Cell type-specific properties and environment shape tissue specificity of cancer genes

Abstract

One of the biggest mysteries in cancer research remains why mutations in certain genes cause cancer only at specific sites in the human body. The poor correlation between the expression level of a cancer gene and the tissues in which it causes malignant transformations raises the question of which factors determine the tissue-specific effects of a mutation. Here, we explore why some cancer genes are associated only with few different cancer types (i.e., are specific), while others are found mutated in a large number of different types of cancer (i.e., are general). We do so by contrasting cellular functions of specific-cancer genes with those of general ones to identify properties that determine where in the body a gene mutation is causing malignant transformations. We identified different groups of cancer genes that did not behave as expected (i.e., DNA repair genes being tissue specific, immune response genes showing a bimodal specificity function or strong association of generally expressed genes to particular cancers). Analysis of these three groups demonstrates the importance of environmental impact for understanding why certain cancer genes are only involved in the development of some cancer types but are rarely found mutated in other types of cancer. ; The research leading to these results has received funding from the German Research Foundation (SCHA 1933/1-1), the Spanish Ministry of Economy and Competitiveness, 'Centro de Excelencia Severo Ochoa 2013–2017', SEV-2012-0208, the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreements n° HEALTH-F4-2011-278568 (PRIMES), from the Spanish Ministerio de Economía y Competitividad (Plan Nacional BIO 2012-39754) and the/nEuropean Fund for Regional Development (EFRD).