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Gastroenterology. 2018 Jan;154(1):181-194.e20. doi: 10.1053/j.gastro.2017.09.005. Epub 2017 Sep 12.

Association Between Germline Mutations in BRF1, a Subunit of the RNA Polymerase III Transcription Complex, and Hereditary Colorectal Cancer.

Author information

1
Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL and CIBERONC, Hospitalet de Llobregat, Barcelona, 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; Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain.
6
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.
7
Laboratorio de Oncología Molecular, Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain.
8
Laboratorio de Oncología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
9
Familial Cancer Unit, Department of Medical Oncology, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
10
Molecular Biology Laboratory, 12 de Octubre University Hospital, Madrid, Spain.
11
Instituto de Biología y Genética Molecular, IBGM-UVA-CSIC, Valladolid, Spain.
12
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Life Science Department, Barcelona; Supercomputing Centre (BSC-CNS), Barcelona, Spain.
13
Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Spain; Department of Clinical Sciences, School of Medicine, University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain.
14
Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL and CIBERONC, Hospitalet de Llobregat, Barcelona, Spain; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain.
15
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
16
Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL and CIBERONC, Hospitalet de Llobregat, Barcelona, Spain. Electronic address: lvalle@iconcologia.net.

Abstract

BACKGROUND & AIMS:

Although there is a genetic predisposition to colorectal cancer (CRC), few of the genes that affect risk have been identified. We performed whole-exome sequence analysis of individuals in a high-risk family without mutations in genes previously associated with CRC risk to identify variants associated with inherited CRC.

METHODS:

We collected blood samples from 3 relatives with CRC in Spain (65, 62, and 40 years old at diagnosis) and performed whole-exome sequence analyses. Rare missense, truncating or splice-site variants shared by the 3 relatives were selected. We used targeted pooled DNA amplification followed by next generation sequencing to screen for mutations in candidate genes in 547 additional hereditary and/or early-onset CRC cases (502 additional families). We carried out protein-dependent yeast growth assays and transfection studies in the HT29 human CRC cell line to test the effects of the identified variants.

RESULTS:

A total of 42 unique or rare (population minor allele frequency below 1%) nonsynonymous genetic variants in 38 genes were shared by all 3 relatives. We selected the BRF1 gene, which encodes an RNA polymerase III transcription initiation factor subunit for further analysis, based on the predicted effect of the identified variant and previous association of BRF1 with cancer. Previously unreported or rare germline variants in BRF1 were identified in 11 of 503 CRC families, a significantly greater proportion than in the control population (34 of 4300). Seven of the identified variants (1 detected in 2 families) affected BRF1 mRNA splicing, protein stability, or expression and/or function.

CONCLUSIONS:

In an analysis of families with a history of CRC, we associated germline mutations in BRF1 with predisposition to CRC. We associated deleterious BRF1 variants with 1.4% of familial CRC cases, in individuals without mutations in high-penetrance genes previously associated with CRC. Our findings add additional evidence to the link between defects in genes that regulate ribosome synthesis and risk of CRC.

KEYWORDS:

Colon Cancer; Familial Colorectal Cancer; Mechanism; Protein Translation

PMID:
28912018
DOI:
10.1053/j.gastro.2017.09.005
[Indexed for MEDLINE]

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