BACKGROUND: A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders. METHODS: Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level. RESULTS: Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues. CONCLUSIONS: Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.

Colon Cancer Genetics Group MRC Human Genetics Unit The University of Edinburgh Western General Hospital Edinburgh EH4 2XU UK

Department of Clinical Genetics Leiden University Medical Center Leiden University Leiden 2300 RC The Netherlands

Department of Endocrinology University of Groningen University Medical Center Groningen Groningen 9700 RB The Netherlands

Department of Gastroenterology and Hepatology Leiden University Medical Center Leiden University Leiden 2300 RC The Netherlands

Department of Gastroenterology Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer University of Barcelona Barcelona Catalonia 08036 Spain

Department of Genetics University of Groningen University Medical Centre Groningen Groningen 9700 RB The Netherlands

Department of Human Genetics Leiden University Medical Center Leiden University Leiden 2300 RC The Netherlands

Department of Pathology Leiden University Medical Center Leiden University Leiden 2300 RC The Netherlands

Fundación Pública Galega de Medicina Xenómica Santiago de Compostela 15706 Spain

Institute of Experimental Medicine Institute of Biology and Medical Genetics Prague 142 00 Czech Republic

Oxford Centre for Cancer Gene Research Wellcome Trust Centre for Human Genetics University of Oxford Oxford OX3 7BN UK

Erratum In

Br J Cancer. 2018 Jan;118(2):e4. doi: 10.1038/bjc.2017.380. PubMed

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