Project description:Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel. The patients ranged in age from 28 to 68 years (mean, 45.6 y; median, 40.5 y). All tumors had diffuse p16 and synaptophysin expression. All but 1 tumor was positive for chromogranin (extent of staining ranged from focal to diffuse). HPV 18 was detected in 6 tumors and HPV 35 in 1 tumor. At least 1 driver mutation was detected in 8 tumors. Four cases harbored TP53 somatic mutations, 3 of which correlated with an aberrant p53 staining pattern. Four PIK3CA mutations (p.G106A, p.N345T, p.E545K, and p.E545D) were detected in 3 tumors, 2 of which also harbored TP53 mutations. Oncogenic driver mutations involving KRAS, Erbb2, c-Myc, NOTCH1, BCL6, or NCOA3 were detected in 4 tumors. Mutations in caretaker tumor suppressors PTEN, RB1, BRCA1, BRCA2, and ARID1B were also identified in 4 tumors that commonly coharbored activating oncogenic mutations. Targeted next-generation gene sequencing identified genetic alterations involving the MAPK, PI3K/AKT/mTOR, and TP53/BRCA pathways in SCNECs. The presence of genetic alterations that are amenable to targeted therapy in SCNECs offers the potential for individualized management strategies for treatment of this aggressive tumor.
| S-EPMC5943084 | biostudies-literature