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Hereditary Cancer in Clinical Practice
Published in: Hereditary Cancer in Clinical Practice 1/2014

Open Access 01-12-2014 | Research

The Norwegian PMS2 founder mutation c.989-1G > T shows high penetrance of microsatellite instable cancers with normal immunohistochemistry

Authors: Eli Marie Grindedal, Harald Aarset, Inga Bjørnevoll, Elin Røyset, Lovise Mæhle, Astrid Stormorken, Cecilie Heramb, Heidi Medvik, Pål Møller, Wenche Sjursen

Published in: Hereditary Cancer in Clinical Practice | Issue 1/2014

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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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Metadata
Title
The Norwegian PMS2 founder mutation c.989-1G > T shows high penetrance of microsatellite instable cancers with normal immunohistochemistry
Authors
Eli Marie Grindedal
Harald Aarset
Inga Bjørnevoll
Elin Røyset
Lovise Mæhle
Astrid Stormorken
Cecilie Heramb
Heidi Medvik
Pål Møller
Wenche Sjursen
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Hereditary Cancer in Clinical Practice / Issue 1/2014
Electronic ISSN: 1897-4287
DOI
https://doi.org/10.1186/1897-4287-12-12

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