828 WERNSTEDT ET AL. To gain new insight into the mechanisms that generate PMS2 mutations, we characterized the alterations found in our cohort in greater detail. The 3,351-bp deletion that included PMS2 exon 8 (Patient CH11) was probably caused by recom- bination of two identically oriented AluSb ele- ments in introns 7 and 8. Together with the two other previously described Alu recombination- mediated deletions, our ﬁnding strengthens the view that the frequency of deletions involving PMS2 is related in part to the high density of Alu elements within the genomic sequence of this gene (van der Klift et al., 2005). The deletion found in patient CH8 was much larger ( 125 kb). It included the entire PMS2 gene and at least three other genes as well. Two of these genes (EIF2AK1 and AIMP2) have tu- mor-suppressing functions. EIF2AK1 suppresses protein synthesis during various conditions of stress by blocking the initiation of translation. This inhibition has been shown to annul the pro- liferative capacity of differentiating erythroid cells (Crosby et al., 2000), and similar effects might occur in colorectal tissues, where EIF2AK1 is highly expressed (our data, not shown). As for the second gene, AIMP2, its promoter region lies head-to-head with and partially over- laps that of PMS2 (NCBI RefSeq NG_008466.1; Nicolaides et al., 1995). The expression of this gene in colorectal tissues is even more abundant than that of PMS2 (our data, not shown): it enco- des a component of the amino-acyl-tRNA synthe- tase complex (Kim et al., 2002), which exerts both antiproliferative and proapoptotic activities in diverse cell types. On TGF-b stimulation, AIMP2 mediates ubiquitination and degradation of FUBP1, a transcriptional activator of the proto- oncogene MYC (Kim et al., 2003). Furthermore, DNA damage due to genotoxic stress is followed by phosphorylation of AIMP2, which then pro- motes apoptosis by protecting TP53 from MDM2-mediated ubiquitination and degradation (Han et al., 2008). AIMP2 also promotes TNF-a- dependent apoptosis via ubiquitination-mediated degradation of TRAF2 (Choi et al., 2009a). Most importantly, reduced AIMP2 expression level in Aimp2 heterozygous mice is associated with increased susceptibility to cancer in the colon and other tissues as well (Choi et al., 2009b). AIMP2 is probably involved in all PMS2 deletions affecting exon 1 and sequences 30 to this exon. Thus far, PMS2 deletions of this type have been reported in eight further families (Hendriks et al., 2006; Overbeek et al., 2007; Senter et al., 2008; Genes, Chromosomes & Cancer DOI 10.1002/gcc Vaughn et al., 2010; Herkert et al., 2011). It may be interesting to investigate in future studies whether inactivation of the AIMP2 gene contrib- utes as a modiﬁer to the expression of Lynch syndrome. The deleterious alteration identiﬁed in patient TR13 was a hybrid PMS2 allele generated by recombination with crossover, one possible reso- lution of a double Holliday junction. The recom- bination breakpoint was located in PMS2 intron 10, just 578 bp 30 of a 2.7-kb sequence that is present in PMS2 and deleted in PMS2CL. This major dissimilarity between gene and pseudogene (Fig. 3B) impedes alignment of the paralogous sequences at the inner ends of the duplicons; consequently, the rate of interparalog recombina- tion should be very low in this region (Fig. 3A) (Hayward et al., 2007). Indeed, of all the break- points reported thus far to cause sequence exchange between the human PMS2 and PMS2CL genes, the one that generated the dele- terious hybrid PMS2 allele found in patient TR13 is the most proximal (i.e., closest to the inner ends of the duplicons). The next closest – located approximately 1,500 bp downstream from the breakpoint we describe – also generated a delete- rious hybrid PMS2 allele associated with Lynch syndrome (Auclair et al., 2007). It contained two adjacent PMS2CL-speciﬁc sequence variants (c.1730dupA and c.1732C>T) in exon 11, which were probably inserted by the nonreciprocal mechanism of gene conversion, another possible result of the resolution of a double Holliday-junc- tion (Auclair et al., 2007). This hybrid allele and the one found in patient TR13 are the only dele- terious PMS2 alterations reported thus far that have been attributed to sequence exchange between PMS2 and PMS2CL. This conﬁrms pre- vious observations that interparalog recombina- tion events located 50 to intron 12 are much less common than those occurring downstream of exon 12 (Hayward et al., 2007; Ganster et al., 2010; van der Klift et al., 2010). We recently characterized a nondeleterious hybrid PMS2 allele produced by recombination with crossover with a breakpoint in intron 12 (Ganster et al., 2010). As discussed above and shown for this hybrid allele, intrachromosomal recombination resulting in crossover of paralog sequences is expected to produce reciprocal hybrid PMS2 and PMS2CL alleles (Fig. 3A). But, the expected hybrid PMS2CL allele was not found in patient TR13 or any of his relatives. Indeed, in this family, the deleterious hybrid