Whole-Exome Sequencing of Esophageal Submucosal Gland Duct Adenocarcinoma

Abstract Purpose Esophageal submucosal gland duct adenocarcinoma (ESGDAC) is an extremely rare histological variant of esophageal epithelial malignant tumors. To date, only few cases of ESGDAC have been reported. No comprehensive molecular analysis of ESGDAC has been conducted. This study focusses on the whole-exome sequencing (WES) to identify somatically acquired mutations and signatures of somatic mutations in ESGDAC. Methods Immunohistochemical analysis and whole-exome sequencing (WES) was performed in 3 ESGDAC genomes.Results In this study, we summarized the clinical, pathological, and immunohistochemical characteristics of patients with ESGDAC, we first performed whole-exome sequencing (WES) to summarize WES coverage statistics for each patient. We also examined cancer predisposition genes, ESGDAC-associated driver genes, and significantly mutated genes (SMGs). WES revealed TP53 as a SMG in ESGDAC. Conclusion We studied the tumor mutation profiling for the development of future targeted therapies for ESGDAC.

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The Profile of Genetic Mutations in Papillary Thyroid Cancer Detected by Whole Exome Sequencing

Cellular Physiology and Biochemistry ◽

10.1159/000493966 ◽

2018 ◽

Vol 50 (1) ◽

pp. 169-178 ◽

Cited By ~ 3

Author(s):

Yi Fang ◽

Xiao Ma ◽

Jing Zeng ◽

Yanwen Jin ◽

Yong Hu ◽

...

Keyword(s):

Thyroid Cancer ◽

Exome Sequencing ◽

Papillary Thyroid Cancer ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Signal Pathways ◽

Papillary Thyroid ◽

Driver Genes ◽

Mutational Status ◽

Whole Exome

Background/Aims: The purpose of the study was to investigate the altered driver genes and signal pathways during progression of papillary thyroid cancer (PTC) via next-generation sequencing technology. Methods: The DNA samples for whole exome sequencing (WES) analyses were extracted from 11 PTC tissues and adjacent normal tissues samples. Direct Sanger sequencing was applied to validate the identified mutations. Results: Among the 11 pairs of tissues specimens, 299 single nucleotide variants (SNVs) in 75 genes were identified. The most common pattern of base pair substitutions was T:A>C:G (49.83%), followed by C:G>T:A (18.06%) and C:G>G:C (15.05%). The altered genes were mainly implicated in MAPK (mitogen-activated protein kinase), PPAR (peroxisome proliferator-activated receptors), and p53 signaling pathways. In addition, 12 novel identified driver genes were validated by Sanger sequencing. The mutations of FAM133A, DPCR1, JAK1, C10orf10, EPB41L3, GPRASP1 and IWS1 exhibited in multiple PTC cases. Furthermore, the PTC cases exhibited individual mutational signature, even the same gene might present different mutational status in different cases. Conclusion: Multiple PTC-related somatic mutations and signal pathways are identified via WES and Sanger sequencing methods. The novel identified mutations in genes such as FAM133A, DPCR1, and JAK1 may be potential therapeutic targets for PTC patients.

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USP8 and TP53 Drivers are Associated with CNV in a Corticotroph Adenoma Cohort Enriched for Aggressive Tumors

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa853 ◽

2020 ◽

Author(s):

Andrew V Uzilov ◽

Patricia Taik ◽

Khadeen C Cheesman ◽

Pedram Javanmard ◽

Kai Ying ◽

...

Keyword(s):

At Risk ◽

Aggressive Behavior ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Somatic Mutations ◽

