title: Candidate predisposing germline copy number variants in early onset colorectal cancer patients.
abstract: OBJECTIVE
  A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called 'missing heritability'. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset.
  
  
  METHODS
  We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter.
  
  
  RESULTS
  We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis.
  
  
  CONCLUSIONS
  These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC.
authors.affiliation: Grupo de Medicina Xenomica-USC, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain.
authors.forename: A J
authors.initials: AJ
authors.lastname: Brea-Fernandez
authors.affiliation: Fundacion Publica Galega de Medicina Xenomica (FPGMX)-SERGAS, Grupo de Medicina Xenomica, Hospital Clínico Universitario, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), IDIS, Edificio de Consultas, planta-2, Choupana s/n, 15706, Santiago de Compostela, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Fernandez-Rozadilla
authors.affiliation: Grupo de Medicina Xenomica-USC, Santiago de Compostela, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Alvarez-Barona
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Azuara
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: M M
authors.initials: MM
authors.lastname: Ginesta
authors.affiliation: Gastroenterology Department, Hospital do Meixoeiro, Vigo, Spain.|Section of Digestive Diseases, Internal Medicine Department, Hospital Sagunto, Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Clofent
authors.affiliation: Gastroenterology Department, Hospital do Meixoeiro, Vigo, Spain.
authors.forename: L
authors.initials: L
authors.lastname: de Castro
authors.affiliation: Servicio de Patologia Digestiva, Hospital Sant Pau, Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: Gastroenterology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Andreu
authors.affiliation: Gastroenterology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: X
authors.initials: X
authors.lastname: Bessa
authors.affiliation: Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Llor
authors.affiliation: Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Xicola
authors.affiliation: Gastroenterology Department, Hospital General de Alicante, Alicante, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Jover
authors.affiliation: Department of Gastroenterology, Hospital Clinic, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Castells
authors.affiliation: Department of Gastroenterology, Hospital Clinic, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Castellvi-Bel
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Capella
authors.affiliation: Grupo de Medicina Xenomica-USC, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain.|Fundacion Publica Galega de Medicina Xenomica (FPGMX)-SERGAS, Grupo de Medicina Xenomica, Hospital Clínico Universitario, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), IDIS, Edificio de Consultas, planta-2, Choupana s/n, 15706, Santiago de Compostela, Spain.|Grupo de Medicina Xenomica-USC, Santiago de Compostela, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: Fundacion Publica Galega de Medicina Xenomica (FPGMX)-SERGAS, Grupo de Medicina Xenomica, Hospital Clínico Universitario, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), IDIS, Edificio de Consultas, planta-2, Choupana s/n, 15706, Santiago de Compostela, Spain. clara.ruiz.ponte@usc.es.
authors.forename: C
authors.initials: C
authors.lastname: Ruiz-Ponte
mesh_terms: D017668:Age of Onset; D015179:Colorectal Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D019656:Loss of Heterozygosity; D009419:Nerve Tissue Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D000098552:Slit Homolog 2 Protein
keywords: Copy number variants; Genetic susceptibility; Germline; Hereditary colorectal cancer