Familial Cancer

, 8:313

Analysis of families with Lynch syndrome complicated by advanced serrated neoplasia: the importance of pathology review and pedigree analysis

  • Michael D. Walsh
  • Daniel D. Buchanan
  • Rhiannon Walters
  • Aedan Roberts
  • Sven Arnold
  • Diane McKeone
  • Mark Clendenning
  • Andrew R. Ruszkiewicz
  • Mark A. Jenkins
  • John L. Hopper
  • Jack Goldblatt
  • Jillian George
  • Graeme K. Suthers
  • Kerry Phillips
  • Graeme P. Young
  • Finlay Macrae
  • Musa Drini
  • Michael O. Woods
  • Susan Parry
  • Jeremy R. Jass
  • Joanne P. Young
Article

DOI: 10.1007/s10689-009-9238-8

Cite this article as:
Walsh, M.D., Buchanan, D.D., Walters, R. et al. Familial Cancer (2009) 8: 313. doi:10.1007/s10689-009-9238-8

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.

Keywords

Lynch syndromeBRAF mutationAdvanced serrated polyps

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Michael D. Walsh
    • 1
    • 2
  • Daniel D. Buchanan
    • 1
    • 2
  • Rhiannon Walters
    • 1
  • Aedan Roberts
    • 1
  • Sven Arnold
    • 1
  • Diane McKeone
    • 1
  • Mark Clendenning
    • 1
  • Andrew R. Ruszkiewicz
    • 3
  • Mark A. Jenkins
    • 4
  • John L. Hopper
    • 4
  • Jack Goldblatt
    • 5
    • 6
  • Jillian George
    • 5
  • Graeme K. Suthers
    • 7
    • 8
  • Kerry Phillips
    • 7
  • Graeme P. Young
    • 9
  • Finlay Macrae
    • 10
  • Musa Drini
    • 10
  • Michael O. Woods
    • 11
  • Susan Parry
    • 12
  • Jeremy R. Jass
    • 13
  • Joanne P. Young
    • 1
    • 2
  1. 1.Familial Cancer LaboratoryQIMRHerstonAustralia
  2. 2.School of MedicineUniversity of QueenslandHerstonAustralia
  3. 3.Institute of Medical and Veterinary ScienceAdelaideAustralia
  4. 4.Centre for MEGA, School of Population HealthUniversity of MelbourneCarltonAustralia
  5. 5.Genetic Services of Western AustraliaSubiacoAustralia
  6. 6.School of Paediatrics and Child Health University of Western AustraliaNedlandsAustralia
  7. 7.South Australian Clinical Genetics ServiceNorth AdelaideAustralia
  8. 8.Department of PaediatricsUniversity of AdelaideAdelaideAustralia
  9. 9.Department of MedicineFlinders UniversityBedford ParkAustralia
  10. 10.Department of Colorectal Medicine and GeneticsThe Royal Melbourne HospitalParkvilleAustralia
  11. 11.Discipline of Genetics, Faculty of MedicineMemorial University of NewfoundlandSt. John’sCanada
  12. 12.Department of GastroenterologyMiddlemore HospitalAucklandNew Zealand
  13. 13.Department of Cellular PathologySt. Mark’s HospitalHarrowUK