title: Contribution of rare germline copy number variations and common susceptibility loci in Lynch syndrome patients negative for mutations in the mismatch repair genes.
abstract: In colorectal carcinoma (CRC), 35% of cases are known to have a hereditary component, while a lower proportion (∼ 5%) can be explained by known genetic factors. In this study, copy number variations (CNVs) were evaluated in 45 unrelated patients with clinical hypothesis of Lynch syndrome (Amsterdam or Bethesda criteria); negative for MLH1, MSH2, MSH6, PMS2, CHEK2*1100delC and TP53 pathogenic mutations; aiming to reveal new predisposing genes. Analyses with two different microarray platforms (Agilent 180K and Affymetrix CytoScan HD) revealed 35 rare CNVs covering 67 known genes in 22 patients. Gains (GALNT6 and GALNT11) and losses (SEMA3C) involving the same gene families related to CRC susceptibility were found among the rare CNVs. Segregation analysis performed on four relatives from one family suggested the involvement of GALNT11 and KMT2C in those at risk of developing CRC. Notably, in silico molecular analysis revealed that 61% (41/67) of the genes covered by rare CNVs were associated with cancer, mainly colorectal (17 genes). Ten common SNPs, previously associated with CRC, were genotyped in 39 index patients and 100 sporadic CRC cases. Although no significant, an increased number of risk alleles was detected in the index cases compared with the sporadic CRC patients. None of the SNPs were covered by CNVs, suggesting an independent effect of each alteration in cancer susceptibility. In conclusion, rare germline CNVs and common SNPs may contribute to an increased risk for hereditary CRC in patients with mismatch repair proficiency.
authors.affiliation: International Research Center (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Rolando A R
authors.initials: RA
authors.lastname: Villacis
authors.affiliation: International Research Center (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Priscila M
authors.initials: PM
authors.lastname: Miranda
authors.affiliation: Institute of Hematology and Oncology, Faculties Little Prince, Curitiba, PR, Brazil.
authors.forename: Israel
authors.initials: I
authors.lastname: Gomy
authors.affiliation: Sírio-Libanês Hospital, Oncology Center, São Paulo, SP, Brazil.
authors.forename: Erika M M
authors.initials: EM
authors.lastname: Santos
authors.affiliation: International Research Center (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Dirce M
authors.initials: DM
authors.lastname: Carraro
authors.affiliation: Department of Oncogenetics, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Achatz
authors.affiliation: Sírio-Libanês Hospital, Oncology Center, São Paulo, SP, Brazil.
authors.forename: Benedito M
authors.initials: BM
authors.lastname: Rossi
authors.affiliation: International Research Center (CIPE), A.C. Camargo Cancer Center, São Paulo, SP, Brazil.|Department of Urology, Faculty of Medicine, University of São Paulo State (UNESP), Botucatu, SP, Brazil.
authors.forename: Silvia R
authors.initials: SR
authors.lastname: Rogatto
mesh_terms: D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D053843:DNA Mismatch Repair; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide
keywords: SNP; cancer predisposition; colorectal cancer; copy number variation; hereditary cancer; lynch syndrome