LINE-1 expression and retrotransposition in Barrett's esophagus and esophageal carcinoma.
Barrett's esophagus (BE) is a common disease in which the lining of the esophagus transitions from stratified squamous epithelium to metaplastic columnar epithelium that predisposes individuals to developing esophageal adenocarcinoma (EAC). We hypothesized that BE provides a unique environment for increased long-interspersed element 1 (LINE-1 or L1) retrotransposition. To this end, we evaluated 5 patients with benign BE, 5 patients with BE and concomitant EAC, and 10 additional patients with EAC to determine L1 activity in this progressive disease. After L1-seq, we confirmed 118 somatic insertions by PCR in 10 of 20 individuals. We observed clonal amplification of several insertions which appeared to originate in normal esophagus (NE) or BE and were later clonally expanded in BE or in EAC. Additionally, we observed evidence of clonality within the EAC cases; specifically, 22 of 25 EAC-only insertions were present identically in distinct regions available from the same tumor, suggesting that these insertions occurred in the founding tumor cell of these lesions. L1 proteins must be expressed for retrotransposition to occur; therefore, we evaluated the expression of open reading frame 1 protein (ORF1p), a protein encoded by L1, in eight of the EAC cases for which formalin-fixed paraffin embedded tissue was available. With immunohistochemistry, we detected ORF1p in all tumors evaluated. Interestingly, we also observed dim ORF1p immunoreactivity in histologically NE of all patients. In summary, our data show that somatic retrotransposition occurs early in many patients with BE and EAC and indicate that early events occurring even in histologically NE cells may be clonally expanded in esophageal adenocarcinogenesis.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Tara T
TT
Doucet-O'Hare
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
Nemanja
N
Rodić
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
Reema
R
Sharma
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Isha
I
Darbari
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Gabriela
G
Abril
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Jungbin A
JA
Choi
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Ji
J
Young Ahn
Division of Gastroenterology and Hepatology, Department of Medicine and Department of Oncology, Johns Hopkins University, Baltimore, MD 21205.
Yulan
Y
Cheng
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
Robert A
RA
Anders
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
Kathleen H
KH
Burns
Division of Gastroenterology and Hepatology, Department of Medicine and Department of Oncology, Johns Hopkins University, Baltimore, MD 21205 smeltzer@jhmi.edu hkazazi1@jhmi.edu.
Stephen J
SJ
Meltzer
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; smeltzer@jhmi.edu hkazazi1@jhmi.edu.
Haig H
HH
Kazazian
D000230:Adenocarcinoma / Q000235:genetics*; D001471:Barrett Esophagus / Q000235:genetics*; D001483:Base Sequence; D004247:DNA; D004938:Esophageal Neoplasms / Q000235:genetics*; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008969:Molecular Sequence Data; D018626:Retroelements
D018626:Retroelements; D004247:DNA
Barrett’s esophagus; LINE-1; esophageal adenocarcinoma; retrotransposition; retrotransposon