Exome sequencing and case-control analyses identify RCC1 as a candidate breast cancer susceptibility gene

Abstract

Breast cancer is a genetic disease but the known genes explain a minority of cases. To elucidate the molecular basis of breast cancer in the Tunisian population, we performed exome sequencing on six BRCA1/BRCA2 mutation-negative patients with familial breast cancer and identified a novel frameshift mutation in RCC1, encoding the Regulator of Chromosome Condensation 1. Subsequent genotyping detected the 19-bp deletion in additional 5 out of 153 (3%) breast cancer patients but in none of 400 female controls (p=0.0015). The deletion was enriched in patients with a positive family history (4%, p=0.0009) and co-segregated with breast cancer in the initial pedigree. The mutant allele was lost in 4/6 breast tumours from mutation carriers which may be consistent with the hypothesis that RCC1 dysfunction provides a selective disadvantage at the stage of tumour progression. In summary, we propose RCC1 as a likely breast cancer susceptibility gene in the Tunisian population. This article is protected by copyright. All rights reserved.

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