The disruption of trace element homeostasis due to aneuploidy as a unifying theme in the etiology of cancer

Abstract

#### #### ABSTRACT FOR SCIENTISTS: While decades of cancer research have firmly established multiple hallmarks of cancer 1,2, cancers genomic landscape remains to be fully understood. Particularly, the phenomenon of aneuploidy gains and losses of large genomic regions, i.e. whole chromosomes or chromosome arms and why most cancer cells are aneuploid remains enigmatic 3. Another frequent observation in many different types of cancer is the deregulation of the homeostasis of the trace elements copper, zinc and iron. Concentrations of copper are markedly increased in cancer tissue and the blood plasma of cancer patients, while zinc levels are typically decreased 49. Here we discuss the hypothesis that the disruption of trace element homeostasis and the phenomenon of aneuploidy might be linked. Our tentative analysis of genomic data from diverse tumor types mainly from The Cancer Genome Atlas (TCGA) project suggests that gains and losses of metal transporter genes occur frequently and correlate well with transporter gene expression levels. Hereby they may confer a cancer-driving selective growth advantage at early and possibly also later stages during cancer development. This idea is consistent with recent observations in yeast, which suggest that through chromosomal gains and losses cells can adapt quickly to new carbon sources 10, nutrient starvation 11 as well as to copper toxicity 12. In human cancer development, candidate driving events may include, among others, the gains of zinc transporter genes SLC39A1 and SLC39A4 on chromosome arms 1q and 8q, respectively, and the losses of zinc transporter genes SLC30A5, SLC39A14 and SLC39A6 on 5q, 8p and 18q. The recurrent gain of 3q might be associated with the iron transporter gene TFRC and the loss of 13q with the copper transporter gene ATP7B. By altering cellular trace element homeostasis such events might contribute to the initiation of the malignant transformation. Intriguingly, attenuation or overexpression of several of these metal transporter genes has been shown to lead to malignant cellular behavior in vitro. Consistently, it has been shown that zinc affects a number of the observed hallmarks of cancer characteristics including DNA repair, inflammation and apoptosis, e.g. through its effects on NF-kappa B signaling. We term this model the aneuploidy metal transporter cancer (AMTC) hypothesis and find it compatible with the cancer-promoting role of point mutations and focal copy number alterations in established tumor suppressor genes and oncogenes (e.g. MYC, MYCN, TP53, PIK3CA, BRCA1, ERBB2). We suggest a number of approaches for how this hypothesis could be tested experimentally and briefly touch on possible implications for cancer etiology, metastasis, drug resistance and therapy. #### #### ABSTRACT FOR KIDS: We humans are made up of many very small building blocks, which are called cells. These cells can be seen with a microscope and they know how to grow and what to do from the information on the DNA of their chromosomes. Sometimes, if this information is messed up, a cell can go crazy and start to grow without control, even in places of the body where it should not. This process is called cancer, a terrible disease that makes people very sick. Scientists do not understand exactly what causes cells to go crazy, so it would be good to find out. Many years ago, scientists observed that chromosomes in these cancer cells are missing or doubled but could not find an explanation for it. More recently, scientists have detected that precious metals to our bodies, which are not gold and silver, but zinc, iron and copper, are not found in the right amounts in these crazy cancer cells. There seems to be not enough zinc and iron but too much copper, and again, scientists do not really understand why. So there are many unanswered questions about these crazy cancer cells and in this article, we describe a pretty simple idea on how chromosome numbers and the metals might be connected: we think that the missing or doubled chromosomes produce less or more transporters of zinc, iron and copper. As a result, cancer cells end up with little zinc and too much copper and these changes contribute to their out-of-control growth. If this idea were true, many people would be excited about it. But first this idea needs to be investigated more deeply in the laboratory, on the computer and in the hospitals. Therefore, we put it out on the internet so that other people can also think about and work on our idea. Now there are plenty of ways to do exciting experiments and with the results, we will hopefully understand much better why cancer cells go crazy and how doctors could improve their therapies to help patients in the future. #### #### ABSTRACT FOR ADULTS: One hundred years ago, it was suggested that cancer is a disease of the chromosomes, based on the observations that whole chromosomes or chromosome arms are missing or duplicated in the genomes of cells in a tumor. This phenomenon is called aneuploidy and is observed in most types of cancer, including breast, lung, prostate, brain and other cancers. However, it is not clear which genes could be responsible for this observation or if this phenomenon is only a side effect of cancer without importance, so it is important to find out. A second observation from basic research is that concentrations of several micronutrients, especially of the trace elements zinc, copper and iron are changed in tumor cells. In this article, we speculate that aneuploidy is the reason for these changes and that together, these two phenomena are responsible for some of the famous hallmarks or characteristics that are known from cancer cells: fast growth, escape from destruction by the immune system and poor DNA repair. This idea is new and has not been tested yet. We name it the aneuploidy metal transporter cancer (AMTC) hypothesis. To test our idea we used a wealth of information that was shared by international projects such as the Human Genome Project or the Cancer Genome Atlas Project. Indeed, we find that many zinc, iron and copper transporter genes in the genome are affected by aneuploidy. While a healthy cell has two copies of each gene, some tumor cells have only one or three copies of these genes. Furthermore, the amounts of protein and the activities of these metal transporters seem to correlate with these gene copy numbers, at least we see that the intermediate molecules and protein precursors called messenger RNA correlate well. Hence, we found that the public data is compatible with our suggested link between metal transporters and cancer. Furthermore, we identified hundreds of studies on zinc biology, evolutionary biology, genome and cancer research that also seem compatible. For example, cancer risk increases in the elderly population as well as in obese people, it also increases after certain bacterial or viral infections and through alcohol consumption. Consistent with the AMTC hypothesis and in particular, the idea that external changes in zinc concentrations in an organ or tissue may kick off the earliest steps of tumor development, all of these risk factors have been correlated with changes in zinc or other trace elements. However, since additional experiments to test the AMTC hypothesis have not yet been performed, direct evidence for our hypothesis is still missing. We hope, however, that our idea will promote further research with the goal to better understand cancer as a first step towards its prevention and the development of improved anti-cancer therapies in the future.