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

Johannes Engelken, Matthias Altmeyer, Renty Franklin

#### #### Abstract for Scientists: While decades of cancer research have firmly established multiple “hallmarks of cancer”, cancer’s 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. This is despite the achievements of cytogenomics and whole genome sequencing which have successfully pinpointed focal amplifications and focal deletions as well as point mutations affecting numerous genes involved in carcinogenesis. A characteristic of many different cancers is the deregulation of the homeostasis of trace elements, such as copper (Cu), zinc (Zn) and iron (Fe). Concentrations of copper are markedly increased in cancer tissue and the blood plasma of cancer patients, while zinc levels are typically decreased. 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, nutrient starvation as well as to copper toxicity. 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 (especially fluctuations in labile and total zinc) such events might contribute to the initiation of the malignant transformation. Consistently, it has been shown that zinc affects a number of the observed hallmark characteristics including DNA repair, inflammation and apoptosis. We term this model the “aneuploidy metal transporter cancer” (AMTC) hypothesis. While the AMTC hypothesis does not contradict the cancer-promoting role of point and focal mutations in established tumor suppressor genes and oncogenes (e.g. MYC, MYCN, TP53, PIK3CA, BRCA1, ERBB2), it seems possible that some of these mutations may be a response to the prior disruption of trace element homeostasis. 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.