Clinical–alimentary tractHeterozygous Mutations in PMS2 Cause Hereditary Nonpolyposis Colorectal Carcinoma (Lynch Syndrome)
Section snippets
Patients and Methods
Mutation analysis for PMS2 mutations was performed in 2 groups of patients.
The first group comprised 112 patients from families suspected of HNPCC, 44 of which fulfill the Amsterdam criteria. This group of 112 patients originates from a group of 184 patients in which mutation analysis of MLH1, MSH2, and MSH6 has been performed previously.25, 26 The 112 patients, in whom no germline mutation in one of the previously mentioned MMR genes was found, were analyzed with Southern blot hybridization
Southern Blot Analysis
In a cohort of 120 patients with colorectal carcinoma from (suspected) HNPCC-affected families, 4 different genomic rearrangements have been identified in PMS2. In family 1 (NL225), we identified a complex PMS2 rearrangement: a deletion of the complete coding sequences of PMS2 in combination with a duplication of the PMS2 pseudogene encompassing exons 9 and 11–15 (Table 2 and Figure 1). In the DNA of the index patient of family 2 (NLB 54.597), a deletion including the sequences of exon 10 was
Discussion
Until now, only 7 patients suspected of having HNPCC with heterozygous PMS2 mutations have been described in the literature. Unfortunately, information on family history and segregation analysis was very limited.3, 16, 17, 18 Other studies in about 200 HNPCC-suspected families did not show any truncating PMS2 mutations.22, 23, 24 These findings explain why many investigators questioned the role of PMS2 in the pathogenesis of HNPCC. In the present study, 120 families were analyzed for mutations
References (44)
- et al.
The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer
Cell
(1993) - et al.
New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC
Gastroenterology
(1999) - et al.
Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations
Am J Hum Genet
(1997) - et al.
Molecular analysis of hereditary nonpolyposis colorectal cancer in the United Stateshigh mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene
Am J Hum Genet
(2003) - et al.
Genomic organization of the human PMS2 gene family
Genomics
(1995) - et al.
Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis
Cell
(1995) - et al.
Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome
Am J Hum Genet
(2004) - et al.
Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer
Gastroenterology
(2005) - et al.
Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors
Am J Pathol
(2003) - et al.
Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutationsimpact on counseling and surveillance
Gastroenterology
(2004)
Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation
Gastroenterology
The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer
J Biol Chem
Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer
Nature
Mutations of two PMS homologues in hereditary nonpolyposis colon cancer
Nature
Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer
Nat Genet
Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred
Cancer Res
The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC)
Dis Colon Rectum
Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients
Nat Med
MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis
Cancer Res
Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair
Nat Genet
Mismatch repair gene PMS2disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation
Cancer Res
Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer
Gastroenterology
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Supported by ZonMw (grant 9607.0136.1).
Y.M.C.H., S.J.-C., and H.M.V. contributed equally to this work.