scholarly journals Whole Exon Sequencing of Primary Lesion and Liver Metastatic Lesion in Pancreatic Neuroendocrine Tumor：A Case Report and Review of the Literature

2021 ◽  
Author(s):  
Yanfen Shi ◽  
Dingrong Zhong ◽  
Yuanliang Li ◽  
Huangying Tan ◽  
Zhaoqing Li ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Liver Lesion ◽  
Metastatic Lesion ◽  
Neuroendocrine Neoplasms ◽  
Case Presentation ◽  
Whole Exome ◽  
Number Variation ◽  
Pancreatic Net ◽  
Net G3 ◽  
Cell Atypia

Abstract Background: Pancreatic neuroendocrine neoplasms(p-NENs) are classified into neuroendocrine tumors (NET) G1, G2, G3, and neuroendocrine carcinoma (NEC) according to WHO classification. NET and NEC are different pathogenesis. The two kinds of tumors that occurred in the same part have not been reported. We found 4 foci of NEN G3 in a primary pancreatic NET G2. The cell atypia was obvious with Ki67 index of 50-70%, focal necrosis, there were 12 hepatic metastatic nodules with similar morphology to NEN G3, which is difficult to identify NEC and NET G3.Case presentation: A patient with pancreatic NET was selected to perform whole exome sequencing on primary pancreatic NET G2 and liver metastatic NEN G3 paraffin tissues.NET G2 had 13 somatic mutations, while NEN G3 had 72 somatic mutations and Copy number variation in 4 genes. P.S493N point mutation of TRIOBP gene was detected in NET G2 and NEN G3. 5-fold amplification of MDM4 is found in the metastatic liver lesion.Conclusion: NET G2 and NEN G3 are closely related to TRIOBP gene. Oncogene amplification (MDM4) in liver metastases may be associated with morphological malignant transformation.

scholarly journals A novel 14q13.1–21.1 deletion identified by CNV-Seq in a patient with brain-lung-thyroid syndrome, tooth agenesis and immunodeficiency

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuyun Hu ◽  
Jun Liu ◽  
Ruolan Guo ◽  
Jun Guo ◽  
Zhipeng Zhao ◽  
...  
Keyword(s):  
De Novo ◽  
Deletion Syndrome ◽  
Tooth Agenesis ◽  
Diagnostic Strategy ◽  
Genomic Disorder ◽  
Case Presentation ◽  
Whole Exome ◽  
Number Variation ◽  
Phenotype Heterogeneity ◽  
Genomic Disorders

Abstract Background Chromosome 14q11-q22 deletion syndrome (OMIM 613457) is a rare genomic disorder. The phenotype heterogeneity depends on the deletion size, breakpoints and genes deleted. Critical genes like FOXG1, NKX2–1, PAX9 were identified. Case presentation We performed whole exome sequencing (WES) and copy number variation sequencing (CNV-seq) for a patient with mild speech and motor developmental delay, short stature, recurrent pulmonary infections, tooth agenesis and triad of brain-lung-thyroid syndrome. By using CNV-seq, we identified a 3.1 Mb de novo interstitial deletion of the 14q13.2q21.1 region encompassing 17 OMIM genes including NKX2–1, PAX9 and NFKBIA. Our patient’s phenotype is consistent with other published 14q13 deletion patients. Conclusion Our results showed the combination of WES and CNV-seq is an effective diagnostic strategy for patients with genetic or genomic disorders. After reviewing published patients, we also proposed a new critical region for 14q13 deletion syndrome with is a more benign disorder compared to 14q11-q22 deletion syndrome.

Rare Germline GLMN Variants Identified from Blue Rubber Bleb Nevus Syndrome Might Impact mTOR Signaling

2020 ◽  
Vol 22 (10) ◽  
pp. 675-682 ◽  
Author(s):  
Jie Yin ◽  
Zhongping Qin ◽  
Kai Wu ◽  
Yufei Zhu ◽  
Landian Hu ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Sanger Sequencing ◽  
Somatic Mutations ◽  
Venous Malformation ◽  
Underlying Disease ◽  
Mtor Signaling ◽  
Functional Effect ◽  
Germline Variants ◽  
Whole Exome

