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Pauline Funchain, Ahmad A Tarhini
Rapidly advancing genomic sequencing technologies are changing all areas of cancer, from diagnosis to surveillance, and prognostication to treatment. The role of genomic testing in melanoma is expanding, and multiple genomically based tests are available, including somatic tumor sequencing for actionable genetic alterations and tumor mutational burden, prognostic gene expression profiling from tumor tissue, and germline genetic testing from blood. The available testing options have varying levels of supporting data, from robust to preliminary...
March 15, 2018: Oncology (Williston Park, NY)
Suzanne M Mahon
People with multiple polyps may have a germline mutation that places them at higher risk for developing colorectal, gastrointestinal, and other cancers. Genetic testing can often identify the specific polyposis syndrome and provide insight into appropriate recommendations for cancer prevention and early detection. Individuals with hereditary polyposis syndromes often begin developing polyps in their teenage years and require aggressive gastrointestinal surveillance to remove polyps. For some, the polyp burden will be too high to manage endoscopically and will require risk-reducing colectomies...
April 1, 2018: Clinical Journal of Oncology Nursing
Jessica L H Walters, Geoffry N De Iuliis, Matthew D Dun, Robert John Aitken, Eileen A McLaughlin, Brett Nixon, Elizabeth G Bromfield
One of the leading causes of male infertility is defective sperm function, a pathology that commonly arises from oxidative stress in the germline. Lipid peroxidation events in the sperm plasma membrane result in the generation of cytotoxic aldehydes such as 4-hydroxynonenal (4HNE), which accentuate the production of reactive oxygen species (ROS) and cause cellular damage. One of the key enzymes involved in the metabolism of polyunsaturated fatty acids to 4HNE in somatic cells is arachidonate 15-lipoxygenase (ALOX15)...
March 13, 2018: Biology of Reproduction
Lu Xie, Wei Guo, Yi Yang, Tao Ji, Jie Xu
5,10-Methylenetrahydrofolate reductase (MTHFR), a key enzyme for folate metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is located at the end of the short arm (1p36.3). Two common non-synonymous variants, the C677T (Ala222Val) and A1298C (Glu429Ala), were mainly described with decreased enzymatic activity and an alteration of intracellular folate distribution. Osteosarcomas are currently treated with high dose of methotrexate (MTX). The decreased enzyme activity of MTHFR theoretically could increase the drug action of MTX and at the same time increase toxic and side effect...
February 20, 2018: Oncotarget
Hao Zhang, Mengmeng Feng, Yi Feng, Zhaode Bu, Ziyu Li, Shuqin Jia, Jiafu Ji
Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Among which, about 1%-3% of gastric cancer patients were characterized by inherited gastric cancer predisposition syndromes, knowing as hereditary diffuse gastric cancer (HDGC). Studies reported that CDH1 germline mutations are the main cause of HDGC. With the help of rapid development of genetic testing technologies and data analysis tools, more and more researchers focus on seeking candidate susceptibility genes for hereditary cancer syndromes...
February 2018: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
Masato Uchiyama, Akiko Nagai, Kaori Muto
Genome editing of human embryos could become a fundamental treatment approach for genetic diseases; however, a few technical and ethical issues need to be resolved before its application in clinical settings. Presently, the Japanese government has issued a statement prohibiting human germline editing and emphasizing the need for discussions that include a wide range of perspectives. However, current discussions tend to exclude the general public. Therefore, we conducted a survey of 10,881 general adults and 1044 patients in Japan who indicated that their disease conditions are related to their genetic makeup, and clarified their attitude toward this technology...
