The driving role of cancer-testis genes: a new perspective for cancer researches

We appreciate the attention Kaczkowski et al. paid to our previous work (1), in which we provided a source of candidate epi-driver genes by studying the cancer-testis (CT) gene expression pattern in normal and tumor tissues. The identification of CT genes and the link between CT genes and cancer epi-drivers are attractive but less-studied topics. We believe that the study of CT genes with special expression patterns provides new perspectives for the identification of cancer epi-drivers.

One of the major points raised by Kaczkowski and his colleagues was that aberrantly expressed genes should not be proposed to be epi-drivers without supporting epigenetic data. They firstly mentioned that several other mechanisms such as mutations in regulatory regions/factors and copy number alterations might also contribute to the expression changes of genes in cancer cells. We don’t think that these mechanisms prevent us from identifying driver genes by investigating aberrantly expression patterns, because epigenetic regulation is widely accepted as one of the major regulation mechanisms of gene expression (2). In addition, previous studies have showed that epigenetic regulators contribute greatly to restricted expression pattern of genes involved in the development of germ cells (3). Being testis-restrictedly expressed genes, it is highly possible that many CT genes can be activated in cancer cells through similar epigenetic modifications in germ cells. We also noticed that CT genes shared several characters with epi-drivers: (I) they were activated aberrantly in tumor tissues; (II) their activation in cancer cells may provide malignant phenotype and selective advantage (gametic recapitulation theory) (4). Thus, we proposed our hypothesis that CT genes might act as epi-driver genes.

Additional evidence further supports the hypothesis. We found that CT genes were more likely to show aberrant activated expression patterns in cancer than other genes. In addition, although there was no known epigenetic evidence, we observed that MEIOB expression was not associated with genomic alterations (including mutations and copy number changes) near MEIOB, but was associated with global copy number aberration level, suggesting that the activation of meiosis-specific protein MEIOB may result in genome instability in cancer cells. The driving role of another extremely-high expressed CT gene (EECTG) LIN28B in multiple cancers has been clearly stated (5,6), but its CT expression pattern was first reported. More importantly, the LIN28B and let-7 regulation loop have been extensively explored (5-7), which evidently suggested that LIN28B was an epi-driver gene.

With these evidences, we think that CT genes are a source (but not the only source) of epi-driver candidates. In our previous study, we aimed to provide a comprehensive landscape of CT genes and to suggest their potential to be epi-drivers rather than to tell all CT genes should be epi-driver genes of cancer. Actually, even for significantly-mutated genes, which are candidates of mut-drivers, additional mechanism studies are warranted to clarify their driving role. Thus, we agree that further epigenetic evidence is necessary to elucidate the activation mechanisms of CT genes in the next stage investigation.

Unlike many cancer studies, we did not use adjacent cancer tissues as control, because they are not equal to normal tissues and may induce unnecessary bias (8,9). They are widely applied simply because a paired normal tissue can hardly be obtained from a tumor patient. As we have showed that CT genes are not expressed or very little expressed in a large number of normal tissues, we believe that it is an advantage of our study to avoid using adjacent cancer tissues as controls. However, we recommend to use adjacent cancer tissues as controls when studying CT genes with low expression level in tumor tissues.

Despite the importance of CT genes, we considered them as a supplement rather than a replacement of mut-drivers. Here, we want to point out that CT genes are aberrantly activated in cancer and should be classified as potential oncogenes. As we all know, a tumor suppressor such as TP53 or PTEN usually cannot be used as a target of molecular targeted therapy. Thus, cancer patients can hardly benefit from the identification of mut-driver genes, even though total mutation rates of the mut-driver genes sometimes reach 100%. It is worth noting that some important tumor suppressors are transcription factors and their mutation may be involved in the activation of CT driver genes. Thus, study on the activation of CT genes and high-frequency tumor suppressor mutations may help provide additional targets for patients with tumor suppressors’ mutations in future precise medicine and may have important clinical implications.

However, as mentioned by Kaczkowski and his colleagues, clinical transformation is difficult, not only for CT genes, but for all known cancer driver genes, though comprehensive mutations spectrums have been fully described in many cancer types. Our study emphasized the driving role of a group of CT genes instead of focusing only on the immunogenicity of CT antigens, thus our results may have tremendous clinical value in both immunotherapy and molecular targeted therapy. Kaczkowski and his colleagues also mentioned neo-antigens, which was a source of mutated genes with products of tumor specific immunogenic protein. Unsurprisingly, we noticed that Li et al. had recently developed a computational method to infer potential immunogenic neo-antigens (10). SPAG5 and TSSK6 were predicted as putative immunogenic cancer/testis antigens in multiple cancers (10). This analysis successfully connected the neo-antigen and CT genes and indicated the importance of these genes in cancer therapy.

At last, we appreciate that the authors emphasize the importance of CT non-coding RNAs (CT-ncRNAs). We observed that CT-ncRNAs may contribute to the activation of CT genes and serve as one of the epigenetic activations of CT genes. However, our bioinformatics analyses were largely limited because little information on ncRNAs was known in both cancer and germ cell development. We hope that more comprehensive studies can further decode the connection between CT-ncRNAs and CT genes and illuminate underlying mechanisms.

Acknowledgments

Funding: This paper was supported by the National Key Basic Research Program Grant (2013CB911400, 2015CB943003), National Natural Science Foundation of China (31530047, 81230067), the Natural Science Foundation of Jiangsu Province (BK20130060), Science Foundation for Distinguished Young Scholars of Jiangsu (BK2012042), the National Science Foundation for Distinguished Young Scholars of China (81225020), the Ten Thousand Talent Program and Distinguished Professor at Jiangsu, the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine) and Top-notch Academic Programs Project of Jiangsu Higher Education Institutions.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Yi-Ming Tao (Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, China).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2016.08.33). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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