Backgrounds and Objective: Blue rubber bleb nevus syndrome (BRBN) or Bean syndrome is a rare Venous Malformation (VM)-associated disorder, which mostly affects the skin and gastrointestinal tract in early childhood. Somatic mutations in TEK have been identified from BRBN patients; however, the etiology of TEK mutation-negative patients of BRBN need further investigation. Method: Two unrelated sporadic BRBNs and one sporadic VM were firstly screened for any rare nonsilent mutation in TEK by Sanger sequencing and subsequently applied to whole-exome sequencing to identify underlying disease causative variants. Overexpression assay and immunoblotting were used to evaluate the functional effect of the candidate disease causative variants. Results: In the VM case, we identified the known causative somatic mutation in the TEK gene c.2740C>T (p.Leu914Phe). In the BRBN patients, we identified two rare germline variants in GLMN gene c.761C>G (p.Pro254Arg) and c.1630G>T(p.Glu544*). The GLMN-P254R-expressing and GLMN-E544X-expressing HUVECs exhibited increased phosphorylation of mTOR-Ser-2448 in comparison with GLMN-WTexpressing HUVECs in vitro. Conclusion: Our results demonstrated that rare germline variants in GLMN might contribute to the pathogenesis of BRBN. Moreover, abnormal mTOR signaling might be the pathogenesis mechanism underlying the dysfunction of GLMN protein.

scholarly journals Mixed neuroendocrine–non-neuroendocrine neoplasms of the gallbladder: a case report

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Tatsuki Ishikawa ◽  
Katsunori Nakano ◽  
Masafumi Osaka ◽  
Kenichi Aratani ◽  
Kadotani Yayoi ◽  
...  
Keyword(s):  
System Analysis ◽  
Cancer Control ◽  
Staging System ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Regional Lymph Nodes ◽  
Abdominal Ultrasonography ◽  
Case Presentation ◽  
History Of ◽  
Lymph Nodes Dissection

Abstract Background  Primary neuroendocrine tumors of the gallbladder (GB-NETs) are rare, accounting for 0.5% of all NETs and 2.1% of all gallbladder cancers. Among GB-NETs, mixed neuroendocrine–non-neuroendocrine neoplasms of the gallbladder (GB-MiNENs) are extremely rare. Case presentation We present the case of a 66-year-old woman who was referred to us for the management of a gallbladder tumor (incidentally found during abdominal ultrasonography indicated for gallbladder stones). The patient had no history of abdominal pain or fever, and the findings on a physical examination were unremarkable. Blood tests showed normal levels of tumor markers. Imaging studies revealed a mass of approximately 10 mm in diameter (with no invasion of the gallbladder bed) located at the fundus of the gallbladder. A gallbladder cancer was suspected. Therefore, an open whole-layer cholecystectomy with regional lymph nodes dissection was performed. The postoperative course was uneventful, and she was discharged on postoperative day 6. Pathological findings showed GB-MiNENs with invasion of the subserosal layer and no lymph node invasion (classified T2aN0M0 pStage IIA according to the Union for International Cancer Control, 8th edition staging system). Analysis of the neuroendocrine markers revealed positive chromogranin A and synaptophysin, and a Ki-67 index above 95%. Fourteen months after the operation, a local recurrence was detected, and she was referred to another hospital for chemotherapy. Conclusions  GB-MiNENs are extremely aggressive tumors despite their tumor size. Optimal therapy should be chosen for each patient.

scholarly journals Retroperitoneal fibrous tumor recurring as lung metastases after 10 years: a case report

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kozue Matsuishi ◽  
Kojiro Eto ◽  
Atsushi Morito ◽  
Hirokazu Hamasaki ◽  
Keisuke Morita ◽  
...  
Keyword(s):  
Case Report ◽  
Solitary Fibrous Tumor ◽  
Distant Metastasis ◽  
Curative Resection ◽  
Lung Metastases ◽  
Lung Resection ◽  
Left Lung ◽  
Metastatic Lesion ◽  
Case Presentation ◽  
Fibrous Tumor

Abstract Background Solitary fibrous tumor (SFT) is a relatively rare mesenchymal tumor that mainly affects adults. Its prognosis is good after curative resection, but distant recurrences after 10 years or longer have been reported. Recurrent SFT usually arises as a local lesion; distant metastasis is rarely reported. Here, we report lung metastases that recurred a decade after excising a retroperitoneal primary SFT. Case presentation A 44-year-old woman had an SFT resected from her right retroperitoneum at our hospital. Ten years later, at age 54, she underwent a lung resection after CT showed three suspected metastases in her left lung. All three were histologically diagnosed as lung metastases from the retroperitoneal SFT. However, whereas the primary SFT had 1–2 mitotic cells/10 high power fields (HPF), the metastatic lesion increased malignancy, at 50/10 HPF. Conclusion Patients who have had resected SFTs should be carefully followed up, as malignancy may change in distant metastasis, as in this case.

