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Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development

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Abstract

Multiple primary tumors (MPT) have been described in carriers of inherited cancer predisposition genes. However, the genetic etiology of a large proportion of MPT cases remains unclear. We reviewed 267 patients with hereditary cancer predisposition syndromes (HCPS) that underwent genetic counseling and selected 22 patients with MPT to perform genomic analysis (CytoScan HD Array, Affymetrix) aiming to identify new alterations related to a high risk of developing MPT. Twenty patients had a positive family history of cancer and 11 met phenotypic criteria for HCPS. Genetic testing for each of the genes associated with these syndromes revealed negative results for pathogenic mutations. Seventeen rare germline copy number variations (CNVs) covering 40 genes were identified in 11 patients, including an EPCAM/MSH2 deletion in one Lynch syndrome patient. An enrichment analysis revealed a significant number of genes (where the CNVs are mapped) associated with carcinogenesis and/or related to functions implicated with tumor development, such as proliferation and cell survival. An interaction network analysis highlighted the importance of TP53 pathway in cancer emergence. A high number of germline copy-neutral loss of heterozygosity (cnLOH) was identified in nine cases, particularly in two patients. Eighteen genes were covered by both rare CNVs and cnLOH, including 14 related to tumorigenesis and seven genes (ABCC1, KDM4C, KIAA0430, MYH11, NDE1, PIWIL2, and ULK2) specifically associated with cellular growth and proliferation. Overall, we identified 14 cases with rare CNVs and/or cnLOH that may contribute to the risk of MPT development.

Key message

  • CNVs may explain the risk of hereditary cancer syndromes in MPT patients.

  • CNVs affecting genes related to cancer are candidates to be involved in MPT risk.

  • EPCAM/MSH2 deletions should be investigated in patients suspected to have LS.

  • Gene enrichment related to the TP53 network is associated with MPT development.

  • cnLOH and CNVs contribute to the risk of MPT development.

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Acknowledgements

The authors would like to thank the patients who accepted to participate in this study. Samples were provided by the A.C. Camargo Cancer Center Biobank, São Paulo, Brazil. We are grateful to the Oncogenetics Department of the A.C. Camargo Cancer Center for its contributions. This study was supported by grants from the Coordination for the Improvement of Higher Education Personnel (CAPES), São Paulo Research Foundation (FAPESP 2013/23277-8) and the National Institute of Science and Technology in Oncogenomics (INCITO - FAPESP 2008/57887-9, and National Council for Scientific and Technological Development (CNPq 573589/08-9).

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Authors and Affiliations

  1. International Center for Research (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil

    Rolando A. R. Villacis, Tatiane R. Basso, Luisa M. Canto, Maísa Pinheiro, Cláudia A. A. de Paula, Dirce M. Carraro & Silvia R. Rogatto

  2. Department of Oncogenetics, A.C. Camargo Cancer Center, São Paulo, SP, Brazil

    Karina M. Santiago & Maria I. Achatz

  3. Department of Genetics, Federal University of Rio Grande do Sul (UFRGS) and Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Juliana Giacomazzi & Patrícia Ashton-Prolla

  4. Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI)/National Institutes of Health (NIH), Bethesda, MD, USA

    Maria I. Achatz

  5. Department of Clinical Genetics, Vejle Sygehus, Kabbeltoft 25, 7100, Vejle, Denmark

    Silvia R. Rogatto

  6. Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark

    Silvia R. Rogatto

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  1. Rolando A. R. Villacis
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  2. Tatiane R. Basso
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  3. Luisa M. Canto
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  4. Maísa Pinheiro
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  6. Juliana Giacomazzi
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  7. Cláudia A. A. de Paula
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  8. Dirce M. Carraro
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  9. Patrícia Ashton-Prolla
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  10. Maria I. Achatz
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  11. Silvia R. Rogatto
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Corresponding author

Correspondence to Silvia R. Rogatto.

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Additional information

Rolando A. R. Villacis and Tatiane R. Basso contributed equally to this study.

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Villacis, R.A.R., Basso, T.R., Canto, L.M. et al. Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development. J Mol Med 95, 523–533 (2017). https://doi.org/10.1007/s00109-017-1507-7

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  • DOI: https://doi.org/10.1007/s00109-017-1507-7

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