Male or female? “Cancer-germline” genes set the first marks

What are “Cancer-Germline” genes?

So-called “Cancer-Germline” (CG) genes form a particular group of human genes that are normally active only in the germ cells of the testis, i.e. the cells that give rise to sperm. The discovery of CG genes dates back to the 1990s, when researchers were surprised to find that these “testicular” genes become aberrantly activated in a variety of cancers.

Why are CG genes activated in tumors?

The control of gene activity in cells partly relies on epigenetic mechanisms — a set of chemical modifications that define active or silent regions on chromosomes. It is known that the distribution of these modifications is profoundly altered in tumors, and that this epigenetic chaos can lead to abnormal activation of certain genes. Professor Charles De Smet’s team at the de Duve Institute (UCLouvain) demonstrated that this is the case for CG genes, which are accidentally switched on when one such modification, DNA methylation, is strongly reduced in tumors. With what consequence? Some researchers suggest that CG gene activation could trigger a spermatogenic program in cancer cells, helping them proliferate without restraint, migrate more easily, or evade cell death mechanisms. But evidence is still lacking, CG genes have yet to reveal all their secrets.

A broader view of CG genes through bioinformatics

To better understand the possible functions of CG genes, the team called on the bioinformatics expertise of Laurent Gatto's laboratory to determine when and where these genes are first activated during life. Their discoveries, published in PLoS Genetics, are both unexpected and fascinating. CG genes are not evenly distributed across our genome, as many of them are located on the X chromosome. Using new computational tools and large datasets from early human embryos, the researchers found that many X-linked CG genes are expressed during the very earliest stages of embryonic development — but only in female embryos, not in male embryos. Why? It turns out that these genes are subject to a special kind of control called “genomic imprinting,” in which only the copy inherited from the father is active, while the maternal copy remains inactive due to DNA methylation marks. Since females inherit two X chromosomes (one from each parent) and males only one (from the mother), only young female embryos express these CG genes (from the paternal copy). The study thus shows that CG genes mark the very first differences between male and female.

New perspectives for CG genes

The sex-specific expression of CG genes quickly fades in the embryo (around five days after fertilization), but it raises intriguing questions. Could these genes, known for their reactivation in cancer, also play a crucial role in early human development? What might their impact be on sexual differentiation? Could their activation in cancer be linked in some way to their embryonic origins?

By tracing these genes from embryo to tumor, the study opens new perspectives on both cancer biology and human development, as well as on the epigenetic mechanisms that tie them together.

Article describing this research

A survey of human cancer-germline genes: Linking X chromosome localization, DNA methylation and sex-biased expression in early embryos.

Loriot A, Devis J, Gatto L, De Smet C

PLoS Genet (2025) 21(10): e1011734