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https://www.readbyqxmd.com/read/28892047/a-system-for-detecting-high-impact-low-frequency-mutations-in-primary-tumors-and-metastases
#1
M Anjanappa, Y Hao, E R Simpson, P Bhat-Nakshatri, J B Nelson, S A Tersey, R G Mirmira, A A Cohen-Gadol, M R Saadatzadeh, L Li, F Fang, K P Nephew, K D Miller, Y Liu, H Nakshatri
Tumor complexity and intratumor heterogeneity contribute to subclonal diversity. Despite advances in next-generation sequencing (NGS) and bioinformatics, detecting rare mutations in primary tumors and metastases contributing to subclonal diversity is a challenge for precision genomics. Here, in order to identify rare mutations, we adapted a recently described epithelial reprograming assay for short-term propagation of epithelial cells from primary and metastatic tumors. Using this approach, we expanded minor clones and obtained epithelial cell-specific DNA/RNA for quantitative NGS analysis...
September 11, 2017: Oncogene
https://www.readbyqxmd.com/read/28801450/genomic-analysis-of-hairy-cell-leukemia-identifies-novel-recurrent-genetic-alterations
#2
Benjamin H Durham, Bartlomiej Getta, Sascha Dietrich, Justin Taylor, Helen Won, James M Bogenberger, Sasinya Scott, Eunhee Kim, Young Rock Chung, Stephen S Chung, Jennifer Hüllein, Tatjana Walther, Lu Wang, Sydney X Lu, Christopher C Oakes, Raoul Tibes, Torsten Haferlach, Barry S Taylor, Martin S Tallman, Michael F Berger, Jae H Park, Thorsten Zenz, Omar Abdel-Wahab
Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the BRAFV600E mutation while ~30% of variant HCL (vHCL) have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1- wildtype vHCL, are not well defined. We therefore performed deep targeted mutational and copy number analysis of cHCL (n=53) and vHCL (n=8). The most common genetic alteration in cHCL outside of BRAFV600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wildtype BRAF, subdividing cHCL into those hemizygous versus heterozygous for the BRAFV600E mutation...
August 11, 2017: Blood
https://www.readbyqxmd.com/read/28708590/whole-exome-analysis-in-osteosarcoma-to-identify-a-personalized-therapy
#3
Caterina Chiappetta, Massimiliano Mancini, Francesca Lessi, Paolo Aretini, Veronica De Gregorio, Chiara Puggioni, Raffaella Carletti, Vincenzo Petrozza, Prospero Civita, Sara Franceschi, Antonio G Naccarato, Carlo Della Rocca, Chiara M Mazzanti, Claudio Di Cristofano
Osteosarcoma is the most common pediatric primary non-hematopoietic bone tumor. Survival of these young patients is related to the response to chemotherapy and development of metastases. Despite many advances in cancer research, chemotherapy regimens for osteosarcoma are still based on non-selective cytotoxic drugs. It is essential to investigate new specific molecular therapies for osteosarcoma to increase the survival rate of these patients. We performed exomic sequence analyses of 8 diagnostic biopsies of patients with conventional high grade osteosarcoma to advance our understanding of their genetic underpinnings and to correlate the genetic alteration with the clinical and pathological features of each patient to identify a personalized therapy...
July 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28675691/pd-1-inhibition-in-congenital-pigment-synthesizing-metastatic-melanoma
#4
Angela C Weyand, Rajen J Mody, Raja M Rabah, Valerie P Opipari
A newborn female child was born with a congenital pigment synthesizing melanoma of the scalp. Further workup revealed metastatic disease within the liver, lungs, and left tibia. Whole exome sequencing was performed on multiple samples that revealed one somatic mutation, lysine methyltransferase 2C (KMT2C), at low allelic frequency but no v-Raf murine sarcoma viral oncogene homolog B (BRAF), NF-1 mutation. Programmed death ligand 1 was moderately expressed. Treatment was initiated with the programmed cell death protein 1 inhibitor nivolumab...
July 4, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28669924/histone-h3-lysine-4-methyltransferase-kmt2d
#5
REVIEW
Eugene Froimchuk, Younghoon Jang, Kai Ge
Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and MLL2 in humans and Mll4 in mice, belongs to a family of mammalian histone H3 lysine 4 (H3K4) methyltransferases. It is a large protein over 5500 amino acids in size and is partially functionally redundant with KMT2C. KMT2D is widely expressed in adult tissues and is essential for early embryonic development. The C-terminal SET domain is responsible for its H3K4 methyltransferase activity and is necessary for maintaining KMT2D protein stability in cells...
