N17: BRF1, A Novel Gene Associated With Hereditary Colorectal Cancer

P. Mur1, N. Sowada2, F. Bellido1, C. Lázaro1, T. Pons3, R. Valdés-Mas4, M. Pineda1, G. Aiza1, S. Iglesias1, J. L.uís Soto5, 6, M. Urioste7, T. Caldés8, M. Balbín9, P. Blay10, D. Rueda11, M. Durán12, A. Valencia3, V. Moreno13, 14, J. Brunet1, 15, I. Blanco1, M. Navarro1, G. A. Calin16, G. Borck2, X. S. Puente4, G. Capellá1, L. Valle1

1 – Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL and CIBERONC, Hospitalet de Llobregat, Spain. 2 – Institute of Human Genetics, University of Ulm, Ulm, Germany. 3 – Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain. 4 – Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain. 5 – Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain. 6 – Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain. 7 – Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO) and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain. 8 – Laboratorio de Oncología Molecular, Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain. 9 – Laboratorio de Oncología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain. 10 – Familial Cancer Unit, Department of Medical Oncology, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain. 11 – Molecular Biology Laboratory, 12 de Octubre University Hospital, Madrid, Spain. 12 – Instituto de Biología y Genética Molecular, IBGM-UVA-CSIC, Valladolid, Spain. 13 – Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Spain. 14 – Department of Clinical Sciences, School of Medicine, University of Barcelona, Hospitalet de Llobregat, Spain. 15 – Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain. 16 – Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

 

Aim: The identification of genes associated with hereditary colorectal cancer (CRC) facilitates the management of families and individuals carrying pathogenic mutations, having a direct impact in the processes of genetic testing and counseling. However, much of the genetic predisposition to CRC remains unexplained.

Method: We performed whole-exome sequencing in 3 CRC-affected relatives of an Amsterdam I CRC family.

Results: Variants located in 38 genes were shared by all affected relatives. A splice-site mutation in BRF1 (subunit of RNA polymerase III transcription initiation factor), stood up as potential causal mutation. BRF1 mutational screening was performed in 547 additional familial CRC cases using pooled DNA and targeted next generation sequencing. Ten novel or rare (population MAF<1%) BRF1 variants were identified in 11 independent CRC families. The deleterious nature of the identified BRF1 mutations were demonstrated for seven of them (1 detected in two families): BRF1 c.1459+2T>C and 6 missense variants, p.T12M, p.V75M, p.S81T, p.C140S, p.P405R and p.R572G, which led to the alteration of protein function and/or protein expression in functional studies carried out in yeast and/or human CRC cell lines. The frequency of mutations in familial CRC cases was significantly higher to the frequency observed in control population.

Conclusion: Germline heterozygous mutations in BRF1 may contribute for at least 1.4% of unexplained familial colorectal cancer cases. If validated in independent series, BRF1 mutation carrier families could benefit in the future from a clinical management based on carrier status and personalized risk assessment.

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