March 15, 2018: Journal of Human Genetics
Jasper Braun, Lukas Nabergall, Rafik Neme, Laura F Landweber, Masahico Saito, Nataša Jonoska
Ciliates have two different types of nuclei per cell, with one acting as a somatic, transcriptionally active nucleus (macronucleus; abbr. MAC) and another serving as a germline nucleus (micronucleus; abbr. MIC). Furthermore, Oxytricha trifallax undergoes extensive genome rearrangements during sexual conjugation and post-zygotic development of daughter cells. These rearrangements are necessary because the precursor MIC loci are often both fragmented and scrambled, with respect to the corresponding MAC loci. Such genome architectures are remarkably tolerant of encrypted MIC loci, because RNA-guided processes during MAC development reorganize the gene fragments in the correct order to resemble the parental MAC sequence...
March 15, 2018: G3: Genes—Genomes—Genetics
Blanca De Unamuno, Zaida García-Casado, José Bañuls, Celia Requena, José Antonio Lopez-Guerrero, Eduardo Nagore
CDKN2A germline mutations increase the risk of melanoma development and are present in 20 and 10% of familial and multiple melanoma cases, respectively. Pancreatic cancer has been associated with CDKN2A in some populations and, accordingly, its presence in first-degree or second-degree relatives of a melanoma patient is considered as a criterion for genetic testing. In this study, we show that in an area with low melanoma incidence, CDKN2A germline mutations in patients with melanoma and personal or family history of pancreatic cancer are mainly present in the setting of familial or multiple melanoma cases...
March 14, 2018: Melanoma Research
Yasunori Sasakura
Transgenesis is an indispensable method for elucidating the cellular and molecular mechanisms underlying biological phenomena. In Ciona, transgenic lines that have a transgene insertion in their genomes have been created. The transgenic lines are valuable because they express reporter genes in a nonmosaic manner. This nonmosaic manner allows us to accurately observe tissues and organs. The insertions of transgenes can destroy genes to create mutants. The insertional mutagenesis is a splendid method for investigating functions of genes...
2018: Advances in Experimental Medicine and Biology
Carol Cremin, Sarah Howard, Lyly Le, Aly Karsan, David F Schaeffer, Daniel Renouf, Kasmintan A Schrader
Background: Approximately 5% to 10% of pancreatic ductal adenocarcinoma (PDAC) has a hereditary basis. In most of these defined hereditary cancer syndromes, PDAC is not the predominant cancer type. Traditional criteria for publicly funded genetic testing typically require the presence of a set combination of the predominant syndrome-associated cancer types in the family history.We report the identification of a CDKN2A pathogenic variant in a PDAC-prone family without the cutaneous features of multiple moles or melanoma that are characteristic of the Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome identified in a universal testing algorithm for inherited mutations in pancreatic cancer patients...
2018: Hereditary Cancer in Clinical Practice
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
Lars Kullmann, Michael P Krahn
The tumor suppressor LKB1 is an essential serine/threonine kinase, which regulates various cellular processes such as cell metabolism, cell proliferation, cell polarity, and cell migration. Germline mutations in the STK11 gene (encoding LKB1) are the cause of the Peutz-Jeghers syndrome, which is characterized by benign polyps in the intestine and a higher risk for the patients to develop intestinal and extraintestinal tumors. Moreover, mutations and misregulation of LKB1 have been reported to occur in most types of tumors and are among the most common aberrations in lung cancer...
March 15, 2018: Oncogene
Ganga Anil Kumar, Kuppuswamy Subramaniam
Pairing of homologous chromosomes is essential for genetic recombination during gametogenesis. In many organisms, chromosome ends are attached to cytoplasmic dynein, and dynein-driven chromosomal movements facilitate the pairing process. Factors that promote / control the cytoskeletal tethering of chromosomes are largely unknown. Here, we show that the conserved RNA-binding protein PUF-8 facilitates the tethering and pairing processes in the C. elegans germline by promoting proteasome activity. We have isolated a hypomorphic allele of pas-1 , which encodes a proteasome core subunit, and find that the homologous chromosomes fail to pair in the puf-8; pas-1 double mutant due to failure of chromosome tethering...
