Striking heterogeneity of somatic L1 retrotransposition in single normal and cancerous gastrointestinal cells

Abstract

Somatic LINE-1 (L1) retrotransposition has been detected in early embryos, adult brains, and the gastrointestinal (GI) tract, and many cancers, including epithelial GI tumors. We previously found numerous somatic L1 insertions in paired normal and GI cancerous tissues. Here, using a modified method of single-cell analysis for somatic L1 insertions, we studied adenocarcinomas of colon, pancreas, and stomach, and found a variable number of somatic L1 insertions in tumors of the same type from patient to patient. We detected no somatic L1 insertions in single cells of 5 of 10 tumors studied. In three tumors, aneuploid cells were detected by FACS. In one pancreatic tumor, there were many more L1 insertions in aneuploid than in euploid tumor cells. In one gastric cancer, both aneuploid and euploid cells contained large numbers of likely clonal insertions. However, in a second gastric cancer with aneuploid cells, no somatic L1 insertions were found. We suggest that when the cellular environment is favorable to retrotransposition, aneuploidy predisposes tumor cells to L1 insertions, and retrotransposition may occur at the transition from euploidy to aneuploidy. Seventeen percent of insertions were also present in normal cells, similar to findings in genomic DNA from normal tissues of GI tumor patients. We provide evidence that: 1) The number of L1 insertions in tumors of the same type is highly variable, 2) most somatic L1 insertions in GI cancer tissues are absent from normal tissues, and 3) under certain conditions, somatic L1 retrotransposition exhibits a propensity for occurring in aneuploid cells.

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

“…Whilst the DNAm of CpG islands is mostly known for tumour suppressor gene silencing, GGDHo can be conducive to altered gene expression, oncogene and retrotransposon activation [148]; functional deficiencies in structural DNA repeats [149]; genetic and chromosomal instability; and ultimately to carcinogenesis. These observations are based on substantial experimental evidence.…”

A Long, Fulfilling Career in Human Genetics

“…My lab has found that a minority of somatic L1 insertions in the bulk DNA of gastric and esophageal cancers are present in normal tissue (36). Likewise, we have found in single cells and whole tissue that about 15-20% of somatic insertions in colon, gastric, and pancreatic cancers are present in the noncancerous cells of these tissues (81). Are the normal cells in the normal tissue in fact normal?…”

Mutagenesis of human genomes by endogenous mobile elements on a population scale

“…With a comprehensive approach using several of these tools, somatic cancers and neuronal tissues could be examined to determine how FL-L1Hs elements evade somatic repression in these tissues and which elements can achieve this status. Other normal epithelial and neuronal tissues in which FL-L1Hs elements can evade somatic repression also could be examined, including the esophagus, pancreas, colon ( Doucet-O'Hare et al 2015 ; Ewing et al 2015 ; Scott et al 2016 ; Yamaguchi et al 2020 ) as well as the liver, brain, embryonic stem cells, and cells undergoing neuronal differentiation ( Sanchez-Luque et al 2019 ). Aberrantly high levels of L1 expression and retrotransposition often are associated with neuronal diseases; in many cases, the underlying mechanisms leading to L1 up-regulation are unknown ( Terry and Devine 2020 ).…”

“…However, it has become clear that L1 also is active in at least some somatic tissues, including neuronal tissues of the brain ( Coufal et al 2009 ; Baillie et al 2011 ; Evrony et al 2012 ; Upton et al 2015 ; for review, see Terry and Devine 2020 ) and human cancers ( Iskow et al 2010 ; Lee et al 2012 ; Solyom et al 2012 ; Shukla et al 2013 ; Helman et al 2014 ; Tubio et al 2014 ; Doucet-O'Hare et al 2015 ; Ewing et al 2015 , 2020 ; Rodić et al 2015 ; Scott et al 2016 ; Rodriguez-Martin et al 2020 ; Yamaguchi et al 2020 ). Growing evidence also suggests that L1 can evade somatic repression in other normal cells and tissues, including the esophagus, pancreas, and colon ( Doucet-O'Hare et al 2015 ; Ewing et al 2015 ; Scott et al 2016 ; Yamaguchi et al 2020 ), as well as the liver, brain, embryonic stem cells, and cells undergoing neuronal differentiation ( Sanchez-Luque et al 2019 ). Many aspects of L1 regulation and dysregulation remain poorly understood in these diverse settings owing to a limited knowledge of the full-length L1 source elements that drive MEI mutagenesis.…”