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The natural history of a combined defect in MSH6 and MUTYH in a HNPCC family

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Abstract

In the inherited syndromes, MUTYH-associated polyposis (MAP) and hereditary nonpolyposis colorectal cancer (HNPCC), somatic mutations occur due to loss of the caretaker function that base-repair (BER) and mismatch repair (MMR) genes have, respectively. Recently, we identified a large branch from a MSH6 HNPCC family in which 19 family members are heterozygous or compound heterozygous for MUTYH germ line mutations. MSH6/MUTYH heterozygote mutation carriers display a predominant HNPCC molecular tumour phenotype, with microsatellite instability and under-representation of G>T transversions. A single unique patient is carrier of the MSH6 germline mutation and is compound heterozygote for MUTYH. Unexpectedly, this patient has an extremely mild clinical phenotype with sofar only few adenomas at age 56. Four out of five adenomas show characteristic G>T transversions in APC and/or KRAS2, as seen in MUTYH associated polyposis. No second hit of MSH6 is apparent in any of the adenomas, due to retained MSH6 nuclear expression and a lack of microsatellite instability. Although this concerns only one case, we argue that the chance to find an additional one is extremely small and currently a mouse model with this genotype combination is not available. Moreover, the patients brother who is also compound heterozygous for MUTYH but lacks the MSH6 germline mutation presented with a full blown polyposis coli. In conclusion, these data would support the notion that abrogation of both MSH6 DNA mismatch repair and base repair might be mutually exclusive in humans.

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Abbreviations

BER:

Base excision repair

MMR:

Mismatch repair

MAP:

MUTYH-associated polyposis

HNPCC:

Hereditary nonpolyposis colorectal cancer

8-oxoG:

8-oxo-guanine

CRC:

Colorectal cancer

MCR:

Mutation cluster region

MSI:

Microsatellite instability

LOH:

Loss of heterozygosity

IHC:

Immunohistochemistry

MSS:

Microsatellite stable

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Authors and Affiliations

  1. Department of Pathology, Leiden University Medical Center, Building L1Q, P.O. Box 9600, 2300 RC, Leiden, The Netherlands

    Marjo van Puijenbroek, Tom van Wezel & Hans Morreau

  2. Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Maartje Nielsen, Tjitske H. C. M. Reinards, Marjan M. Weiss, Yvonne M. C. Hendriks, Carli M. J. Tops, Juul Wijnen & Frederik J. Hes

  3. Department of Clinical Genetics, Erasmus University Rotterdam, Rotterdam, The Netherlands

    Anja Wagner

  4. The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands

    Hans F. A. Vasen

Authors
  1. Marjo van Puijenbroek
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  2. Maartje Nielsen
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  3. Tjitske H. C. M. Reinards
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  4. Marjan M. Weiss
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  5. Anja Wagner
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  6. Yvonne M. C. Hendriks
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  7. Hans F. A. Vasen
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  8. Carli M. J. Tops
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  9. Juul Wijnen
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  10. Tom van Wezel
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  11. Frederik J. Hes
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  12. Hans Morreau
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Corresponding author

Correspondence to Hans Morreau.

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van Puijenbroek, M., Nielsen, M., Reinards, T.H.C.M. et al. The natural history of a combined defect in MSH6 and MUTYH in a HNPCC family. Familial Cancer 6, 43–51 (2007). https://doi.org/10.1007/s10689-006-9103-y

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  • DOI: https://doi.org/10.1007/s10689-006-9103-y

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