Correction: Inherited variants in genes somatically mutated in thyroid cancer.
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ABSTRACT:
SUBMITTER: Campo C
PROVIDER: S-EPMC6080776 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Correction: Inherited variants in genes somatically mutated in thyroid cancer.
Campo Chiara C Köhler Aleksandra A Figlioli Gisella G Elisei Rossella R Romei Cristina C Cipollini Monica M Bambi Franco F Hemminki Kari K Gemignani Federica F Landi Stefano S Försti Asta A
PloS one 20180807 8
[This corrects the article DOI: 10.1371/journal.pone.0174995.]. ...[more]
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Project description:BackgroundTumour suppressor genes when mutated in the germline cause various cancers, but they can also be somatically mutated in sporadic tumours. We hypothesized that there may also be cancer-related germline variants in the genes commonly mutated in sporadic well-differentiated thyroid cancer (WDTC).MethodsWe performed a two-stage case-control association study with a total of 2214 cases and 2108 healthy controls from an Italian population. By genotyping 34 single nucleotide polymorphisms (SNPs), we covered a total of 59 missense SNPs and SNPs located in the 5' and 3' untranslated regions (UTRs) of 10 different genes.ResultsThe Italian1 series showed a suggestive association for 8 SNPs, from which three were replicated in the Italian2 series. The meta-analysis revealed a study-wide significant association for rs459552 (OR: 0.84, 95%CI: 0.75-0.94) and rs1800900 (OR: 1.15, 95%CI: 1.05-1.27), located in the APC and GNAS genes, respectively. The APC rs459552 is a missense SNP, located in a conserved amino acid position, but without any functional consequences. The GNAS rs1800900 is located at a conserved 5'UTR and according to the experimental ENCODE data it may affect promoter and histone marks in different cell types.ConclusionsThe results of this study yield new insights on WDTC, showing that inherited variants in the APC and GNAS genes can play a role in the etiology of thyroid cancer. Further studies are necessary to better understand the role of the identified SNPs in the development of WDTC and to functionally validate our in silico predictions.
| S-EPMC5391920 | biostudies-literature
Project description:ObjectiveTo assess whether Parkinson disease (PD) genes are somatically mutated in cutaneous melanoma (CM) tissue, because CM occurs in patients with PD at higher rates than in the general population and PD is more common than expected in CM cohorts.MethodsWe cross-referenced somatic mutations in metastatic CM detected by whole-exome sequencing with the 15 known PD (PARK) genes. We computed the empirical distribution of the sum of mutations in each gene (Smut) and of the number of tissue samples in which a given gene was mutated at least once (SSampl) for each of the analyzable genes, determined the 90th and 95th percentiles of the empirical distributions of these sums, and verified the location of PARK genes in these distributions. Identical analyses were applied to adenocarcinoma of lung (ADENOCA-LUNG) and squamous cell carcinoma of lung (SQUAMCA-LUNG). We also analyzed the distribution of the number of mutated PARK genes in CM samples vs the 2 lung cancers.ResultsSomatic CM mutation analysis (n = 246) detected 315,914 mutations in 18,758 genes. Somatic CM mutations were found in 14 of 15 PARK genes. Forty-eight percent of CM samples carried ≥1 PARK mutation and 25% carried multiple PARK mutations. PARK8 mutations occurred above the 95th percentile of the empirical distribution for SMut and SSampl. Significantly more CM samples harbored multiple PARK gene mutations compared with SQUAMCA-LUNG (p = 0.0026) and with ADENOCA-LUNG (p < 0.0001).ConclusionsThe overrepresentation of somatic PARK mutations in CM suggests shared dysregulated pathways for CM and PD.
| S-EPMC4832432 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified 13 susceptibility loci for renal cell carcinoma (RCC). Additional genetic loci of risk remain to be explored. Moreover, the role of germline genetic variants in predicting RCC recurrence and overall survival (OS) is less understood. In this study, we focused on 127 significantly mutated genes from The Cancer Genome Atlas (TCGA) Pan-Cancer Analysis across 12 major cancer sites to identify potential genetic variants predictive of RCC risk and clinical outcomes. In a three-phase design with a total of 2657 RCC cases and 5315 healthy controls, two single nucleotide polymorphisms (SNPs) that map to PIK3CG (rs6466135:A, ORmeta = 0.85, 95% CI = 0.77-0.94, Pmeta = 1.4 × 10-3) and ATM (rs611646:T, ORmeta = 1.17, 95% CI = 1.05-1.31, Pmeta = 3.5 × 10-3) were significantly associated with RCC risk. With respect to RCC recurrence and OS, two separate datasets with a total of 661 stages I-III RCC patients (discovery: 367; validation: 294) were analyzed. The most significant association was observed for rs10932384:C (ERBB4) with both outcomes (recurrence: HRmeta = 0.52, 95% CI = 0.39-0.68, Pmeta = 3.81 × 10-6; OS: HRmeta = 0.50, 95% CI = 0.37-0.67, Pmeta = 6.00 × 10-6). In addition, six SNPs were significantly associated with either RCC recurrence or OS but not both (Pmeta < 0.01). Rs10932384:C was significantly correlated with mutation frequency of ERBB4 in clear cell RCC (ccRCC) patients (P = 0.003, Fisher's exact test). Cis-eQTL was observed for several SNPs in blood/transformed fibroblasts but not in RCC tumor tissues. In summary, we identified promising genetic predictors of recurrence and OS among RCC patients with localized disease.
