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Somatic mutation

Dian He, Yuan Li, Yunli Yu, Gang Cai, Fu Ouyang, Yuchan Lin, Hongjuan Lu, Lan Chu
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder that primarily affects the skin and the nervous system. This condition is called segmental NF1 (also called neurofibromatosis type V) when clinical features are limited to one area of the body. Segmental NF1 is generally thought to result from somatic mosaicism due to a postzygotic mutation in the NF1 gene, thus a test for NF1 gene abnormalities in peripheral blood is usually negative. Here we report a 31-year-old male presenting with epileptic seizures, who had a history of neurofibromas confirmed by biopsy, but lacked a family history of neurofibromatosis...
March 1, 2018: Clinical Neurology and Neurosurgery
Daisuke Higeta, Rie Yamaguchi, Takeshi Takagi, Gen Nishimura, Kiyoko Sameshima, Kayoko Saito, Takashi Minegishi
Campomelic dysplasia is an autosomal dominant skeletal dysplasia caused by heterozygous SOX9 mutations. Most patients are sporadic due to a de novo mutation. Familial campomelic dysplasia is very rare. We report on a familial campomelic dysplasia caused by maternal germinal mosaicism. Two siblings showed the classic campomelic dysplasia phenotype with a novel SOX9 mutation (NM_000346.3: c.441delC, p.(Asn147Lysfs*36)). Radiological examination of the mother showed mild skeletal changes. Then, her somatic mosaicism of the mutation was ascertained...
March 14, 2018: Congenital Anomalies
Ursula J Lemberger, Claudia D Fuchs, Christian Schöfer, Andrea Bileck, Christopher Gerner, Tatjana Stojakovic, Makoto M Taketo, Michael Trauner, Gerda Egger, Christoph H Österreicher
Background: Wnt/β-catenin signaling plays a crucial role in embryogenesis, tissue homeostasis, metabolism and malignant transformation of different organs including the liver. Continuous β-catenin signaling due to somatic mutations in exon 3 of the Ctnnb1 gene is associated with different liver diseases including cancer and cholestasis. Results: Expression of a degradation resistant form of β-catenin in hepatocytes resulted in 100% mortality within 31 days after birth...
February 16, 2018: Oncotarget
Xiao Sun, Tanxiao Huang, Fangsheng Cheng, Kaibing Huang, Ming Liu, Wan He, Mingwei Li, Xiaoni Zhang, Mingyan Xu, Shifu Chen, Ligang Xia
Postoperative monitoring for patients with colorectal cancer (CRC) requires sensitive biomarkers that are associated with medical response and adjuvant therapy following surgery. Conventional tumor biomarkers [including carcinoembryonic antigen (CEA), CA19-9 and CA125] are widely used, but none of the markers provide high sensitivity or specificity. Previous studies indicated that circulating tumor DNA (ctDNA) is useful for postoperative monitoring of patients with cancer. However, the majority of previous studies involved patients with lung cancer, and therefore further studies are required which investigate patients with CRC...
April 2018: Oncology Letters
Natalie Herold, Barbara Wappenschmidt, Birgid Markiefka, Katharina Keupp, Sandra Kröber, Eric Hahnen, Rita Schmutzler, Kerstin Rhiem
Non-small cell neuroendocrine carcinomas (NSCNEC) account for 2% of gynecological cancer cases and are associated with a poor prognosis due to delayed diagnosis and aggressive tumor behavior. BRCA2 -associated ovarian carcinomas predominantly possess a high-grade serous phenotype, which respond to platinum and targeted therapy with PARP inhibitors. Presented here is the case of an adult patient with NSCNEC of the ovaries associated with a deleterious BRCA2 germline mutation. The pathogenic mutation was also confirmed on the somatic level, while the wild-type allele had a high variant fraction, suggesting loss of heterozygosity...
April 2018: Oncology Letters
Henrik Devitt Møller, Marghoob Mohiyuddin, Iñigo Prada-Luengo, M Reza Sailani, Jens Frey Halling, Peter Plomgaard, Lasse Maretty, Anders Johannes Hansen, Michael P Snyder, Henriette Pilegaard, Hugo Y K Lam, Birgitte Regenberg
The human genome is generally organized into stable chromosomes, and only tumor cells are known to accumulate kilobase (kb)-sized extrachromosomal circular DNA elements (eccDNAs). However, it must be expected that kb eccDNAs exist in normal cells as a result of mutations. Here, we purify and sequence eccDNAs from muscle and blood samples from 16 healthy men, detecting ~100,000 unique eccDNA types from 16 million nuclei. Half of these structures carry genes or gene fragments and the majority are smaller than 25 kb...