Care Center ◽

Tertiary Care ◽

Driver Genes ◽

Cushing Disease ◽

Whole Exome

Abstract Context Pituitary corticotroph adenomas are rare tumors that can be associated with excess adrenocorticotropin (ACTH) and adrenal cortisol production, resulting in the clinically debilitating endocrine condition Cushing disease. A subset of corticotroph tumors behave aggressively, and genomic drivers behind the development of these tumors are largely unknown. Objective To investigate genomic drivers of corticotroph tumors at risk for aggressive behavior. Design Whole-exome sequencing of patient-matched corticotroph tumor and normal deoxyribonucleic acid (DNA) from a patient cohort enriched for tumors at risk for aggressive behavior. Setting Tertiary care center Patients Twenty-seven corticotroph tumors from 22 patients were analyzed. Twelve tumors were macroadenomas, of which 6 were silent ACTH tumors, 2 were Crooke’s cell tumors, and 1 was a corticotroph carcinoma. Intervention Whole-exome sequencing. Main outcome measure Somatic mutation genomic biomarkers. Results We found recurrent somatic mutations in USP8 and TP53 genes, both with higher allelic fractions than other somatic mutations. These mutations were mutually exclusive, with TP53 mutations occurring only in USP8 wildtype (WT) tumors, indicating they may be independent driver genes. USP8-WT tumors were characterized by extensive somatic copy number variation compared with USP8-mutated tumors. Independent of molecular driver status, we found an association between invasiveness, macroadenomas, and aneuploidy. Conclusions Our data suggest that corticotroph tumors may be categorized into a USP8-mutated, genome-stable subtype versus a USP8-WT, genome-disrupted subtype, the latter of which has a TP53-mutated subtype with high level of chromosome instability. These findings could help identify high risk corticotroph tumors, namely those with widespread CNV, that may need closer monitoring and more aggressive treatment.

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Identification of cancer driver genes in focal genomic aberrations from whole-exome sequencing data

Bioinformatics ◽

10.1093/bioinformatics/btx620 ◽

2017 ◽

Vol 34 (3) ◽

pp. 519-521 ◽

Cited By ~ 1

Author(s):

Ho Jang ◽

Hyunju Lee

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sequencing Data ◽

Driver Genes ◽

Cancer Driver ◽

Exome Sequencing Data ◽

Whole Exome ◽

Whole Exome Sequencing Data ◽

Genomic Aberrations ◽

Cancer Driver Genes

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Genomic Characterization of Chinese Ovarian Clear Cell Carcinoma Identifies Driver Genes by Whole Exome Sequencing

SSRN Electronic Journal ◽

10.2139/ssrn.3501019 ◽

2019 ◽

Author(s):

Qin Yang ◽

Yuan Ren ◽

Huan Yi ◽

Tianjiao Luo ◽

Fangliang Xing ◽

...

Keyword(s):

Cell Carcinoma ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clear Cell ◽

Clear Cell Carcinoma ◽

Ovarian Clear Cell Carcinoma ◽

Driver Genes ◽

Whole Exome ◽

Genomic Characterization

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Abstract 2751: Identification of predisposition genes involved in thyroid and breast carcinomas in patients with family history of these tumors by whole exome sequencing

10.1158/1538-7445.am2015-2751 ◽

2015 ◽

Author(s):

Maisa Pinheiro ◽

Fabio Marchi ◽

Sandra Drigo ◽

Patricia Reis ◽

Luiz Lehmann Coutinho ◽

...

Keyword(s):

Family History ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Breast Carcinomas ◽

Whole Exome ◽

Predisposition Genes ◽

History Of

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Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer

Genetics in Medicine ◽

10.1038/gim.2014.89 ◽

2014 ◽

Vol 17 (2) ◽

pp. 131-142 ◽

Cited By ~ 56

Author(s):

Clara Esteban-Jurado ◽

◽

Maria Vila-Casadesús ◽

Pilar Garre ◽

Juan José Lozano ◽

...

Keyword(s):

Colorectal Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Familial Colorectal Cancer ◽

Pathogenic Variants ◽

Whole Exome ◽

Predisposition Genes

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Whole Exome Sequencing Identifies APCDD1 and HDAC5 Genes as Potentially Cancer Predisposing in Familial Colorectal Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22041837 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1837

Author(s):

Diamanto Skopelitou ◽

Beiping Miao ◽

Aayushi Srivastava ◽

Abhishek Kumar ◽

Magdalena Kuświk ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Promoter Activity ◽

Luciferase Reporter ◽

Complex Disorders ◽

Whole Exome ◽

Predisposition Genes ◽

Reporter Assays ◽

Proliferation Assays ◽

Genetic Burden

Germline mutations in predisposition genes account for only 20% of all familial colorectal cancers (CRC) and the remaining genetic burden may be due to rare high- to moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer-predisposing variants, we performed whole exome sequencing on three CRC cases and three unaffected members of a Polish family and identified two novel heterozygous variants: a coding variant in APC downregulated 1 gene (APCDD1, p.R299H) and a non-coding variant in the 5′ untranslated region (UTR) of histone deacetylase 5 gene (HDAC5). Sanger sequencing confirmed the variants segregating with the disease and Taqman assays revealed 8 additional APCDD1 variants in a cohort of 1705 familial CRC patients and no further HDAC5 variants. Proliferation assays indicated an insignificant proliferative impact for the APCDD1 variant. Luciferase reporter assays using the HDAC5 variant resulted in an enhanced promoter activity. Targeting of transcription factor binding sites of SNAI-2 and TCF4 interrupted by the HDAC5 variant showed a significant impact of TCF4 on promoter activity of mutated HDAC5. Our findings contribute not only to the identification of unrecognized genetic causes of familial CRC but also underline the importance of 5’UTR variants affecting transcriptional regulation and the pathogenesis of complex disorders.

