Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DMA mismatch repair

Abstract

Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer (HNPCC; refs 1-5). An important role for DNA replication errors in colorectal tumorigenesis has been suggested by the finding of frequent alterations in the length of specific mononucleotide tracts within genes controlling cell growth, including TGF-beta receptor type II (ref. 6), BAX (ref. 7) and APC (ref. 8). A broader role for MMR deficiency in human tumorigenesis is implicated by microsatellite instability in a fraction of sporadic tumours, including gastric, endometrial and colorectal malignancies. To better define the role of individual MMR genes in cancer susceptibility and MMR functions, we have generated mice deficient for the murine homologues of the human genes MLH1, PMS1 and PMS2. Surprisingly, we find that these mice show different tumour susceptibilities, most notably, to intestinal adenomas and adenocarcinomas, and different mutational spectra. Our results suggest that a general increase in replication errors may not be sufficient for intestinal tumour formation and that these genes share overlapping, but not identical functions.

Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability

“…Tumors from two HNPCC families were previously reported to bear germline defects in hPMS2 Nicolaides et al, 1994), however cell lines from these tumors were not isolated. Further, mice that are homozygous de®cient for the PMS2 gene do not develop intestinal tumors despite in vivo demonstration of a 100-fold elevated frequency of +1 and 71 frameshift mutations (Baker et al, 1995;Prolla et al, 1998). Indeed, the only previous well described human cancer cell line bearing a hPMS2 mutation is the endometrial cancer cell line, HEC-1-A, in which the hPMS2 mutation occurs concurrently with an inactivating hMSH6 mutation (Risinger et al, 1998).…”

“…Germ line mutations in hPMS2 have been described in two HNPCC kindreds Nicolaides et al, 1994). However, hPMS2 de®cient gene knockout mice do not develop colon cancers (Baker et al, 1995;Prolla et al, 1998), and the hPMS2 mutant HEC-1-A human endometrial cancer cell line has recently been determined to also bear mutant hMSH6 (Risinger et al, 1995;. Thus the extent to which hPMS2 mutation contributes to sporadic MSI colon cancer has remained unde®ned.…”

Mouse models for colorectal cancer

“…As a consequence, the defective MMR in MSH6 de®cient tumors does not result in a RER+ phenotype. This observation has important implications because an involvement of MSH6 in HNPCC (Prolla et al, 1998) might not have been identi®ed if the RER+ phenotype is used as a diagnostic criterion. Families with germ line mutations in the MSH6 gene have been identi®ed Edelmann et al, 1997;Miyaki et al, 1997).…”

“…Targeted inactivation of the mutL homologue, Mlh1, in mice leads to infertility and tumor susceptibility (Edelmann et al, 1996(Edelmann et al, , 1999bBaker et al, 1996;Prolla et al, 1998). Mlh17/7 mice do not produce any mature sperm due to a pachytene arrest in meiosis.…”

“…The meiotic phenotype in PMS2 de®cient mice di ers from that of MLH1 de®cient mice in that chromosomal asynapsis and non homologous pairing are frequent events in meiosis I of Pms27/7 mice. Pms27/7 mice are susceptible to the development of lymphomas and some rarer types of tumors (Prolla et al, 1998). Cell lines derived from these mice display MI at both mono-and dinucleotide repeat loci.…”