A J Brea-Fernandez1, C Fernandez-Rozadilla2, M Alvarez-Barona3, D Azuara4, M M Ginesta4, J Clofent5,6, L de Castro5, D Gonzalez7, M Andreu8, X Bessa8, X Llor9, R Xicola9, R Jover10, A Castells11, S Castellvi-Bel11, G Capella4, A Carracedo1,2,3, C Ruiz-Ponte12. 1. Grupo de Medicina Xenomica-USC, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain. 2. 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. 3. Grupo de Medicina Xenomica-USC, Santiago de Compostela, Spain. 4. Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain. 5. Gastroenterology Department, Hospital do Meixoeiro, Vigo, Spain. 6. Section of Digestive Diseases, Internal Medicine Department, Hospital Sagunto, Valencia, Spain. 7. Servicio de Patologia Digestiva, Hospital Sant Pau, Barcelona, Spain. 8. Gastroenterology Department, Hospital del Mar, Barcelona, Spain. 9. Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, Chicago, IL, USA. 10. Gastroenterology Department, Hospital General de Alicante, Alicante, Spain. 11. 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. 12. 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.
Abstract
PURPOSE: 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/PATIENTS: 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.
PURPOSE: 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/PATIENTS: We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRCpatients (<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.
Entities:
Keywords:
Copy number variants; Genetic susceptibility; Germline; Hereditary colorectal cancer
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