Gastroenterology

Gastroenterology

Volume 130, Issue 2, February 2006, Pages 312-322
Gastroenterology

Clinical–alimentary tract
Heterozygous Mutations in PMS2 Cause Hereditary Nonpolyposis Colorectal Carcinoma (Lynch Syndrome)

https://doi.org/10.1053/j.gastro.2005.10.052Get rights and content

Background #x0026; Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. Methods: We performed Southern blot analysis in 112 patients from MLH1-, MSH2-, and MSH6-negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer, we performed immunohistochemistry using antibodies against MLH1, MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. Results: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. Conclusions: We show that heterozygous truncating mutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with absent staining for the PMS2 protein.

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)

  • S. Gallinger et al.

    Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation

    Gastroenterology

    (2004)
  • S. Guerrette et al.

    The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer

    J Biol Chem

    (1999)
  • C.E. Bronner et al.

    Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer

    Nature

    (1994)
  • N.C. Nicolaides et al.

    Mutations of two PMS homologues in hereditary nonpolyposis colon cancer

    Nature

    (1994)
  • M. Miyaki et al.

    Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer

    Nat Genet

    (1997)
  • Y. Akiyama et al.

    Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred

    Cancer Res

    (1997)
  • H.F. Vasen et al.

    The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC)

    Dis Colon Rectum

    (1991)
  • B. Liu et al.

    Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients

    Nat Med

    (1996)
  • A.H. Reitmair et al.

    MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis

    Cancer Res

    (1996)
  • T.A. Prolla et al.

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

    Nat Genet

    (1998)
  • H. Nakagawa et al.

    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

    (2004)
  • D.L. Worthly et al.

    Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer

    Gastroenterology

    (2005)
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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.

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