Long interspersed element-1 protein expression is a hallmark of many human cancers

Abstract

Cancers comprise a heterogeneous group of human diseases. Unifying characteristics include unchecked abilities of tumor cells to proliferate and spread anatomically, and the presence of clonal advantageous genetic changes. However, universal and highly specific tumor markers are unknown. Herein, we report widespread long interspersed element-1 (LINE-1) repeat expression in human cancers. We show that nearly half of all human cancers are immunoreactive for a LINE-1-encoded protein. LINE-1 protein expression is a common feature of many types of high-grade malignant cancers, is rarely detected in early stages of tumorigenesis, and is absent from normal somatic tissues. Studies have shown that LINE-1 contributes to genetic changes in cancers, with somatic LINE-1 insertions seen in selected types of human cancers, particularly colon cancer. We sought to correlate this observation with expression of the LINE-1-encoded protein, open reading frame 1 protein, and found that LINE-1 open reading frame 1 protein is a surprisingly broad, yet highly tumor-specific, antigen.

Figure 1

LINE-1–encoded protein ORF1p is undetectable in mature human somatic tissues and commonly expressed in a wide range of human cancers. Representative photomicrographs are shown in pairs, with normal tissues on the left; tissues are counterstained (blue). Photomicrographs on the right show LINE-1 ORF1p immunoreactivity (brown) detected with a rabbit polyclonal ORF1p antibody in various human neoplasms, including colon carcinoma (A), renal cell carcinoma (B), lymphoma (C), hepatocellular carcinoma (D), lung carcinoma (E), breast carcinoma (F), pancreatic carcinoma (G), and biliary tract carcinoma (H). Original magnification, ×160 (A–H). Scale bar = 20 μm. N, normal tissue; T, tumor.

Figure 2

LINE-1 ORF1p is present in a wide range of human neoplasms. A: LINE-1 expression as a percentage of LINE-1–immunoreactive cases in different primary tumor types. LINE-1 immunolabeling in low- versus high-grade mesenchymal tumors (B), lymphomas (C), pancreatic ductal neoplasms (D), and astrocytic neoplasms (E), expressed as a percentage of cases. The number above each column in panels B–E designates the number of cases examined for LINE-1 immunolabeling.

Figure 3

LINE-1 expression correlates with TP53 deficiency. A: Comparison of published TP53 mutation rates versus LINE-1 immunolabeling in different carcinomas. B and C: A diagram (B) and representative photomicrographs (B) depicting LINE-1 immunolabeling and TP53 deficiency in lung carcinomas, pancreatic carcinomas, ovarian carcinomas, and secondary GBMs. Immunoreactivity for TP53 is an indicator of overexpression of a mutated protein. The number of cases is denoted on the x axis of the bar graph. ^∗P < 0.05, based on the binomial test. Original magnification, ×160 (A–C). Scale bar = 20 μm. N, normal tissue; T, tumor.