Massive expression of germ cell-specific genes is a hallmark of cancer and a potential target for novel treatment development

Jan Willem Bruggeman,Paul Lodder,Sjoerd Repping,Jan Koster,Geert Hamer

doi:10.1038/s41388-018-0357-2

Jan Willem Bruggeman, Paul Lodder + Show 3 more

Open Access

https://doi.org/10.1038/s41388-018-0357-2

Copy DOI

Journal: Oncogene	Publication Date: Jun 15, 2018
Citations: 43	License type: open-access

Affiliation: University of Amsterdam, Academic Medical Center

Abstract

Cancer cells have been found to frequently express genes that are normally restricted to the testis, often referred to as cancer/testis (CT) antigens or genes. Because germ cell-specific antigens are not recognized as “self” by the innate immune system, CT-genes have previously been suggested as ideal candidate targets for cancer therapy. The use of CT-genes in cancer therapy has thus far been unsuccessful, most likely because their identification has relied on gene expression in whole testis, including the testicular somatic cells, precluding the detection of true germ cell-specific genes. By comparing the transcriptomes of micro-dissected germ cell subtypes, representing the main developmental stages of human spermatogenesis, with the publicly accessible transcriptomes of 2617 samples from 49 different healthy somatic tissues and 9232 samples from 33 tumor types, we here discover hundreds of true germ cell-specific cancer expressed genes. Strikingly, we found these germ cell cancer genes (GC-genes) to be widely expressed in all analyzed tumors. Many GC-genes appeared to be involved in processes that are likely to actively promote tumor viability, proliferation and metastasis. Targeting these true GC-genes thus has the potential to inhibit tumor growth with infertility being the only possible side effect. Moreover, we identified a subset of GC-genes that are not expressed in spermatogonial stem cells. Targeting of this GC-gene subset is predicted to only lead to temporary infertility, as untargeted spermatogonial stem cells can recover spermatogenesis after treatment. Our GC-gene dataset enables improved understanding of tumor biology and provides multiple novel targets for cancer treatment.

Highlights

Many genes have been identified that drive the transition process of healthy cells into cancer cells
With the aim to identify true germ cell-specific cancer genes (GC-genes), we here used the transcriptomes of specific germ cell-types present in healthy human spermatogenesis, which we recently unraveled in our laboratory [15]. We compared this dataset with data from the Genotype-Tissue Expression (GTEx) project [16] and The Cancer Genome Atlas (TCGA) [17] to achieve tumor specificity of germ cell gene expression
Where discovery of most cancer/ testis (CT)-genes depended on whole testis expression data, we here used a unique list of 16 589 genes expressed in human male germ cells generated in our laboratory [15] to identify true germ cell-specific cancer genes (GC-genes)

Summary

Introduction

Many genes have been identified that drive the transition process of healthy cells into cancer cells. Massive expression of germ cell-specific genes is a hallmark of cancer... Recent studies have shown that expression of several germ cell-specific genes actively contributes to both tumor development and survival [8, 9].

Results

Conclusion