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Clinical and histomolecular endometrial tumor characterization of patients at-risk for Lynch syndrome in South of Brazil

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Abstract

Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2. Clinically, Lynch syndrome is characterized by early onset (45 years) of colorectal cancer (CRC), as well as extra-colonic cancer. Male and female carriers of Lynch syndrome-associated mutations have different lifetime risks for CRC and in women endometrial cancer (EC) may be the most common tumor. Whenever Amsterdam criteria are not fulfilled, the currently recommended laboratory screening strategies involve microsatellite instability testing and immunohistochemistry staining of the tumor for the major MMR proteins. The aim of this study was to estimate the frequency of MMR deficiencies in women diagnosed with EC who are at-risk for Lynch syndrome. Thirty women diagnosed with EC under the age of 50 years and/or women with EC and a first degree relative diagnosed with a Lynch syndrome-associated tumor were included. To assess MMR deficiencies four methods were used: multiplex PCR, Single Strand Conformation Polymorphism, Immunohistochemistry and Methylation Specific–Multiplex Ligation-dependent Probe Amplification. Twelve (40%) patients with EC fulfilling one of the inclusion criteria had results indicative of MMR deficiency. The identification of 5 women with clear evidence of MMR deficiency and absence of either Amsterdam or Bethesda criteria among 10 diagnosed with EC under the age of 50 years reinforces previous suggestions by some authors that these women should be considered at risk and always screened for Lynch syndrome after informed consent.

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Abbreviations

CRC:

Colorectal cancer

DAB:

Diaminobenzidine

DNA:

deoxyribonucleotide acid

EC:

Endometrial cancer

FH:

Familial history

FIPe—HCPA:

Fundação de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre

IHC:

Immunohistochemistry

MLH1:

MutL homolog 1

MMR:

Mismatch repair

MSH2:

MutS homolog 2

MSH6:

MutS homolog 6

MS:

Microsatellite stability

MSI:

Microsatellite instability

MS–MLPA:

Methylation specific multiplex ligation-dependent probe amplification

PCR:

Polymerase chain reaction

PMS2:

Postmeiotic segregation increased 2

SSCP:

Single strand conformational polymorphism

Tris–EDTA:

Tris base, ethylenediaminetetracetic acid, disodium salt

UFRGS:

Universidade Federal do Rio Grande do Sul

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Acknowledgments

We are indebted to the patients and their family members who agreed to participate in this study and to Fundação de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPe-HCPA) and Programa de Pós-Graduação em Ciências Gastroenterológicas (UFRGS) who provided funding for this study. We also thank Drs. Miguel Varela and Gabriel Prolla for patient referrals. We are also indebted to Jan Schouten (MRC-Holland, Amsterdam, The Netherlands) for the technical support with MS–MLPA. We thank Dr Vinicius Duval da Silva and Thiago Giugliani (Laboratório de Patología, Hospital São Lucas, Porto Alegre, Brazil) for their stimulating discussions and technical support in IHC protocols, and Aishameraine Venes Schmidt (UFRGS) for help with the data analyses.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Medicina: Ciências Gastroenterológicas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

    Silvia Liliana Cossio & João Carlos Prolla

  2. Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos 2350, 90035-903, Porto Alegre, RS, Brazil

    Silvia Liliana Cossio & Patricia Koehler-Santos

  3. Instituto Nacional de Genética Médica Populacional (INAGEMP), Porto Alegre, RS, Brazil

    Silvia Liliana Cossio & Patricia Ashton-Prolla

  4. Programa de Pós-Graduação em Medicina: Ciências Médicas, UFRGS, Porto Alegre, RS, Brazil

    Patricia Koehler-Santos

  5. Complexo Hospitalar Santa Casa de Porto Alegre, Porto Alegre, RS, Brazil

    Suzana Arenhart Pessini

  6. Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil

    Suzana Arenhart Pessini

  7. Serviço de Ginecologia e Obstetrícia, HCPA, Porto Alegre, RS, Brazil

    Heleuza Mónego

  8. Serviço de Patologia, HCPA, Porto Alegre, RS, Brazil

    Maria Isabel Edelweiss, Luise Meurer & João Carlos Prolla

  9. Departamento de Patologia, UFRGS, Porto Alegre, RS, Brazil

    Maria Isabel Edelweiss & Luise Meurer

  10. MRC-Holland, Amsterdam, The Netherlands

    Abdellatif Errami & Jordy Coffa

  11. Laboratório de Identificação Genética, Centro de Pesquisa Experimental, HCPA, Porto Alegre, RS, Brazil

    Hugo Bock

  12. Programa de Pós-Graduação em Biologia Celular e Molecular, UFRGS, Porto Alegre, RS, Brazil

    Hugo Bock

  13. Departamento de Bioquímica, UFRGS, Porto Alegre, RS, Brazil

    Maria Luiza Saraiva-Pereira

  14. Serviço de Genética Médica and Laboratório de Identificação Genética, Centro de Pesquisa Experimental, HCPA, Porto Alegre, RS, Brazil

    Maria Luiza Saraiva-Pereira

  15. Departamento de Genética, UFRGS, Porto Alegre, RS, Brazil

    Patricia Ashton-Prolla

  16. Serviço de Genética Médica, Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, HCPA, Porto Alegre, RS, Brazil

    Patricia Ashton-Prolla

Authors
  1. Silvia Liliana Cossio
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  2. Patricia Koehler-Santos
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  3. Suzana Arenhart Pessini
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  4. Heleuza Mónego
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  5. Maria Isabel Edelweiss
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  6. Luise Meurer
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  7. Abdellatif Errami
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  8. Jordy Coffa
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  9. Hugo Bock
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  10. Maria Luiza Saraiva-Pereira
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  11. Patricia Ashton-Prolla
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  12. João Carlos Prolla
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Corresponding author

Correspondence to Silvia Liliana Cossio.

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Cossio, S.L., Koehler-Santos, P., Pessini, S.A. et al. Clinical and histomolecular endometrial tumor characterization of patients at-risk for Lynch syndrome in South of Brazil. Familial Cancer 9, 131–139 (2010). https://doi.org/10.1007/s10689-009-9297-x

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  • DOI: https://doi.org/10.1007/s10689-009-9297-x

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