September 5, 2017: Gene
https://www.readbyqxmd.com/read/28636652/integrative-analysis-of-genomic-alterations-in-triple-negative-breast-cancer-in-association-with-homologous-recombination-deficiency
#6
Masahito Kawazu, Shinya Kojima, Toshihide Ueno, Yasushi Totoki, Hiromi Nakamura, Akiko Kunita, Wei Qu, Jun Yoshimura, Manabu Soda, Takahiko Yasuda, Natsuko Hama, Mihoko Saito-Adachi, Kazuhito Sato, Shinji Kohsaka, Eirin Sai, Masako Ikemura, Shigeru Yamamoto, Tomoko Ogawa, Masashi Fukayama, Keiichiro Tada, Yasuyuki Seto, Shinichi Morishita, Shoichi Hazama, Tatsuhiro Shibata, Yoshihiro Yamashita, Hiroyuki Mano
Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present comprehensive characterization of the genetic alterations in TNBC performed by high coverage whole genome sequencing together with transcriptome and whole exome sequencing. Silencing of the BRCA1 gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication...
June 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28569218/a-knowledge-based-framework-for-the-discovery-of-cancer-predisposing-variants-using-large-scale-sequencing-breast-cancer-data
#7
Giorgio E M Melloni, Luca Mazzarella, Loris Bernard, Margherita Bodini, Anna Russo, Lucilla Luzi, Pier Giuseppe Pelicci, Laura Riva
BACKGROUND: The landscape of cancer-predisposing genes has been extensively investigated in the last 30 years with various methodologies ranging from candidate gene to genome-wide association studies. However, sequencing data are still poorly exploited in cancer predisposition studies due to the lack of statistical power when comparing millions of variants at once. METHOD: To overcome these power limitations, we propose a knowledge-based framework founded on the characteristics of known cancer-predisposing variants and genes...
May 31, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28548470/whole-exome-sequencing-of-etv6-runx1-in-four-childhood-acute-lymphoblastic-leukaemia-cases
#8
Zubaidah Zakaria, Norodiyah Othman, Azli Ismail, Nor Rizan Kamaluddin, Ezalia Esa, Eni Juraida Abdul Rahman, Yuslina Mat Yusoff, Fazlin Mohd Fauzi, Ten Sew Keoh
Background: ETV6/RUNX1 gene fusion is the most frequently seen chromosomal abnormality in childhood acute lymphobastic leukamia (ALL). However, additional genetic changes are known to be required for the development of this type of leukaemia. Therefore, we here aimed to assess the somatic mutational profile of four ALL cases carrying the ETV6/RUNX1 fusion gene using whole-exome sequencing. Methods: DNA was isolated from bone marrow samples using a QIAmp DNA Blood Mini kit and subsequently sequenced using the Illumina MiSeq system...
April 1, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/28506208/a-strategy-to-apply-quantitative-epistasis-analysis-on-developmental-traits
#9
Marta K Labocha, Wang Yuan, Boanerges Aleman-Meza, Weiwei Zhong
BACKGROUND: Genetic interactions are keys to understand complex traits and evolution. Epistasis analysis is an effective method to map genetic interactions. Large-scale quantitative epistasis analysis has been well established for single cells. However, there is a substantial lack of such studies in multicellular organisms and their complex phenotypes such as development. Here we present a method to extend quantitative epistasis analysis to developmental traits. METHODS: In the nematode Caenorhabditis elegans, we applied RNA interference on mutants to inactivate two genes, used an imaging system to quantitatively measure phenotypes, and developed a set of statistical methods to extract genetic interactions from phenotypic measurement...
