Abstract
Hereditary non-polyposis colorectal cancer is a cancer predisposition syndrome known to be caused by heterozygous germline mutations in DNA mismatch repair genes (MMR) most commonly hMLH1, hMSH2, hMSH6. Heterozygous mutations in one of these genes confer an increased risk, mainly for colon and endometrial cancer. Recently, several publications identified that biallelic mutations in the MMR genes are associated with a more severe phenotype, including childhood malignancies and signs of neurofibromatosis type I (NF1). We report on a non-consanguineous Ashkenazi Jewish family with two affected siblings with features of NF1, colon cancer and astrocytoma at age 13 and 14. Their mother developed endometrial cancer at age 54. Their father had leukoplakia of the vocal cords with a family history of pancreatic cancer. Molecular and pathology studies were done on the tumor tissue and on genomic DNA of family members. Tumor testing demonstrated a high degree of microsatellite instability (MSI analysis), expression of MLH1 and absence of expression of both MSH2 and MSH6 proteins. A biallelic c.1906G > C (p.A636P) mutation in the hMSH2 gene was detected in the blood of one affected child. Parental genetic testing showed that each parent was heterozygote for the mutation. The c.1906G > C mutation is a founder mutation in the Ashkenazi Jewish population. To our knowledge this is the first report of homozygosity for this founder mutation.
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Abbreviations
- AC:
-
Amsterdam criteria
- CCS:
-
Childhood cancer syndrome
- CRC:
-
Colorectal cancer
- DHPLC:
-
Denaturing high performance liquid chromatography
- HNPCC:
-
Hereditary non-polyposis colorectal cancer
- IHC:
-
Immunohistochemistry
- MLPA:
-
Multiplex ligase dependent probe amplification
- MMR:
-
Mismatch repair
- MMR-D:
-
Mismatch repair deficiency
- MSI:
-
Microsatellite instability
- NF1:
-
Neurofibromatosis type 1
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This work was supported, in part, by the Israeli Cancer Association, and by the Levinace Friedl foundation.
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Toledano, H., Goldberg, Y., Kedar-Barnes, I. et al. Homozygosity of MSH2 c.1906G→C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I. Familial Cancer 8, 187–194 (2009). https://doi.org/10.1007/s10689-008-9227-3
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DOI: https://doi.org/10.1007/s10689-008-9227-3