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Whole-Exome Sequencing Reveals New Potential Mutations Genes for Primary Mucosa-Associated Lymphoid Tissue Lymphoma Arising From the Kidney

Frontiers in Oncology ◽

10.3389/fonc.2020.609839 ◽

2021 ◽

Vol 10 ◽

Author(s):

Shuang Wen ◽

Tianqing Liu ◽

Hongshuo Zhang ◽

Xu Zhou ◽

Huidan Jin ◽

...

Keyword(s):

Exome Sequencing ◽

Tumor Cells ◽

Whole Exome Sequencing ◽

Lymphoid Tissue ◽

Clinical Investigation ◽

Driver Mutations ◽

Low Grade ◽

Driver Genes ◽

Molecular Features ◽

Whole Exome

Low-grade B cell lymphomas of mucosa-associated lymphoid tissue (MALT) lymphomas involving the kidney were extremely rare, genetic alteration or molecular features was not yet explored, which may lead to limited choices for postoperative adjuvant or targeted. Whole-exome sequencing based tumor mutation profiling was performed on the tumor sample from a 77-year-old female presenting with discomfort at the waist was pathologically diagnosed as MALT lymphomas in the right kidney. We identified 101 somatic SNVs, and the majority of the identified SNVs were located in CDS and intronic regions. A total of 190 gain counts of CNVs with a total size of 488,744,073 was also investigated. After filtering with the CGC database, seven predisposing genes (ARID4A, COL2A1, FANCL, ABL2, HSP90AB1, FANCA, and DIS3) were found in renal MALT specimen. Furthermore, we compared somatic variation with known driver genes and validated three mutational driver genes including ACSL3, PHOX2B, and ADCY1. Sanger sequencing of germline DNA revealed the presence of a mutant base T of PHOX2B and a mutant base C of ADCY1 in the sequence, which were discovered for the first time in MALT lymphomas involving the kidney. Moreover, immunohistochemical analysis revealed that tumor cells were positive for CD20, CD79a, PAX5, CD21, and CD23, and expression of CD3, CD5, and CD8 were observed in reactive T lymphocytes surrounding tumor cells. These findings illustrated that concurrent aberrant PHOX2B and ADCY1 signaling may be a catastrophic event resulting in disease progression and inhibition of the putative driver mutations may be alternative adjuvant therapy for MALT lymphoma in the kidney which warrants further clinical investigation.

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Whole Exome Sequencing Identifies APCDD1 and HDAC5 Genes as Potentially Cancer Predisposing in Familial Colorectal Cancer

10.20944/preprints202102.0040.v1 ◽

2021 ◽

Author(s):

Diamanto Skopelitou ◽

Beiping Miao ◽

Aayushi Srivastava ◽

Abhishek Kumar ◽

Magdalena Kuświk ◽

...

Keyword(s):

Colorectal Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Promoter Activity ◽

Luciferase Reporter ◽

Familial Colorectal Cancer ◽

Complex Disorders ◽

Whole Exome ◽

Predisposition Genes ◽

Genetic Burden

Germline mutations in predisposition genes account for only 20% of all familial colorectal cancer (CRC) and the remaining genetic burden may be due to rare high-to-moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer predisposing variants, we performed whole exome sequencing on three CRC cases and three unaffected members of a Polish family and identified two novel heterozygous variants; a coding variant in APC down-regulated 1 gene (APCDD1, p.R299H) and a non-coding variant in the 5’ untranslated region (UTR) of histone deacetylase 5 gene (HDAC5). Sanger sequencing confirmed the variants segregating with the disease and Taqman assays revealed 8 additional APCDD1 variants in a cohort of 1705 familial CRC patients and no further HDAC5 variants. Proliferation assays indicated an insignificant proliferative impact for the APCDD1 variant. Luciferase reporter assays using the HDAC5 variant resulted in an enhanced promoter activity. Targeting of transcription factor binding sites of SNAI-2 and TCF4 interrupted by HDAC5 variant showed a significant impact of TCF4 on promoter activity of mutated HDAC5. Our findings contribute not only to the identification of unrecognized genetic causes of familial CRC but also underline the importance of 5´UTR variants affecting transcriptional regulation and the pathogenesis of complex disorders.

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