Somatically Acquired LINE-1 Insertions in Normal Esophagus Undergo Clonal Expansion in Esophageal Squamous Cell Carcinoma.
Squamous cell carcinoma of the esophagus (SCC) is the most common form of esophageal cancer in the world and is typically diagnosed at an advanced stage when successful treatment is challenging. Understanding the mutational profile of this cancer may identify new treatment strategies. Because somatic retrotransposition has been shown in tumors of the gastrointestinal system, we focused on LINE-1 (L1) mobilization as a source of genetic instability in this cancer. We hypothesized that retrotransposition is ongoing in SCC patients. The expression of L1 encoded proteins is necessary for retrotransposition to occur; therefore, we evaluated the expression of L1 open reading frame 1 protein (ORF1p). Using immunohistochemistry, we detected ORF1p expression in all four SCC cases evaluated. Using L1-seq, we identified and validated 74 somatic insertions in eight tumors of the nine evaluated. Of these, 12 insertions appeared to be somatic, not genetically inherited, and sub-clonal (i.e., present in less than one copy per genome equivalent) in the adjacent normal esophagus (NE), while clonal in the tumor. Our results indicate that L1 retrotransposition is active in SCC of the esophagus and that insertion events are present in histologically NE that expands clonally in the subsequent tumor.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Baltimore, Maryland.|National Institutes of Health: National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.
Tara T
TT
Doucet-O'Hare
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Reema
R
Sharma
Dermatology Department, Yale School of Medicine, New Haven, Connecticut.
Nemanja
N
Rodić
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Robert A
RA
Anders
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Kathleen H
KH
Burns
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Haig H
HH
Kazazian
D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism; D000077277:Esophageal Squamous Cell Carcinoma; D004947:Esophagus / Q000378:metabolism; D005260:Female; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA
C531245:ORF1 protein, human; D011506:Proteins
L1; LINE-1; esophagus; retrotransposition; squamous cell carcinoma; sub-clonal