The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations

Gastroenterology. 2008 Aug;135(2):419-28. doi: 10.1053/j.gastro.2008.04.026. Epub 2008 May 2.

Abstract

Background & aims: Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers.

Methods: We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment.

Results: Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed.

Conclusions: PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / analysis
  • Adenosine Triphosphatases / genetics*
  • Adult
  • Aged
  • Colorectal Neoplasms / chemistry
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / chemistry
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • DNA Mutational Analysis / methods
  • DNA Repair Enzymes / analysis
  • DNA Repair Enzymes / genetics*
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / genetics*
  • Endometrial Neoplasms / chemistry
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genotype
  • Germ-Line Mutation*
  • Heterozygote
  • Humans
  • Immunohistochemistry
  • Ligase Chain Reaction
  • Male
  • Middle Aged
  • Mismatch Repair Endonuclease PMS2
  • Odds Ratio
  • Penetrance
  • Phenotype
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins B-raf / genetics
  • Risk Assessment

Substances

  • DNA-Binding Proteins
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • DNA Repair Enzymes