A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer

Although human LINE-1 (L1) elements are actively mobilized in many cancers, a role for somatic L1 retrotransposition in tumor initiation has not been conclusively demonstrated. Here, we identify a novel somatic L1 insertion in the APC tumor suppressor gene that provided us with a unique opportunity to determine whether such insertions can actually initiate colorectal cancer (CRC), and if so, how this might occur. Our data support a model whereby a hot L1 source element on Chromosome 17 of the patient's genome evaded somatic repression in normal colon tissues and thereby initiated CRC by mutating the APC gene. This insertion worked together with a point mutation in the second APC allele to initiate tumorigenesis through the classic two-hit CRC pathway. We also show that L1 source profiles vary considerably depending on the ancestry of an individual, and that population-specific hot L1 elements represent a novel form of cancer risk.

[1]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration , 2012, Briefings Bioinform..

[2]  J. Jurka,et al.  Repbase Update, a database of eukaryotic repetitive elements , 2005, Cytogenetic and Genome Research.

[3]  D. Largaespada,et al.  Extensive somatic L1 retrotransposition in colorectal tumors , 2012, Genome research.

[4]  C. Walsh,et al.  Single-Neuron Sequencing Analysis of L1 Retrotransposition and Somatic Mutation in the Human Brain , 2012, Cell.

[5]  Jef D Boeke,et al.  High Frequency Retrotransposition in Cultured Mammalian Cells , 1996, Cell.

[6]  K. Burns,et al.  LINE-1 expression and retrotransposition in Barrett’s esophagus and esophageal carcinoma , 2015, Proceedings of the National Academy of Sciences.

[7]  B. Job,et al.  Genomic Aberrations in Lung Adenocarcinoma in Never Smokers , 2010, PloS one.

[8]  J. V. Moran,et al.  LINE-1 elements in structural variation and disease. , 2011, Annual review of genomics and human genetics.

[9]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[10]  Lovelace J. Luquette,et al.  Landscape of Somatic Retrotransposition in Human Cancers , 2012, Science.

[11]  J. Mattick,et al.  Somatic retrotransposition alters the genetic landscape of the human brain , 2011, Nature.

[12]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[13]  Piero Carninci,et al.  Edinburgh Research Explorer Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma , 2022 .

[14]  Christine A Iacobuzio-Donahue,et al.  Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma , 2015, Nature Medicine.

[15]  E. Ostertag,et al.  Twin priming: a proposed mechanism for the creation of inversions in L1 retrotransposition. , 2001, Genome research.

[16]  M. Bertagnolli,et al.  Molecular origins of cancer: Molecular basis of colorectal cancer. , 2009, The New England journal of medicine.

[17]  H. Kazazian,et al.  High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes. , 2010, Genome research.

[18]  Kai Ye,et al.  MSIsensor: microsatellite instability detection using paired tumor-normal sequence data , 2014, Bioinform..

[19]  Mingming Jia,et al.  COSMIC: exploring the world's knowledge of somatic mutations in human cancer , 2014, Nucleic Acids Res..

[20]  S. Boissinot,et al.  L1 (LINE-1) retrotransposon evolution and amplification in recent human history. , 2000, Molecular biology and evolution.

[21]  J. Hurley,et al.  The molecular genetics of colorectal cancer , 2013, Frontline Gastroenterology.

[22]  A. F. Scott,et al.  Two additional potential retrotransposons isolated from a human L1 subfamily that contains an active retrotransposable element. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[24]  R. Siebert,et al.  ST18 is a breast cancer tumor suppressor gene at human chromosome 8q11.2 , 2004, Oncogene.

[25]  D. Valle,et al.  Mobile Interspersed Repeats Are Major Structural Variants in the Human Genome , 2010, Cell.

[26]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[27]  T. Eickbush,et al.  Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: A mechanism for non-LTR retrotransposition , 1993, Cell.

[28]  K. Kasai,et al.  Increased L1 Retrotransposition in the Neuronal Genome in Schizophrenia , 2014, Neuron.

[29]  J. V. Moran,et al.  Hot L1s account for the bulk of retrotransposition in the human population , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  “Monoallelic germline methylation and sequence variant in the promoter of the RB1 gene: a possible constitutive epimutation in hereditary retinoblastoma” , 2016, Clinical Epigenetics.

[31]  S Ichii,et al.  Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. , 1992, Human molecular genetics.

[32]  Glenn Tesler,et al.  Mapping single molecule sequencing reads using basic local alignment with successive refinement (BLASR): application and theory , 2012, BMC Bioinformatics.

[33]  E. Fearon.  Molecular Genetics of Colorectal Cancer , 1995, Annals of the New York Academy of Sciences.

[34]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[35]  J. V. Moran,et al.  Exon shuffling by L1 retrotransposition. , 1999, Science.

[36]  Fred H. Gage,et al.  Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition , 2005, Nature.

[37]  J. Jurka,et al.  Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Andrew F. Neuwald,et al.  Natural Mutagenesis of Human Genomes by Endogenous Retrotransposons , 2010, Cell.

[39]  Geoffrey J. Faulkner,et al.  Ubiquitous L1 Mosaicism in Hippocampal Neurons , 2015, Cell.

[40]  Gad Getz,et al.  Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing , 2014, Genome research.

[41]  Gabor T. Marth,et al.  An integrated map of structural variation in 2,504 human genomes , 2015, Nature.

[42]  Evan E. Eichler,et al.  LINE-1 Retrotransposition Activity in Human Genomes , 2010, Cell.

[43]  Adrian M. Stütz,et al.  A Comprehensive Map of Mobile Element Insertion Polymorphisms in Humans , 2011, PLoS genetics.

[44]  Akhilesh Pandey,et al.  Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution , 2015, Genome research.

[45]  Y. Sakaki,et al.  Identification of critical CpG sites for repression of L1 transcription by DNA methylation. , 1997, Gene.

[46]  Andrew Menzies,et al.  Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes , 2014, Science.

[47]  P. Polakis.  Mutations in the APC gene and their implications for protein structure and function. , 1995, Current opinion in genetics & development.

[48]  J. V. Moran,et al.  Multiple Fates of L1 Retrotransposition Intermediates in Cultured Human Cells , 2005, Molecular and Cellular Biology.

[49]  K. Kinzler,et al.  Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. , 1992, Cancer research.

[50]  Gene W. Yeo,et al.  L1 retrotransposition in human neural progenitor cells , 2009, Nature.