Tumors Widely Express Hundreds of Embryonic Germline Genes.

Abstract

Simple SummaryMany current cancer treatments also target healthy cells, leading to severe side effects, including infertility. Alternative more cancer specific targets, not expressed in any healthy tissue, would result in fewer side effects. To this aim we identified hundreds of genes expressed by cancer cells that are normally only expressed during the embryonic development of reproductive cells. Because these genes are not expressed in any healthy adult tissue, including the adult testis or ovary, their possible targeting is likely not to have any side effects. Moreover, many of these germ cell genes appear to contribute to typical cancer cell characteristics such as genome instability and metastasis. We indeed found that a relatively high amount of germ cell genes in lung cancer leads to a poor prognosis. We expect that these results will lead to a better understanding of cancer and provide multiple new targets with reduced side effects.We have recently described a class of 756 genes that are widely expressed in cancers, but are normally restricted to adult germ cells, referred to as germ cell cancer genes (GC genes). We hypothesized that carcinogenesis involves the reactivation of biomolecular processes and regulatory mechanisms that, under normal circumstances, are restricted to germline development. This would imply that cancer cells share gene expression profiles with primordial germ cells (PGCs). We therefore compared the transcriptomes of human PGCs (hPGCs) and PGC-like cells (PGCLCs) with 17,382 samples from 54 healthy somatic tissues (GTEx) and 11,003 samples from 33 tumor types (TCGA), and identified 672 GC genes, expanding the known GC gene pool by 387 genes (51%). We found that GC genes are expressed in clusters that are often expressed in multiple tumor types. Moreover, the amount of GC gene expression correlates with poor survival in patients with lung adenocarcinoma. As GC genes specific to the embryonic germline are not expressed in any adult tissue, targeting these in cancer treatment may result in fewer side effects than targeting conventional cancer/testis (CT) or GC genes and may preserve fertility. We anticipate that our extended GC dataset enables improved understanding of tumor development and may provide multiple novel targets for cancer treatment development.