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Project description:Introduction: The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrences. PC is insensitive to conventional chemotherapy, and it would be necessary to reveal the molecular mechanisms of metastasis and develop targeted therapeutics. Methods: We performed the comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and the RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 PC. Results: We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated with the frequency of 21 % (3/14) and 14% (2/14), respectively. The mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in 36% (5/14) in a mutually exclusive manner. The pathway analysis of mutated genes revealed the enrichment of genes involved in the mitogen-activated protein kinase (MAPK) signaling, regulation of actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling pathways. RNA sequencing reveals a total of 8 novel fusion transcripts including one derived from chromosomal translocation between the TRIB2 and PRKCE genes. All the 8 fusion genes were detected in primary PC that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PC that had relapsed after surgical resection. Conclusions: In this study we identified novel somatic mutations and chromosomal rearrangements by examining clinically aggressive cases that had developed postsurgical metastasis. It is essential to validate their clinical significance in an independent larger patient cohort.
2020-08-04 | GSE142190 | GEO
Project description:Introduction: The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrences. PC is insensitive to conventional chemotherapy, and it would be necessary to reveal the molecular mechanisms of metastasis and develop targeted therapeutics. Methods: We performed the comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and the RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 PC. Results: We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated with the frequency of 21 % (3/14) and 14% (2/14), respectively. The mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in 36% (5/14) in a mutually exclusive manner. The pathway analysis of mutated genes revealed the enrichment of genes involved in the mitogen-activated protein kinase (MAPK) signaling, regulation of actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling pathways. RNA sequencing reveals a total of 8 novel fusion transcripts including one derived from chromosomal translocation between the TRIB2 and PRKCE genes. All the 8 fusion genes were detected in primary PC that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PC that had relapsed after surgical resection. Conclusions: In this study we identified novel somatic mutations and chromosomal rearrangements by examining clinically aggressive cases that had developed postsurgical metastasis. It is essential to validate their clinical significance in an independent larger patient cohort.
2020-08-04 | GSE142186 | GEO
Project description:Introduction: The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrences. PC is insensitive to conventional chemotherapy, and it would be necessary to reveal the molecular mechanisms of metastasis and develop targeted therapeutics. Methods: We performed the comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and the RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 PC. Results: We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated with the frequency of 21 % (3/14) and 14% (2/14), respectively. The mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in 36% (5/14) in a mutually exclusive manner. The pathway analysis of mutated genes revealed the enrichment of genes involved in the mitogen-activated protein kinase (MAPK) signaling, regulation of actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling pathways. RNA sequencing reveals a total of 8 novel fusion transcripts including one derived from chromosomal translocation between the TRIB2 and PRKCE genes. All the 8 fusion genes were detected in primary PC that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PC that had relapsed after surgical resection. Conclusions: In this study we identified novel somatic mutations and chromosomal rearrangements by examining clinically aggressive cases that had developed postsurgical metastasis. It is essential to validate their clinical significance in an independent larger patient cohort.
2020-08-04 | GSE141755 | GEO
Project description:Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence (Exome)
| PRJNA596346 | ENA
Project description:Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence
| PRJNA596184 | ENA
Project description:Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence (Affymetrix)
| PRJNA594630 | ENA
Project description:Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence (RNA)
| PRJNA596178 | ENA
Project description:Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics.
| S-EPMC9126845 | biostudies-literature
Project description:BACKGROUND:Acute unprovoked idiopathic fatal pulmonary embolism (IFPE) causes sudden death without an identifiable thrombogenic risk. We aimed to investigate the underlying genomic risks of IFPE through whole exome sequencing (WES). METHODS:We reviewed 14years of consecutive out-of-hospital fatal pulmonary embolism records (n=1478) from the ethnically diverse population of New York City. We selected 68 qualifying IFPE cases for WES. We compared the WES data of IFPE cases to those of 9332 controls to determine if there is an excess of rare damaging variants in the genome using ethnicity-matched controls in collapsing analyses. FINDINGS:We found nine of the 68 decedents (13·2%) who died of IFPE had at least one pathogenic or likely pathogenic variant in one of the three anti-coagulant genes: SERPINC1 (Antithrombin III), PROC, and PROS1. The odds ratio of developing IFPE as a variant carrier for SERPINC1 is 144·2 (95% CI, 26·3-779·4; P=1·7×10-7), for PROC is 85·6 (95% CI, 13·0-448·9; P=2.0×10-5), and for PROS1 is 56·4 (95% CI, 5·3-351·1; P=0·001). The average age-at-death of anti-coagulant gene variant carriers is significantly younger than that of non-carriers (28·56years versus 38·02years; P=0·01). INTERPRETATION:This study showed the important role of severe thrombophilia due to natural anti-coagulant deficiency in IFPE. Evaluating severe thrombophilia in out-of-hospital fatal PE beyond IFPE is warranted.
| S-EPMC5360570 | biostudies-literature
Project description:Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disorder characterized by progressive loss of pulmonary microvessels. Although mutations in the bone morphogenetic receptor 2 (BMPR2) are found in 80% of heritable and ?15% of patients with IPAH, their low penetrance (?20%) suggests that other unidentified genetic modifiers are required for manifestation of the disease phenotype. Use of whole-exome sequencing (WES) has recently led to the discovery of novel susceptibility genes in heritable PAH, but whether WES can also accelerate gene discovery in IPAH remains unknown.To determine whether WES can help identify novel gene modifiers in patients with IPAH.Exome capture and sequencing was performed on genomic DNA isolated from 12 unrelated patients with IPAH lacking BMPR2 mutations. Observed genetic variants were prioritized according to their pathogenic potential using ANNOVAR.A total of nine genes were identified as high-priority candidates. Our top hit was topoisomerase DNA binding II binding protein 1 (TopBP1), a gene involved in the response to DNA damage and replication stress. We found that TopBP1 expression was reduced in vascular lesions and pulmonary endothelial cells isolated from patients with IPAH. Although TopBP1 deficiency made endothelial cells susceptible to DNA damage and apoptosis in response to hydroxyurea, its restoration resulted in less DNA damage and improved cell survival.WES led to the discovery of TopBP1, a gene whose deficiency may increase susceptibility to small vessel loss in IPAH. We predict that use of WES will help identify gene modifiers that influence an individual's risk of developing IPAH.
| S-EPMC4225850 | biostudies-literature