scholarly journals Germline and somatic mutations in the pathology of pineal cyst: A whole‐exome sequencing study of 93 individuals

2021 ◽  
Author(s):  
Yuanqing Yan ◽  
Rebecca Martinez ◽  
Maria N. Rasheed ◽  
Joshua Cahal ◽  
Zhen Xu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Pineal Cyst ◽  
Whole Exome

scholarly journals A simple method to estimate the in-house limit of detection for genetic mutations with low allele frequencies in whole-exome sequencing analysis by next-generation sequencing

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Takumi Miura ◽  
Satoshi Yasuda ◽  
Yoji Sato
Keyword(s):  
Next Generation Sequencing ◽  
Allele Frequency ◽  
Somatic Mutations ◽  
Limit Of Detection ◽  
Allele Frequencies ◽  
Genetic Mutations ◽  
Sequencing Data ◽  
Simple Method ◽  
Whole Exome ◽  
Generation Sequencing

Abstract Background Next-generation sequencing (NGS) has profoundly changed the approach to genetic/genomic research. Particularly, the clinical utility of NGS in detecting mutations associated with disease risk has contributed to the development of effective therapeutic strategies. Recently, comprehensive analysis of somatic genetic mutations by NGS has also been used as a new approach for controlling the quality of cell substrates for manufacturing biopharmaceuticals. However, the quality evaluation of cell substrates by NGS largely depends on the limit of detection (LOD) for rare somatic mutations. The purpose of this study was to develop a simple method for evaluating the ability of whole-exome sequencing (WES) by NGS to detect mutations with low allele frequency. To estimate the LOD of WES for low-frequency somatic mutations, we repeatedly and independently performed WES of a reference genomic DNA using the same NGS platform and assay design. LOD was defined as the allele frequency with a relative standard deviation (RSD) value of 30% and was estimated by a moving average curve of the relation between RSD and allele frequency. Results Allele frequencies of 20 mutations in the reference material that had been pre-validated by droplet digital PCR (ddPCR) were obtained from 5, 15, 30, or 40 G base pair (Gbp) sequencing data per run. There was a significant association between the allele frequencies measured by WES and those pre-validated by ddPCR, whose p-value decreased as the sequencing data size increased. By this method, the LOD of allele frequency in WES with the sequencing data of 15 Gbp or more was estimated to be between 5 and 10%. Conclusions For properly interpreting the WES data of somatic genetic mutations, it is necessary to have a cutoff threshold of low allele frequencies. The in-house LOD estimated by the simple method shown in this study provides a rationale for setting the cutoff.

scholarly journals Genomic alterations caused by HPV integration in a cohort of Chinese endocervical adenocarcinomas

2021 ◽  
Author(s):  
Wenhui Li ◽  
Wanjun Lei ◽  
Xiaopei Chao ◽  
Xiaochen Song ◽  
Yalan Bi ◽  
...  
Keyword(s):  
Copy Number ◽  
Somatic Mutations ◽  
Hpv Infection ◽  
Copy Number Variations ◽  
Cervical Adenocarcinoma ◽  
Structural Variations ◽  
Driver Genes ◽  
Genetic Changes ◽  
Genomic Changes ◽  
Whole Exome

AbstractThe association between human papillomavirus (HPV) integration and relevant genomic changes in uterine cervical adenocarcinoma is poorly understood. This study is to depict the genomic mutational landscape in a cohort of 20 patients. HPV+ and HPV− groups were defined as patients with and without HPV integration in the host genome. The genetic changes between these two groups were described and compared by whole-genome sequencing (WGS) and whole-exome sequencing (WES). WGS identified 2916 copy number variations and 743 structural variations. WES identified 6113 somatic mutations, with a mutational burden of 2.4 mutations/Mb. Six genes were predicted as driver genes: PIK3CA, KRAS, TRAPPC12, NDN, GOLGA6L4 and BAIAP3. PIK3CA, NDN, GOLGA6L4, and BAIAP3 were recognized as significantly mutated genes (SMGs). HPV was detected in 95% (19/20) of patients with cervical adenocarcinoma, 7 of whom (36.8%) had HPV integration (HPV+ group). In total, 1036 genes with somatic mutations were confirmed in the HPV+ group, while 289 genes with somatic mutations were confirmed in the group without HPV integration (HPV− group); only 2.1% were shared between the two groups. In the HPV+ group, GOLGA6L4 and BAIAP3 were confirmed as SMGs, while PIK3CA, NDN, KRAS, FUT1, and GOLGA6L64 were identified in the HPV− group. ZDHHC3, PKD1P1, and TGIF2 showed copy number amplifications after HPV integration. In addition, the HPV+ group had significantly more neoantigens. HPV integration rather than HPV infection results in different genomic changes in cervical adenocarcinoma.

