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. 2011 Aug;48(8):530-4.
doi: 10.1136/jmedgenet-2011-100082. Epub 2011 Jun 2.

Determining the frequency of de novo germline mutations in DNA mismatch repair genes

Aung Ko Win  1 , Mark A Jenkins, Daniel D Buchanan, Mark Clendenning, Joanne P Young, Graham G Giles, Jack Goldblatt, Barbara A Leggett, John L Hopper, Stephen N Thibodeau, Noralane M Lindor
Affiliations

Determining the frequency of de novo germline mutations in DNA mismatch repair genes

Aung Ko Win et al. J Med Genet. 2011 Aug.

Abstract

Background: Carriers of a germline mutation in a DNA mismatch repair (MMR) gene--that is, persons with Lynch syndrome--have substantially high risks of colorectal (CRC), endometrial, and several other cancers. The proportion of carriers who have de novo mutations (not inherited from either parent) is not known. This study reports a case series of de novo mutations in MMR genes and estimates the frequency of de novo mutation in MMR genes using the Colon Cancer Family Registry.

Methods: Screening for germline MLH1, MSH2, MSH6, and PMS2 mutations was performed for all incident CRC cases recruited from cancer registries (population based probands) displaying microsatellite instability (MSI) or loss of expression of MMR genes by immunohistochemistry (IHC) and probands with CRC in multi-case families recruited from clinics (clinic based probands), regardless of MSI or IHC status. All relatives of probands with a pathogenic mutation who donated a blood sample underwent testing for the mutation identified in the proband.

Results: Of 261 probands (202 clinic based, 59 population based) with MMR gene mutations for whom it was possible to determine the origin of the mutation, six (2.3%, 95% CI 0.9% to 5.0%) were confirmed as de novo, and the remaining 255 (97.7%, 95% CI 95.0% to 99.1%) were inherited. Of the de novo mutation carriers, three were clinic based probands (1.5%, 95% CI 0.3% to 4.5%) and three were population based probands (5.1%, 95% CI 1.2% to 14.5%). Two were in MLH1, three in MSH2, and one in MSH6.

Conclusion: De novo MMR gene mutations are uncommon causes of Lynch syndrome.

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Figures

Figure 1
Figure 1
(A–F) Status of mismatch repair gene mutation and cancer diagnosis for family members of de novo germline mismatch repair gene mutation carriers. Square for male, circle for female, diamond for unidentified sex, shaded for cancer-affected (cancer diagnoses are named with corresponding age), unshaded for cancer-unaffected, arrow for proband, +/− for carrier, −/− for non-carrier, D for age of death in years, L for last known age in years. To increase confidentiality, the sex of all relatives is provided as unidentified, except for those who were parents or when diagnosed with sex specific cancers.
Figure 1
Figure 1
(A–F) Status of mismatch repair gene mutation and cancer diagnosis for family members of de novo germline mismatch repair gene mutation carriers. Square for male, circle for female, diamond for unidentified sex, shaded for cancer-affected (cancer diagnoses are named with corresponding age), unshaded for cancer-unaffected, arrow for proband, +/− for carrier, −/− for non-carrier, D for age of death in years, L for last known age in years. To increase confidentiality, the sex of all relatives is provided as unidentified, except for those who were parents or when diagnosed with sex specific cancers.
See this image and copyright information in PMC

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