May 15, 2017: BMC Genetics
https://www.readbyqxmd.com/read/28483418/mll3-and-mll4-facilitate-enhancer-rna-synthesis-and-transcription-from-promoters-independently-of-h3k4-monomethylation
#10
Kristel M Dorighi, Tomek Swigut, Telmo Henriques, Natarajan V Bhanu, Benjamin S Scruggs, Nataliya Nady, Christopher D Still, Benjamin A Garcia, Karen Adelman, Joanna Wysocka
Monomethylation of histone H3 at lysine 4 (H3K4me1) and acetylation of histone H3 at lysine 27 (H3K27ac) are correlated with transcriptionally engaged enhancer elements, but the functional impact of these modifications on enhancer activity is not well understood. Here we used CRISPR/Cas9 genome editing to separate catalytic activity-dependent and independent functions of Mll3 (Kmt2c) and Mll4 (Kmt2d, Mll2), the major enhancer H3K4 monomethyltransferases. Loss of H3K4me1 from enhancers in Mll3/4 catalytically deficient cells causes partial reduction of H3K27ac, but has surprisingly minor effects on transcription from either enhancers or promoters...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28389907/targeted-next-generation-sequencing-identified-novel-mutations-in-triple-negative-myeloproliferative-neoplasms
#11
Yu-Cheng Chang, Huan-Chau Lin, Yi-Hao Chiang, Caleb Gon-Shen Chen, Ling Huang, Wei-Ting Wang, Chun-Chia Cheng, Johnson Lin, Yi-Fang Chang, Ming-Chih Chang, Ruey-Kuen Hsieh, Shu-Jen Chen, Ken-Hong Lim, Yuan-Yeh Kuo
Mutations in JAK2, MPL and CALR genes have been identified in the majority of myeloproliferative neoplasm (MPN) patients, and patients negative for these three mutations are the so-called triple-negative (TN) MPN. In this study, we examined the mutational profiles of 16 triple-negative MPN patients including 7 essential thrombocythemia (ET), 1 primary myelofibrosis and 8 polycythemia vera (PV). Targeted next-generation sequencing was performed using the ACTOnco Comprehensive Cancer Panel (Ion AmpliSeq Comprehensive Cancer Panel, Life Technologies) to target all coding exons of 409 cancer-related genes...
May 2017: Medical Oncology
https://www.readbyqxmd.com/read/28375985/distinct-functions-of-histone-h3-lysine-4-methyltransferases-in-normal-and-malignant-hematopoiesis
#12
Weiwei Yang, Patricia Ernst
PURPOSE OF REVIEW: Histone H3, lysine 4 (H3K4) methylation is one chromatin modification that defines distinct regulatory states of euchromatin. Mammals express six main histone methyltransferase (HMT) enzymes that modify H3K4 by monomethylation, dimethylation or trimethylation. Recent studies examine roles of some of these HMTs and their cofactors in hematopoiesis and leukemia. We discuss these emerging studies together with prior embryonic stem data, revealing how these enzymes function...
July 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28013028/h3k4-methyltransferase-activity-is-required-for-mll4-protein-stability
#13
Younghoon Jang, Chaochen Wang, Lenan Zhuang, Chengyu Liu, Kai Ge
Transcriptional enhancers play a key role in cell type-specific gene expression and cell fate transition. Enhancers are marked by histone H3K4 mono- and di-methylation (H3K4me1/2). The tumor suppressor MLL4 (KMT2D) is a major enhancer H3K4 mono- and di-methyltransferase with a partial functional redundancy with MLL3 (KMT2C). However, the functional role of MLL4 enzymatic activity remains elusive. To address this issue, we have generated MLL4 enzyme-dead knock-in (KI) embryonic stem (ES) cells and mice, which carry Y5477A/Y5523A/Y5563A mutations in the enzymatic SET domain of the MLL4 protein...
June 30, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27997699/chromatin-remodelling-and-dna-repair-genes-are-frequently-mutated-in-endometrioid-endometrial-carcinoma
#14
Pablo García-Sanz, Juan Carlos Triviño, Alba Mota, María Pérez López, Eva Colás, Alejandro Rojo-Sebastián, Ángel García, Sonia Gatius, María Ruiz, Jaime Prat, Rafael López-López, Miguel Abal, Antonio Gil-Moreno, Jaume Reventós, Xavier Matias-Guiu, Gema Moreno-Bueno
In developed countries, endometrial carcinoma is the most common cancer that affects the female genital tract. Endometrial carcinoma is divided into two main histological types, type I or endometrioid and type II or non-endometrioid, each of which have characteristic, although not exclusive, molecular alterations and mutational profiles. Nevertheless, information about the implication and relevance of some of these genes in this disease is lacking. We sought here to identify new recurrently mutated genes in endometrioid cancers that play a role in tumourigenesis and that influence the clinical outcome...