| S-EPMC5972595 | biostudies-literature
Project description:A recent study published by Sjoblom and colleagues [T. Sjoblom, S. Jones, L.D. Wood, D.W. Parsons, J. Lin, T.D. Barber, D. Mandelker, R.J. Leary, J. Ptak, N. Silliman, S. Szabo, P. Buckhaults, C. Farrell, P. Meeh, S.D. Markowitz, J. Willis, D. Dawson, J.K. Willson, A.F. Gazdar, J. Hartigan, L. Wu, C. Liu, G. Parmigiani, B.H. Park, K.E. Bachman, N. Papadopoulos, B. Vogelstein, K.W. Kinzler, V.E. Velculescu, The consensus coding sequences of human breast and colorectal cancers. Science 314 (2006) 268-274.] performed comprehensive sequencing of 13,023 human genes and identified mutations in genes specific to breast and colorectal tumors, providing insight into organ-specific tumor biology. Here we present a systematic analysis of the functional classifications of Sjoblom's "CAN" genes, a subset of these validated mutant genes, that identifies novel organ-specific biological themes and molecular pathways associated with disease-specific etiology. This analysis links four somatically mutated genes associated with diverse oncological types to colorectal and breast cancers through established TGF-beta1-regulated interactions, revealing mechanistic differences in these cancers and providing potential diagnostic and therapeutic targets.
| S-EPMC2492759 | biostudies-literature
Project description:Mutant epitopes encoded by cancer genes are virtually always located in the interior of cells, making them invisible to conventional antibodies. We here describe an approach to identify single-chain variable fragments (scFvs) specific for mutant peptides presented on the cell surface by HLA molecules. We demonstrate that these scFvs can be successfully converted to full-length antibodies, termed MANAbodies, targeting "Mutation-Associated Neo-Antigens" bound to HLA. A phage display library representing a highly diverse array of single-chain variable fragment sequences was first designed and constructed. A competitive selection protocol was then used to identify clones specific for mutant peptides bound to predefined HLA types. In this way, we obtained two scFvs, one specific for a peptide encoded by a common KRAS mutant and the other by a common epidermal growth factor receptor (EGFR) mutant. The scFvs bound to these peptides only when the peptides were complexed with HLA-A2 (KRAS peptide) or HLA-A3 (EGFR peptide). We converted one scFv to a full-length antibody (MANAbody) and demonstrate that the MANAbody specifically reacts with mutant peptide-HLA complex even when the peptide differs by only one amino acid from the normal, WT form.
| S-EPMC4538619 | biostudies-literature
Project description:Phosphoinositide 3-kinase (PI3K) is an important therapeutic target. Mutations in PIK3CA, which encodes p110α, the catalytic subunit of PI3K, occur in endometrioid endometrial cancers (EEC) and nonendometrioid endometrial cancers (NEEC). The goal of this study was to determine whether PIK3R1, which encodes p85α, the inhibitory subunit of PI3K, is mutated in endometrial carcinoma. We carried out exonic sequencing of PIK3R1 from 42 EECs and 66 NEECs. The pattern of PIK3R1 mutations was compared with the patterns of PIK3CA, PTEN, and KRAS mutations. The biochemical effect of seven PIK3R1 mutations was examined by stable expression in U2OS cells, followed by coimmunoprecipitation analysis of p110α, and Western blotting of phospho-AKT(Ser473) (p-AKT(Ser473)). We found that PIK3R1 was somatically mutated in 43% of EECs and 12% of NEECs. The majority of mutations (93.3%) were localized to the p85α-nSH2 and -iSH2 domains. Several mutations were recurrent. PIK3R1 mutations were significantly (P = 0.0015) more frequent in PIK3CA-wild type EECs (70%) than in PIK3CA mutant EECs (18%). Introduction of wild-type p85α into U2OS cells reduced the level of p-AKT(Ser473) compared with the vector control. Five p85α mutants, p85αdelH450-E451, p85αdelK459, p85αdelY463-L466, p85αdelR574-T576, and the p85αN564D positive control, were shown to bind p110α and led to increased levels of p-AKT(Ser473). The p85αR348X and p85αK511VfsX2 mutants did not bind p110α and showed no appreciable change in p-AKT(Ser473) levels. In conclusion, our study has revealed a new mode of PI3K alteration in primary endometrial tumors and warrants future studies to determine whether PIK3R1 mutations correlate with clinical outcome to targeted therapies directed against the PI3K pathway in EEC and NEEC.
