Abstract
The identification of Lynch syndrome has been greatly assisted by the advent of tumour immunohistochemistry (IHC) for mismatch repair (MMR) proteins, and by the recognition of the role of acquired somatic BRAF mutation in sporadic MMR-deficient colorectal cancer (CRC). However, somatic BRAF mutation may also be present in the tumours in families with a predisposition to develop serrated polyps in the colorectum. In a subgroup of affected members in these families, CRCs emerge which demonstrate clear evidence of MMR deficiency with absent MLH1 staining and high-level microsatellite instability (MSI). This may result in these families being erroneously classified as Lynch syndrome, or conversely, an individual is considered “sporadic” due to the presence of a somatic BRAF mutation in a tumour. In this report, we describe two Lynch syndrome families who demonstrated several such inconsistencies. In one family, IHC deficiency of both MSH2 and MLH1 was demonstrated in tumours from different affected family members, presenting a confusing diagnostic picture. In the second family, MLH1 loss was observed in the lesions of both MLH1 mutation carriers and those who showed normal MLH1 germline sequence. Both families had Lynch syndrome complicated by an independently segregating serrated neoplasia phenotype, suggesting that in families such as these, tumour and germline studies of several key members, rather than of a single proband, are indicated to clarify the spectrum of risk.
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Acknowledgments
This work was supported by grants from the Cancer Council Queensland, the Hicks Foundation in Victoria, and the National Cancer Institute under RFA CA-95-011 (Australasian Colorectal Cancer Family Registry Centre UO1 CA097735), and through cooperative agreements with members of the Colon Cancer Family Registry and P·I.s. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. The authors are grateful to members of the two families who have given significant time and effort to the contribution of data, for the assistance of Maggie Angelakos in the retrieval and preparation of pedigrees for this manuscript, Lesley Jaskowski for data retrieval, and to the many pathology laboratories involved for supply of archived tissue for analysis.
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Walsh, M.D., Buchanan, D.D., Walters, R. et al. Analysis of families with Lynch syndrome complicated by advanced serrated neoplasia: the importance of pathology review and pedigree analysis. Familial Cancer 8, 313–323 (2009). https://doi.org/10.1007/s10689-009-9238-8
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DOI: https://doi.org/10.1007/s10689-009-9238-8