A systematic screen of breast cancer patients' exomes for retrotransposon insertions reveals disease associated genes

BackgroundRetrotransposons are genetic elements that jump within the genome via an RNA intermediate. Although they had a strong impact on human genome evolution, only a very tiny fraction of them can be reactivated nowadays, most often with neutral or detrimental consequences. The pathological outcomes associated with such genetic alterations are poorly investigated in the clinic, merely due to their difficult detection. ResultsWe developed a strategy to detect rare retrotransposon mediated insertions in Whole Exome Sequencing data from 65 familial breast cancer patients. When restricting our search to high confidence retrotransposition events occurring in less than 10% of the samples, we identified only ten different Alu elements, two L1 elements, one SVA and two processed pseudogenes. Only two of these insertions occurred within protein coding sequences and interestingly, several of the targeted genes have been previously linked to cancer, in three cases even to increased breast cancer risk (GHR, DMBT1 and NEK10). When investigating the molecular consequences of four Alu insertions at the mRNA level, we found that the element present in the 3UTR of GHR repressed expression of the corresponding allele. oMreover, the analysis of a near exonic Alu insertion in PTPN14 (a mediator of P53 tumor suppressor activity) revealed that this gene was imprinted and that the presence of an intronic Alu element can lead to loss of imprinting. ConclusionsOur data underline the relevance of incorporating the search for uncommon retrotransposition events in Next Generation Sequencing pipelines when analyzing patients with a suspected genetic disease.