| S-EPMC3117071 | biostudies-literature
Project description:MicroRNAs are key regulators of gene expression and have been shown to have altered expression in a variety of cancer types, including epithelial ovarian cancer. MiRNA function is most often achieved through binding to the 3'-untranslated region of the target protein coding gene. Mutation screening using massively-parallel sequencing of 712 miRNA genes in 86 ovarian cancer cases identified only 5 mutated miRNA genes, each in a different case. One mutation was located in the mature miRNA, and three mutations were predicted to alter the secondary structure of the miRNA transcript. Screening of the 3'-untranslated region of 18 candidate cancer genes identified one mutation in each of AKT2, EGFR, ERRB2 and CTNNB1. The functional effect of these mutations is unclear, as expression data available for AKT2 and EGFR showed no increase in gene transcript. Mutations in miRNA genes and 3'-untranslated regions are thus uncommon in ovarian cancer.
| S-EPMC3334977 | biostudies-literature
Project description:Immunoglobulin (Ig)M+IgD+ B cells are generally assumed to represent antigen-inexperienced, naive B cells expressing variable (V) region genes without somatic mutations. We report here that human IgM+IgD+ peripheral blood (PB) B cells expressing the CD27 cell surface antigen carry mutated V genes, in contrast to CD27-negative IgM+IgD+ B cells. IgM+IgD+CD27(+) B cells resemble class-switched and IgM-only memory cells in terms of cell phenotype, and comprise approximately 15% of PB B lymphocytes in healthy adults. Moreover, a very small population (<1% of PB B cells) of highly mutated IgD-only B cells was detected, which likely represent the PB counterpart of IgD-only tonsillar germinal center and plasma cells. Overall, the B cell pool in the PB of adults consists of approximately 40% mutated memory B cells and 60% unmutated, naive IgD+CD27(-) B cells (including CD5(+) B cells). In the somatically mutated B cells, VH region genes carry a two- to threefold higher load of somatic mutation than rearranged Vkappa genes. This might be due to an intrinsically lower mutation rate in kappa light chain genes compared with heavy chain genes and/or result from kappa light chain gene rearrangements in GC B cells. A common feature of the somatically mutated B cell subsets is the expression of the CD27 cell surface antigen which therefore may represent a general marker for memory B cells in humans.
| S-EPMC2212515 | biostudies-literature
Project description:We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk.Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog) was associated with risk of serous cancer (p = 0.03); haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog) were associated with risk of invasive disease (p = 0.03). MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95% CI 0.66-0.98; p = 0.03). SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p<0.05), and there was increased risk at HEXIM1 rs1053578 (p = 0.04, OR 1.40, 95% CI 1.02-1.91).Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasive serous ovarian cancer.
| S-EPMC2811736 | biostudies-literature
Project description:BACKGROUND: The developmental stage from which stems the malignant B cell population in Burkitt's lymphoma (BL) is unclear. An approach to answering this question is provided by the sequence analysis of rear-ranged immunoglobulin (Ig) variable region (V) genes from BL for evidence of somatic mutations, together with a phenotypic characterization. As somatic hypermutation of Ig V region genes occurs in germinal center B cells, somatically mutated Ig genes are found in germinal center B cells and their descendents. MATERIALS AND METHODS: Rearranged V kappa region genes from 10 kappa-expressing sporadic and endemic BL-derived cell lines (9 IgM and 1 IgG positive) and three kappa-expressing endemic BL biopsy specimens were amplified by polymerase chain reaction and sequenced. In addition, VH region gene sequences from these cell lines were determined. RESULTS: All BL cell lines and the three biopsy specimens carried somatically mutated V region genes. The average mutation frequency of rearranged V kappa genes from eight BL cell lines established from sporadic BL was 1.8%. A higher frequency (6%) was found in five endemic cases (three biopsy specimens and two BL cell lines). CONCLUSIONS: The detection of somatic mutations in the rearranged V region genes suggests that both sporadic and endemic BL represent a B-cell malignancy originating from germinal center B cells or their descendants. Interestingly, the mutation frequency detected in sporadic BL is in a range similar to that characteristic for IgM-expressing B cells in the human peripheral blood and for mu chain-expressing germinal center B cells, whereas the mutation frequency found in endemic BL is significantly higher.
| S-EPMC2229966 | biostudies-other