March 14, 2018: Nature Communications
Lisa M Ebert, Wenbo Yu, Tessa Gargett, Michael P Brown
Chimeric antigen receptor (CAR)-T cell therapy has been clinically validated as a curative treatment for the difficult to treat malignancies of relapsed/refractory B-cell acute lymphoblastic leukaemia and lymphoma. Here, the CAR-T cells are re-directed towards a single antigen, CD19, which is recognised as a virtually ideal CAR target antigen because it has strong, uniform expression on cancer cells, and is otherwise expressed only on healthy B cells, which are 'dispensable'. Notwithstanding the clinical success of CD19-CAR-T cell therapy, its single specificity has driven therapeutic resistance in 30% or more of cases with CD19-negative leukaemic relapses...
March 14, 2018: Biochemical Society Transactions
Mathew A Cherian, Sydney Olson, Hemalatha Sundaramoorthi, Kitra Cates, Xiaogang Cheng, John Harding, Andrew Martens, Grant A Challen, Manoj Tyagi, Lee Ratner, Daniel Rauch
The human T cell leukemia virus-1 (HTLV-1) oncoprotein Tax drives cell proliferation and resistance to apoptosis early in the pathogenesis of adult T-cell leukemia (ATL). Subsequently, likely as a result of specific immuno-editing, Tax expression is downregulated and functionally replaced by somatic driver mutations of the host genome. Both amplification and point mutations of interferon regulatory factor 4 (IRF4) have been previously detected in ATL, and the K59R mutation is the most common single-nucleotide variation in IRF4 and is found exclusively in ATL...
March 14, 2018: Journal of Biological Chemistry
Ling Deng, Xuehua Zhu, Yun Sun, Jiemin Wang, Xiaorong Zhong, Jiayuan Li, Min Hu, Hong Zheng
Purpose: The prevalence of PIK3CA in Chinese breast cancer patients may be underestimated. Therefore, we investigated the distribution of somatic PIK3CA/AKT1 mutations in Chinese breast cancer patients and explored their roles in tumor phenotypes and disease prognosis. Materials and Methods: Tumors from five hundred and seven breast cancer patients were prospectively collected from the West China Hospital between 2008 and 2013. Whole exons of AKT1 and PIK3CA were detected in fresh-frozen tumors using next-generation sequencing, and correlations between PIK3CA/AKT1 mutations and clinicopathological features were analyzed...
March 15, 2018: Cancer Research and Treatment: Official Journal of Korean Cancer Association
Irene Gullo, Rui Batista, Pedro Rodrigues-Pereira, Paula Soares, Helena Barroca, Maria do Bom-Sucesso, Manuel Sobrinho-Simões
Objectives: Multinodular goiter (MNG) and well-differentiated thyroid carcinoma (WDTC) are emerging phenotypes of DICER1 syndrome. Methods: Histologic and molecular findings of botryoid-type embryonal rhabdomyosarcoma (bERMS) and thyroid nodules from a 12-year-old DICER1 mutation carrier (p.Arg1060Ilefs*7) were investigated, providing interesting clues for understanding thyroid carcinogenesis. Results: The patient had bERMS at age 7 years...
March 10, 2018: American Journal of Clinical Pathology
Naoki Ikari, Shota Aoyama, Akiyoshi Seshimo, Yuji Suehiro, Tomoko Motohashi, Shohei Mitani, Sawako Yoshina, Etsuko Tanji, Akiko Serizawa, Takuji Yamada, Kiyoaki Taniguchi, Masakazu Yamamoto, Toru Furukawa
Background and aim: Intramucosal gastric adenocarcinoma of the well-moderately differentiated type only exhibits lymph node metastasis in extremely rare cases. We encountered such case and investigated both the lymphangiogenic properties and somatic mutations in the cancer to understand the prometastatic features of early-stage gastric cancer. Methods: We quantitatively measured the density of lymphatic vessels and identified mutations in 412 cancer-associated genes through next-generation target resequencing of DNA extracted from tumor cells in a formalin-fixed and paraffin-embedded tissue...
February 13, 2018: Oncotarget
Meenakshi Mehrotra, Rajesh R Singh, Sanam Loghavi, Dzifa Yawa Duose, Bedia A Barkoh, Carmen Behrens, Keyur P Patel, Mark J Routbort, Scott Kopetz, Russell R Broaddus, L Jeffrey Medeiros, Ignacio I Wistuba, Rajyalakshmi Luthra
A suitable clinical-grade platform is required for detection of somatic mutations with high sensitivity in cell-free DNA (cfDNA) of patients with solid tumors. In this study, we evaluated in parallel ultra-deep NGS with MassARRAY and allele-specific droplet digital PCR (ddPCR) for cfDNA genotyping and correlated cfDNA yield and mutation status with overall survival (OS) of patients. We assessed plasma samples from 46 patients with various advanced metastatic solid tumors and known mutations by deep sequencing using an Ampliseq cancer hotspot panel V2 on Ion Proton...