scholarly journals Mutation Profile of Aggressive Pheochromocytoma and Paraganglioma with Comparison of TCGA Data

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2389
Author(s):  
Yun Mi Choi ◽  
Jinyeong Lim ◽  
Min Ji Jeon ◽  
Yu-Mi Lee ◽  
Tae-Yon Sung ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
The Cancer Genome Atlas ◽  
Sequencing Analysis ◽  
Poor Overall Survival ◽  
Sdhb Mutation ◽  
Targeted Next Generation Sequencing ◽  
Mutation Profile ◽  
Next Generation Sequencing Analysis ◽  
Number Variation ◽  
Frequent Mutations

In pheochromocytoma and paraganglioma (PPGL), germline or somatic mutations in one of the known susceptibility genes are identified in up to 60% patients. However, the peculiar genetic events that drive the aggressive behavior including metastasis in PPGL are poorly understood. We performed targeted next-generation sequencing analysis to characterize the mutation profile in fifteen aggressive PPGL patients and compared accessible data of aggressive PPGLs from The Cancer Genome Atlas (TCGA) with findings of our cohort. A total of 115 germline and 34 somatic variants were identified with a median 0.58 per megabase tumor mutation burden in our cohort. The most frequent mutation was SDHB germline mutation (27%) and the second frequent mutations were somatic mutations for SETD2, NF1, and HRAS (13%, respectively). Patients were subtyped into three categories based on the kind of mutated genes: pseudohypoxia (n = 5), kinase (n = 5), and unknown (n = 5) group. In copy number variation analysis, deletion of chromosome arm 1p harboring SDHB gene was the most frequently observed. In our cohort, SDHB mutation and pseudohypoxia subtype were significantly associated with poor overall survival. In conclusion, subtyping of mutation profile can be helpful in aggressive PPGL patients with heterogeneous prognosis to make relevant follow-up plan and achieve proper treatment.

Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors

2021 ◽  
Author(s):  
Juan Chen ◽  
Yan Li ◽  
Jianlei Wu ◽  
Yakun Liu ◽  
Shan Kang
Keyword(s):  
Germ Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Peripheral Blood ◽  
Copy Number ◽  
Somatic Mutations ◽  
Germ Cell Tumors ◽  
Germline Mutations ◽  
Deletion Region ◽  
Whole Exome

Abstract Background Malignant ovarian germ cell tumors (MOGCTs) are rare and heterogeneous ovary tumors. We aimed to identify potential germline mutations and somatic mutations in MOGCTs by whole-exome sequencing. Methods The peripheral blood and tumor samples from these patients were used to identify germline mutations and somatic mutations, respectively. For those genes corresponding to copy number alterations (CNA) deletion and duplication region, functional annotation of was performed. Immunohistochemistry was performed to evaluate the expression of mutated genes corresponding to CNA deletion region. Results In peripheral blood, copy number loss and gain were mostly found in yolk sac tumors (YST). Moreover, POU5F1 was the most significant mutated gene with mutation frequency > 10% in both CNA deletion and duplication region. In addition, strong cytoplasm staining of POU5F1 (corresponding to CNA deletion region) was found in 2 YST and nuclear staining in 2 dysgerminomas (DG) tumor samples. Genes corresponding to CNA deletion region were significantly enriched in the signaling pathway of regulating pluripotency of stem cells. In addition, genes corresponding to CNA duplication region were significantly enriched in the signaling pathways of RIG-I-like receptor, Toll-like receptor, NF-kappa B and Jak–STAT. KRT4, RPL14, PCSK6, PABPC3 and SARM1 mutations were detected in both peripheral blood and tumor samples. Conclusions Identification of potential germline mutations and somatic mutations in MOGCTs may provide a new field in understanding the genetic feature of the rare biological tumor type in the ovary.

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