title: Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development.
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.
  
  
  
  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.
authors.affiliation: International Center for Research (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Rolando A R
authors.initials: RAR
authors.lastname: Villacis
authors.affiliation: International Center for Research (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Tatiane R
authors.initials: TR
authors.lastname: Basso
authors.affiliation: International Center for Research (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Canto
authors.affiliation: International Center for Research (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Maísa
authors.initials: M
authors.lastname: Pinheiro
authors.affiliation: Department of Oncogenetics, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Karina M
authors.initials: KM
authors.lastname: Santiago
authors.affiliation: 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.
authors.forename: Juliana
authors.initials: J
authors.lastname: Giacomazzi
authors.affiliation: International Center for Research (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Cláudia A A
authors.initials: CAA
authors.lastname: de Paula
authors.affiliation: International Center for Research (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Dirce M
authors.initials: DM
authors.lastname: Carraro
authors.affiliation: 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.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Ashton-Prolla
authors.affiliation: Department of Oncogenetics, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.|Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI)/National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Achatz
authors.affiliation: International Center for Research (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil. silvia.regina.rogatto@rsyd.dk.|Department of Clinical Genetics, Vejle Sygehus, Kabbeltoft 25, 7100, Vejle, Denmark. silvia.regina.rogatto@rsyd.dk.|Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark. silvia.regina.rogatto@rsyd.dk.
authors.forename: Silvia R
authors.initials: SR
authors.lastname: Rogatto
mesh_terms: D000328:Adult; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D000071858:Epithelial Cell Adhesion Molecule / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*
chemical_list: C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
keywords: CNV; Hereditary cancer predisposition syndromes; Microarray; Multiple primary tumors; cnLOH