The online version of this article (doi:10.1186/1897-4287-12-12) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
EMG took part in the genetic work up of the families including genetic counseling, contributed to the design of the study, carried out the compilation of the data, the statistical analysis, and coordinated formatting and writing of the manuscript. HA performed the IHC tumour testing. IB took part in the genetic work up of the families including genetic counseling and compiled the data from St. Olavs Hospital. ER performed the IHC tumour testing. LM was involved in the genetic work up of the families including genetic counseling, conceived the study and was involved in its design and formatting of the manuscript. AS was involved in the genetic work up of the families including genetic counseling, was involved in the study design, and formatting of the manuscript. CH was involved in the genetic work up of the families and contributed to the formatting of the manuscript. HM was involved in the genetic work up of the families including genetic counseling, and contributed to the formatting of the manuscript. PM was involved in the genetic work up of the families, including the genetic counseling, conceived the study, contributed to the design of the study, the statistical analysis and the formatting and writing of the manuscript. WS performed the molecular genetic testing, conceived the study and was involved in its design and formatting of the manuscript. All authors read and approved the final manuscript.
Using immunohistochemistry (IHC) to select cases for mismatch repair (MMR) genetic testing, we failed to identify a large kindred with the deleterious PMS2 mutation c.989-1G > T. The purpose of the study was to examine the sensitivity of IHC and microsatellite instability-analysis (MSI) to identify carriers of the mutation, and to estimate its penetrance and expressions.
All carriers and obligate carriers of the mutation were identified. All cancer diagnoses were confirmed. IHC and MSI-analysis were performed on available tumours. Penetrances of cancers included in the Amsterdam and the Bethesda Criteria, for MSI-high tumours and MSI-high and low tumours were calculated by the Kaplan-Meier algorithm.
Probability for co-segregation of the mutation and cancers by chance was 0.000004. Fifty-six carriers or obligate carriers were identified. There was normal staining for PMS2 in 15/18 (83.3%) of tumours included in the AMS1/AMS2/Bethesda criteria. MSI-analysis showed that 15/21 (71.4%) of tumours were MSI-high and 4/21 (19.0%) were MSI-low. Penetrance at 70 years was 30.6% for AMS1 cancers (colorectal cancers), 42.8% for AMS2 cancers, 47.2% for Bethesda cancers, 55.6% for MSI-high and MSI-low cancers and 52.2% for MSI-high cancers.
The mutation met class 5 criteria for pathogenicity. IHC was insensitive in detecting tumours caused by the mutation. Penetrance of cancers that displayed MSI was 56% at 70 years. Besides colorectal cancers, the most frequent expressions were carcinoma of the endometrium and breast in females and stomach and prostate in males.
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- The Norwegian PMS2 founder mutation c.989-1G > T shows high penetrance of microsatellite instable cancers with normal immunohistochemistry
Eli Marie Grindedal
- BioMed Central
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