Alu in Lynch syndrome: a danger SINE?

Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline loss of a DNA mismatch repair gene. In a significant proportion of cases, loss of function of the MSH2 mismatch repair gene is caused by large heterogeneous deletions involving MSH2 and/or the adjacent EPCAM gene. These deletions usually result from homologous malrecombination events between Alu elements, a family of short interspersed nuclear elements (SINE). Recent recognition that the extent of these deletions influences phenotypic outcome provided new impetus for fine-mapping the breakpoints. In doing so, Pérez-Cabornero and colleagues uncovered new evidence for Alu-mediated ancestral founder deletions within MSH2 in the Spanish Lynch syndrome population (as reported beginning on pages 1546 and 1556 in this issue of the journal). This is the first such finding to date and prompted a revisitation of the role of Alu elements in the causation of Lynch syndrome. Whether Alu density is a danger sign for genomic regions prone to rearrangement and what additional factors may be required to actuate these events remain to be discovered.