PBOV1 Is a Human De Novo Gene with Tumor-Specific Expression That Is Associated with a Positive Clinical Outcome of Cancer

Abstract

PBOV1 is a known human protein-coding gene with an uncharacterized function. We have previously found that PBOV1 lacks orthologs in non-primate genomes and is expressed in a wide range of tumor types. Here we report that PBOV1 protein-coding sequence is human-specific and has originated de novo in the primate evolution through a series of frame-shift and stop codon mutations. We profiled PBOV1 expression in multiple cancer and normal tissue samples and found that it was expressed in 19 out of 34 tumors of various origins but completely lacked expression in any of the normal adult or fetal human tissues. We found that, unlike the cancer/testis antigens that are typically controlled by CpG island-containing promoters, PBOV1 was expressed from a GC-poor TATA-containing promoter which was not influenced by CpG demethylation and was inactive in testis. Our analysis of public microarray data suggests that PBOV1 activation in tumors could be dependent on the Hedgehog signaling pathway. Despite the recent de novo origin and the lack of identifiable functional signatures, a missense SNP in the PBOV1 coding sequence has been previously associated with an increased risk of breast cancer. Using publicly available microarray datasets, we found that high levels of PBOV1 expression in breast cancer and glioma samples were significantly associated with a positive outcome of the cancer disease. We also found that PBOV1 was highly expressed in primary but not in recurrent high-grade gliomas, suggesting the presence of a negative selection against PBOV1-expressing cancer cells. Our findings could contribute to the understanding of the mechanisms behind de novo gene origin and the possible role of tumors in this process.

Identification and evolution of the orphan genes in the domestic silkworm,Bombyx mori

“…Wu et al (2011) identified 60 de novo genes in human [22]. Moreover, de novo genes could play essential roles during the evolution of organisms [44,45]. In this study, we also identified five de novo originated OGs in the silkworm ( Supplementary Table S6).…”

New genes contribute to genetic and phenotypic novelties in human evolution

“…Meanwhile, it was found that new genes could also repress tumorigenesis. For instance, prostate and breast cancer overexpressed gene 1 ( PBOV1 ) evolved as a human specific de novo gene, whose expression is associated positively with the survival possibility of patients [30]. …”

PBOV1 as a potential biomarker for more advanced prostate cancer based on protein and digital histomorphometric analysis

“…For example, high expression of PBOV1 correlated positively with relapse-free survival outcomes in breast cancer and glioma in a study based on clinically annotated public microarray data. 15 These results suggested possible "immunoediting" of PBOV1-expressing tumor cells, whereby PBOV1 serves as a tumor antigen facilitating immune attack and elimination of tumor cells based on the presence of PBOV1. A more recent study demonstrated that high levels of PBOV1 mRNA and protein levels in ovarian cancer correlate positively with longer survival and negatively with ascending histological grade, 16 also consistent with a possible immune-stimulatory role for PBOV1 in this setting.…”

“…Proteins were extracted using previously described methods. 20 The PBOV1 antibody used in this study was validated as previously described 12 and recognizes epitope B of the PBOV1 protein (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Beta actin (1:15,000, Sigma-Aldrich, St. Louis, MO) was used as a control for data normalization.…”

“…While these results implicate PBOV1 in tumor proliferation, other studies found that phenotypes associated with PBOV1 are context dependent and vary with cell type or tissue. For example, high expression of PBOV1 correlated positively with relapse‐free survival outcomes in breast cancer and glioma in a study based on clinically annotated public microarray data . These results suggested possible “immunoediting” of PBOV1‐expressing tumor cells, whereby PBOV1 serves as a tumor antigen facilitating immune attack and elimination of tumor cells based on the presence of PBOV1.…”