February 13, 2018: Oncotarget
Emily C Sheppard, Rikke Brandstrup Morrish, Michael J Dillon, Rebecca Leyland, Richard Chahwan
Epigenetic modifications, such as histone modifications, DNA methylation status, and non-coding RNAs (ncRNA), all contribute to antibody maturation during somatic hypermutation (SHM) and class-switch recombination (CSR). Histone modifications alter the chromatin landscape and, together with DNA primary and tertiary structures, they help recruit Activation-Induced Cytidine Deaminase (AID) to the immunoglobulin (Ig) locus. AID is a potent DNA mutator, which catalyzes cytosine-to-uracil deamination on single-stranded DNA to create U:G mismatches...
2018: Frontiers in Immunology
Monica Vaccari, Genoveffa Franchini
Germinal centers (GCs) are organized lymphoid tissue microstructures where B cells proliferate and differentiate into memory B cells and plasma cells. A few distinctive subsets of highly specialized T cells gain access to the GCs by expressing the B cell zone-homing C-X-C chemokine receptor type 5 (CXCR5) while losing the T cell zone-homing chemokine receptor CCR7. Help from T cells is critical to induce B cell proliferation and somatic hyper mutation and to limit GC reactions. CD4+ T follicular helper (TFH ) cells required for the formation of GCs and for the generation of long-lived, high-affinity B cells...
2018: Frontiers in Immunology
Josef Davidsson, Andreas Puschmann, Ulf Tedgård, David Bryder, Lars Nilsson, Jörg Cammenga
Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia-pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9L's normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutation's effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L...
February 25, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Peiye Shen, Ying Jing, Ruiyun Zhang, Mei-Chun Cai, Pengfei Ma, Haige Chen, Guanglei Zhuang
Neuroendocrine bladder cancer is a relatively rare but often lethal malignancy, with cell of origin, oncogenomic architecture and standard treatment poorly defined. Here we performed comprehensive whole-genome and transcriptome sequencing on a unique cohort of genitourinary neuroendocrine neoplasms, mainly small cell carcinomas of the urinary bladder. The mutational landscape and signatures of neuroendocrine bladder cancer strikingly resembled those in conventional urothelial carcinoma, along with typically mixed histologies, supporting a common cellular origin...
March 14, 2018: Oncogene
Emilie Clement, Hiroyuki Inuzuka, Naoe T Nihira, Wenyi Wei, Alex Toker
The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways...
March 13, 2018: Science Signaling
Belinda Rahman, Anne Lanceley, Rebecca S Kristeleit, Jonathan A Ledermann, Michelle Lockley, Mary McCormack, Tim Mould, Lucy Side
BACKGROUND: Ovarian cancer is the fifth most common cause of cancer death for women in the UK. Up to 18% of cases can be attributed to germline mutations in BRCA1 and BRCA2 genes. Identifying patients who carry a BRCA mutation provides important information about potential response to treatment and eligibility for therapies such as poly ADP ribose polymerase (PARP) inhibitors. Implementation of systematic genetic testing of patients with ovarian cancer via oncology clinics (mainstreamed genetic testing, MGT) is increasing...
March 13, 2018: Journal of Medical Genetics
Ying Pang, Garima Gupta, Chunzhang Yang, Herui Wang, Thanh-Truc Huynh, Ziedulla Abdullaev, Svetlana D Pack, Melanie J Percy, Terence R J Lappin, Zhengping Zhuang, Karel Pacak
BACKGROUND: The role of the hypoxia signaling pathway in the pathogenesis of pheochromocytoma/paraganglioma (PPGL)-polycythemia syndrome has been elucidated. Novel somatic mutations in hypoxia-inducible factor type 2A (HIF2A) and germline mutations in prolyl hydroxylase type 1 and type 2 (PHD1 and PHD2) have been identified to cause upregulation of the hypoxia signaling pathway and its target genes including erythropoietin (EPO) and its receptor (EPOR). However, in a minority of patients presenting with this syndrome, the genetics and molecular pathogenesis remain unexplained...
March 13, 2018: BMC Cancer
Patrick Kwok-Shing Ng, Jun Li, Kang Jin Jeong, Shan Shao, Hu Chen, Yiu Huen Tsang, Sohini Sengupta, Zixing Wang, Venkata Hemanjani Bhavana, Richard Tran, Stephanie Soewito, Darlan Conterno Minussi, Daniela Moreno, Kathleen Kong, Turgut Dogruluk, Hengyu Lu, Jianjiong Gao, Collin Tokheim, Daniel Cui Zhou, Amber M Johnson, Jia Zeng, Carman Ka Man Ip, Zhenlin Ju, Matthew Wester, Shuangxing Yu, Yongsheng Li, Christopher P Vellano, Nikolaus Schultz, Rachel Karchin, Li Ding, Yiling Lu, Lydia Wai Ting Cheung, Ken Chen, Kenna R Shaw, Funda Meric-Bernstam, Kenneth L Scott, Song Yi, Nidhi Sahni, Han Liang, Gordon B Mills
The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes...
March 12, 2018: Cancer Cell
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