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11 Publications visible to you, out of a total of 11
WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Abstract (Expand)

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, … however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother's, and, to a lesser extent, with father's TL having the strongest influence on the offspring. In this cohort, mother's, but not father's age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

Authors: Lilit Nersisyan, Maria Nikoghosyan, Laurent C. Francioli, Androniki Menelaou, Sara L. Pulit, Clara C. Elbers, Wigard P. Kloosterman, Jessica van Setten, Isaäc J. Nijman, Ivo Renkens, Paul I. W. de Bakker, Freerk van Dijk, Pieter B. T. Neerincx, Patrick Deelen, Alexandros Kanterakis, Martijn Dijkstra, Heorhiy Byelas, K. Joeri van der Velde, Mathieu Platteel, Morris A. Swertz, Cisca Wijmenga, Pier Francesco Palamara, Itsik Pe’er, Kai Ye, Eric-Wubbo Lameijer, Matthijs H. Moed, Marian Beekman, Anton J. M. de Craen, H. Eka D. Suchiman, P. Eline Slagboom, Victor Guryev, Abdel Abdellaoui, Jouke Jan Hottenga, Mathijs Kattenberg, Gonneke Willemsen, Dorret I. Boomsma, Elisabeth M. van Leeuwen, Lennart C. Karssen, Najaf Amin, Fernando Rivadeneira, Aaron Isaacs, Albert Hofman, André G. Uitterlinden, Cornelia M. van Duijn, Mannis van Oven, Manfred Kayser, Martijn Vermaat, Jeroen F. J. Laros, Johan T. den Dunnen, David van Enckevort, Hailiang Mei, Mingkun Li, Mark Stoneking, Barbera D. C. van Schaik, Jan Bot, Tobias Marschall, Alexander Schönhuth, Jayne Y. Hehir-Kwa, Robert E. Handsaker, Paz Polak, Mashaal Sohail, Dana Vuzman, Karol Estrada, Steven A. McCarroll, Shamil R. Sunyaev, Fereydoun Hormozdiari, Vyacheslav Koval, Carolina Medina-Gomez, Ben Oostra, Jan H. Veldink, Leonard H. van den Berg, Steven J. Pitts, Shobha Potluri, Purnima Sundar, David R. Cox, Peter de Knijff, Qibin Li, Yingrui Li, Yuanping Du, Ruoyan Chen, Hongzhi Cao, Jun Wang, Ning Li, Sujie Cao, Jasper A. Bovenberg, Gert-Jan B. van Ommen, Arsen Arakelyan

Date Published: 10th Dec 2019

Publication Type: Journal

Telomere Length Maintenance and Its Transcriptional Regulation in Lynch Syndrome and Sporadic Colorectal Carcinoma

Abstract (Expand)

Background: Activation of telomere maintenance mechanisms (TMMs) is a hallmark of most cancers, and is required to prevent genome instability and to establish cellular immortality through reconstitution … of capping of chromosome ends. TMM depends on the cancer type. Comparative studies linking tumor biology and TMM have potential impact for evaluating cancer onset and development. Methods: We have studied alterations of telomere length, their sequence composition and transcriptional regulation in mismatch repair deficient colorectal cancers arising in Lynch syndrome (LS-CRC) and microsatellite instable (MSI) sporadic CRC (MSI s-CRC), and for comparison, in microsatellite stable (MSS) s-CRC and in benign colon mucosa. Our study applied bioinformatics analysis of whole genome DNA and RNA sequencing data and a pathway model to study telomere length alterations and the potential effect of the "classical" telomerase (TEL-) and alternative (ALT-) TMM using transcriptomic signatures. Results: We have found progressive decrease of mean telomere length in all cancer subtypes compared with reference systems. Our results support the view that telomere attrition is an early event in tumorigenesis. TMM gets activated in all tumors studied due to concerted overexpression of a large fraction of genes with direct relation to telomere function, where only a very small fraction of them showed recurrent mutations. TEL-related transcriptional state was dominating in all CRC subtypes, showing, however, subtype-specific activation patterns; while contribution of the ALT-TMM was slightly more prominent in the hypermutated MSI s-CRC and LS-CRC. TEL-TMM is mainly activated by over-expression of DKC1 and/or TERT genes and their interaction partners, where DKC1 is more prominent in MSS than in MSI s-CRC and can serve as a transcriptomic marker of TMM activity. Conclusions: Our results suggest that transcriptional patterns are indicative for TMM pathway activation with subtle differences between TEL and ALT mechanisms in a CRC subtype-specific fashion. Sequencing data potentially provide a suited measure to study alterations of telomere length and of underlying transcriptional regulation. Further studies are needed to improve this method. Keywords: DNAseq and RNAseq data analysis; colorectal cancer; mismatch repair; pathway models; telomerase and alternative telomere maintenance; telomere attrition; telomere length; telomere repeat variants.

