Abstract
Hereditary non-polyposis colorectal cancer and familial adenomatus polyposis are autosomal dominant diseases accounting for 5–7% of all colorectal cancer cases. Inheritance of mutations associated with both syndromes in the same individual has, so far, only been observed in a few cases. This report outlines the findings in a proband of a HNPCC family, who presented with colorectal cancer and with multiple adenomas at the age of 18. He was shown to be compound heterozygous for MSH6 mutations: a nonsense mutation in exon 4 (c.1836 C>A, p.S612X); and a missense mutation in exon 5 (c.3226 C>T, p.R1076C). In addition, an APC missense mutation was revealed (c.7504 G>A, p.G2502S). Immunohisto-chemical analysis showed lack of expression of MSH6 in tumour tissue, as well as accumulation of betacatenin in the nuclei of the tumour cells. We suggest that the presence of mutations in both alleles of one gene and mutations in different genes, may influence the phenotype in hereditary colorectal cancer. Biallelic and/or polygenic mutations should be suspected when facing unusual severe variants of “classic monogenic phenotypes”, such as HNPCC.
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Abbreviations
- APC:
-
Adenomatous polyposis coli
- MMR:
-
Mismatch repair
- HNPCC:
-
Hereditary non-polyposis colorectal cancer
- FAP:
-
Familial adenomatous polyposis
- CRC:
-
Colorectal cancer
- IHC:
-
Immunohistochemistry
- NF-1:
-
Neurofibromatosis type 1
- MLPA:
-
Multiplex-ligation-probe-amplification
- CHRPE:
-
Congenital hypertrophy of the retinal pigment epithelium
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Acknowledgements
We are indebted to the Department of Pathology at various hospitals for giving us access to stored paraffin blocks. The information obtained from the HNPCC-registry is highly acknowledged.
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Okkels, H., Sunde, L., Lindorff-Larsen, K. et al. Polyposis and early cancer in a patient with low penetrant mutations in MSH6 and APC: hereditary colorectal cancer as a polygenic trait. Int J Colorectal Dis 21, 847–850 (2006). https://doi.org/10.1007/s00384-006-0086-9
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DOI: https://doi.org/10.1007/s00384-006-0086-9