March 14, 2018: Development
Lishuang Shen, Marcella Attimonelli, Renkui Bai, Marie T Lott, Douglas C Wallace, Marni J Falk, Xiaowu Gai
Accurate mitochondrial DNA (mtDNA) variant annotation is essential for the clinical diagnosis of diverse human diseases. Substantial challenges to this process include the inconsistency in mtDNA nomenclatures, the existence of multiple reference genomes, and a lack of reference population frequency data. Clinicians need a simple bioinformatics tool that is user-friendly, and bioinformaticians need a powerful informatics resource for programmatic usage. Here, we report the development and functionality of the MSeqDR mtDNA Variant Tool set (mvTool), a one-stop mtDNA variant annotation and analysis web service...
March 14, 2018: Human Mutation
Léopoldine Bricaire, Capucine Richard, Mathieu Gauthé, Béatrix Cochand-Priollet, Sébastien Gaujoux
We present the case of a severe familial primary hyperparathyroidism related to a germline deletion in the HRPT2 (CDC73) gene. Morphological explorations revealed 2 potential hyperfunctioning parathyroid glands: a left cervical lesion on the neck ultrasound, and an ectopic mediastinal lesion on the parathyroid scintigraphy using Tc-methoxyisobutylisonitrile and on F-fluorocholine PET/CT. Surgery removal and histopathological examination determined that the mediastinal mass corresponded to a thymoma and the cervical lesion to a parathyroid adenoma...
March 13, 2018: Clinical Nuclear Medicine
Shigeo Yamaguchi, Tomoaki Fujii, Yuki Izumi, Yuki Fukumura, Min Han, Hideki Yamaguchi, Tomomi Akita, Chikamasa Yamashita, Shunsuke Kato, Takao Sekiya
During next generation sequencing (NGS) analysis, many missense mutations were found in a well-known oncogene, many of which were variant of uncertain significance mutations. We recently treated an adult patient with pancreatoblastoma by chemotherapy. Using an NGS cancer panel, we found a previously unreported missense mutation in the 1835 codon of the adenomatous polyposis coli ( APC ) gene. We also found a heterogeneous mutation in the 1835 codon of the APC gene in the patient's germline by Sanger sequencing...
February 13, 2018: Oncotarget
Nicholas C Eastley, Barbara Ottolini, Rita Neumann, Jin-Li Luo, Robert K Hastings, Imran Khan, David A Moore, Claire P Esler, Jacqueline A Shaw, Nicola J Royle, Robert U Ashford
Following treatment 40% of soft tissue sarcoma (STS) patients suffer disease recurrence. In certain cancers circulating cell free DNA (cfDNA) and circulating tumour-derived DNA (ctDNA) characteristics correlate closely with disease burden, making them exciting potential sources of biomarkers. Despite this, the circulating nucleic acid characteristics of only 2 STS patients have been reported to date. To address this we used an Ion AmpliSeq™ panel custom specifically designed for STS patients to conduct a genetic characterisation of plasma cfDNA, buffy coat (germline) DNA and where available Formalin-Fixed Paraffin-Embedded (FFPE) primary STS tissue DNA in a cohort of 11 metastatic STS patients...
February 13, 2018: Oncotarget
Cilia Mejia-Lancheros, John Mehegan, Celine M Murrin, Cecily C Kelleher
BACKGROUND/OBJECTIVES: The role of smoking from the paternal line during the pre-conception period on grand-child's overweight/obesity and associated underlying pathways are uncertain. We examined whether the smoking status from the paternal line was associated with the grand-child's higher weight at birth, and overweight or obesity at 5 and 9 years of age. The grandparental smoking effect from the maternal line was also explored. SUBJECTS/METHODS: Participants were fathers and grandparents and grand-children from the Lifeways Cross Generational Cohort (N = 1021 for the analysis at birth; N = 562 and N = 284 for the analysis at 5 and 9 years, respectively)...
March 13, 2018: International Journal of Obesity: Journal of the International Association for the Study of Obesity
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
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
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