April 1, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27986439/expression-levels-of-kmt2c-and-slc20a1-identified-by-information-theoretical-analysis-are-powerful-prognostic-biomarkers-in-estrogen-receptor-positive-breast-cancer
#15
Keiko Sato, Kazunori Akimoto
INTRODUCTION: In general, it has been considered that estrogen receptor-positive (ER(+)) breast cancer has a good prognosis and is responsive to endocrine therapy. However, one third of patients with ER(+) breast cancer exhibit endocrine therapy resistance, and many patients develop recurrence and die 5 to 10 years after diagnosis. In ER(+) breast cancer, a major problem is to distinguish those patients most likely to develop recurrence or metastatic disease within 10 years after diagnosis from those with a sufficiently good prognosis...
June 2017: Clinical Breast Cancer
https://www.readbyqxmd.com/read/27713405/molecular-analysis-of-aggressive-renal-cell-carcinoma-with-unclassified-histology-reveals-distinct-subsets
#16
Ying-Bei Chen, Jianing Xu, Anders Jacobsen Skanderup, Yiyu Dong, A Rose Brannon, Lu Wang, Helen H Won, Patricia I Wang, Gouri J Nanjangud, Achim A Jungbluth, Wei Li, Virginia Ojeda, A Ari Hakimi, Martin H Voss, Nikolaus Schultz, Robert J Motzer, Paul Russo, Emily H Cheng, Filippo G Giancotti, William Lee, Michael F Berger, Satish K Tickoo, Victor E Reuter, James J Hsieh
Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%)...
October 7, 2016: Nature Communications
https://www.readbyqxmd.com/read/27698142/enhancer-priming-by-h3k4-methyltransferase-mll4-controls-cell-fate-transition
#17
Chaochen Wang, Ji-Eun Lee, Binbin Lai, Todd S Macfarlan, Shiliyang Xu, Lenan Zhuang, Chengyu Liu, Weiqun Peng, Kai Ge
Transcriptional enhancers control cell-type-specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes...
October 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27632392/the-contribution-of-mosaic-variants-to-autism-spectrum-disorder
#18
Donald Freed, Jonathan Pevsner
De novo mutation is highly implicated in autism spectrum disorder (ASD). However, the contribution of post-zygotic mutation to ASD is poorly characterized. We performed both exome sequencing of paired samples and analysis of de novo variants from whole-exome sequencing of 2,388 families. While we find little evidence for tissue-specific mosaic mutation, multi-tissue post-zygotic mutation (i.e. mosaicism) is frequent, with detectable mosaic variation comprising 5.4% of all de novo mutations. We identify three mosaic missense and likely-gene disrupting mutations in genes previously implicated in ASD (KMT2C, NCKAP1, and MYH10) in probands but none in siblings...
September 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27626165/mutational-burdens-and-evolutionary-ages-of-thyroid-follicular-adenoma-are-comparable-to-those-of-follicular-carcinoma
#19
Seung-Hyun Jung, Min Sung Kim, Chan Kwon Jung, Hyun-Chun Park, So Youn Kim, Jieying Liu, Ja-Seong Bae, Sung Hak Lee, Tae-Min Kim, Sug Hyung Lee, Yeun-Jun Chung
Follicular thyroid adenoma (FTA) precedes follicular thyroid carcinoma (FTC) by definition with a favorable prognosis compared to FTC. However, the genetic mechanism of FTA to FTC progression remains unknown. For this, it is required to disclose FTA and FTC genomes in mutational and evolutionary perspectives. We performed whole-exome sequencing and copy number profiling of 14 FTAs and 13 FTCs, which exhibited previously-known gene mutations (NRAS, HRAS, BRAF, TSHR and EIF1AX) and copy number alterations (CNAs) (22q loss and 1q gain) in follicular tumors...
October 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27491809/genetic-events-in-the-progression-of-adenoid-cystic-carcinoma-of-the-breast-to-high-grade-triple-negative-breast-cancer
#20
Nicola Fusco, Felipe C Geyer, Maria R De Filippo, Luciano G Martelotto, Charlotte K Y Ng, Salvatore Piscuoglio, Elena Guerini-Rocco, Anne M Schultheis, Laetitia Fuhrmann, Lu Wang, Achim A Jungbluth, Kathleen A Burke, Raymond S Lim, Anne Vincent-Salomon, Masamichi Bamba, Suzuko Moritani, Sunil S Badve, Shu Ichihara, Ian O Ellis, Jorge S Reis-Filho, Britta Weigelt
Adenoid cystic carcinoma of the breast is a rare histological type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes...
November 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
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