PBOV1 is a human de novo gene with tumor-specific expression that is associated with a positive clinical outcome of cancer

PLoS One. 2013;8(2):e56162. doi: 10.1371/journal.pone.0056162. Epub 2013 Feb 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Evolution, Molecular
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic*
  • Glioma / genetics
  • Glioma / pathology
  • Hedgehog Proteins / genetics
  • Humans
  • Male
  • Molecular Sequence Data
  • Neoplasm Proteins / classification
  • Neoplasm Proteins / genetics*
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Oligonucleotide Array Sequence Analysis
  • Phylogeny
  • Prognosis
  • Sequence Homology, Amino Acid
  • Signal Transduction / genetics

Substances

  • Hedgehog Proteins
  • IHH protein, human
  • Neoplasm Proteins
  • PBOV1 protein, human

Grants and funding

This work was funded by the Biomedical Centre and by the Russian-Belorussian program #K-32-NIR/111-3. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, except for Prof. Andrey P. Kozlov who, being the head of the Biomedical Centre, simultaneously authorized the funding and supervised this work.