Copy number alterations (CNAs) in cancer patients show a large variability in their number, length and position, but the sources of this variability are not known. CNA number and length are linked to patient survival, suggesting clinical relevance. We have identified genes that tend to be mutated in samples that have few or many CNAs, which we term CONIM genes (COpy Number Instability Modulators). CONIM proteins cluster into a densely connected subnetwork of physical interactions and many of them are epigenetic modifiers. Therefore, we investigated how the epigenome of the tissue-of-origin influences the position of CNA breakpoints and the properties of the resulting CNAs. We found that the presence of heterochromatin in the tissue-of-origin contributes to the recurrence and length of CNAs in the respective cancer type.

The research leading to these results 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 BIO2012-39754) and from the European Fund for Regional Development (EFRD).