PMS2 inactivation by a complex rearrangement involving an HERV retroelement and the inverted 100-kb duplicon on 7p22.1

Abstract

Biallelic PMS2 mutations are responsible for more than half of all cases of constitutional mismatch repair deficiency (CMMRD), a recessively inherited childhood cancer predisposition syndrome. The mismatch repair gene PMS2 is partly embedded within one copy of an inverted 100-kb low-copy repeat (LCR) on 7p22.1. In an individual with CMMRD syndrome, PMS2 was found to be homozygously inactivated by a complex chromosomal rearrangement, which separates the 5'-part from the 3'-part of the gene. The rearrangement involves sequences of the inverted 100-kb LCR and a human endogenous retrovirus element and may be associated with an inversion that is indistinguishable from the known inversion polymorphism affecting the ~0.7-Mb sequence intervening the LCR. Its formation is best explained by a replication-based mechanism (RBM) such as fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR). This finding supports the hypothesis that the inverted LCR can not only facilitate the formation of the non-allelic homologous recombination-mediated inversion polymorphism but it also promotes the occurrence of more complex rearrangements that can be associated with a large inversion, as well, but are mediated by a RBM. This further suggests that among the inversion polymorphism on 7p22.1, more complex rearrangements might be hidden. Furthermore, as the locus is embedded in a common fragile site (CFS) region, this rearrangement also supports the recently raised hypothesis that CFS sequence motifs may facilitate replication-based rearrangement mechanisms.

Targeted deep-intronic sequencing in a cohort of unexplained cases of suspected Lynch syndrome

“…For most of the samples, analysis of somatic alterations is not possible as the tumors are not available. Nevertheless, complex rearrangements may have been missed in the unexplained LS cases because they are located outside of the targeted region or may be hidden in regions difficult to analyze, e.g., in common fragile site region, as it was the case in a study of Vogt et al [49] where they found a "PMS2 inactivation by a complex rearrangement involving an HERV retroelement and the inverted 100-kb duplicon on 7p22.1".…”

Replication stress at microsatellites causes DNA double-strand breaks and break-induced replication

“…In humans, a growing cohort of neurodegenerative diseases has been attributed to DNA instability at microsatellite DNA noncanonical structures (3,4,7,(11)(12)(13)(14)(15)(16)(17)(18). Thus, replication fork barriers are believed to provoke fork stalling and template switching (FoSTeS), and microhomology-mediated break induced replication (MMBIR) (19)(20)(21)(22)(23)(24)(25)(26). The induction of gross chromosomal rearrangements (GCRs) due to FoSTeS/MMBIR has been implicated in the etiology of several developmental disorders including blepharophimosis syndrome (MIM# 110100) (23), CHARGE syndrome (MIM#214800) (27), and Pelizaeus-Merzbacher disease (MIM#312080) (28).…”

Making a virtue of necessity: the pleiotropic role of human endogenous retroviruses in cancer

“…Moreover, oncogenic gene fusions involving the ETS (E26 transformation-specific) gene family are created in human prostate cancer by recurrent chromosomal translocation and one of the 5′ fusion partners for such translocations was identified as a HERV-K provirus [ 58 ]. A chromosomal rearrangement involving a HERV provirus has also been described in the inactivation of the mismatch repair endonuclease PMS2 gene, loss of which predisposes to mismatch repair cancer syndrome and colorectal cancer [ 59 ].…”