Authors: Lilit Nersisyan, Lydia Hopp, Henry Loeffler-Wirth, Jörg Galle, Markus Loeffler, Arsen Arakelyan, Hans Binder

Date Published: 5th Nov 2019

Publication Type: Journal

A modular transcriptome map of mature B cell lymphomas

Abstract (Expand)

Background: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic … phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. Conclusions: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities. Keywords: B cell malignancies; Gene regulation; Machine learning; Molecular subtypes; Tumor heterogeneity.

Authors: Henry Loeffler-Wirth, Markus Kreuz, Lydia Hopp, Arsen Arakelyan, Andrea Haake, Sergio B. Cogliatti, Alfred C. Feller, Martin-Leo Hansmann, Dido Lenze, Peter Möller, Hans Konrad Müller-Hermelink, Erik Fortenbacher, Edith Willscher, German Ott, Andreas Rosenwald, Christiane Pott, Carsten Schwaenen, Heiko Trautmann, Swen Wessendorf, Harald Stein, Monika Szczepanowski, Lorenz Trümper, Michael Hummel, Wolfram Klapper, Reiner Siebert, Markus Loeffler, Hans Binder

Date Published: 30th Apr 2019

Publication Type: Journal

Characterization of BRCA1/2 mutations in patients with family history of breast cancer in Armenia.

Abstract (Expand)

Background. Breast cancer is one of the most common cancers in women worldwide. The germline mutations of the BRCA1 and BRCA2 genes are the most significant and well characterized genetic risk factors … for hereditary breast cancer. Intensive research in the last decades has demonstrated that the incidence of mutations varies widely among different populations. In this study we attempted to perform a pilot study for identification and characterization of mutations in BRCA1 and BRCA2 genes among Armenian patients with family history of breast cancer and their healthy relatives. Methods. We performed targeted exome sequencing for BRCA1 and BRCA2 genes in 6 patients and their healthy relatives. After alignment of short reads to the reference genome, germline single nucleotide variation and indel discovery was performed using GATK software. Functional implications of identified variants were assessed using ENSEMBL Variant Effect Predictor tool. Results. In total, 39 single nucleotide variations and 4 indels were identified, from which 15 SNPs and 3 indels were novel. No known pathogenic mutations were identified, but 2 SNPs causing missense amino acid mutations had significantly increased frequencies in the study group compared to the 1000 Genome populations. Conclusions. Our results demonstrate the importance of screening of BRCA1 and BRCA2 gene variants in the Armenian population in order to identity specifics of mutation spectrum and frequencies and enable accurate risk assessment of hereditary breast cancers. Keywords: BRCA1; BRCA2; breast cancer; mutation screening; targeted exome sequencing.

Authors: Sofi Atshemyan, Andranik Chavushyan, Nerses Berberian, Arthur Sahakyan, Roksana Zakharyan, Arsen Arakelyan

Date Published: 10th Jan 2017

Publication Type: Journal

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