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 (5%, p = 0.0009) and co-segregated with breast cancer in the initial pedigree. The mutant allele was lost in 4/6 breast tumors from mutation carriers which may be consistent with the hypothesis that RCC1 dysfunction provides a selective disadvantage at the stage of tumor progression. In summary, we propose RCC1 as a likely breast cancer susceptibility gene in the Tunisian population.

The Multifaceted Roles of RCC1 in Tumorigenesis

“…Clinicopathologically, the loss of RCC1 expression in gastric cancer leads directly to the development of tumor differentiation and invasion depth ( Lin et al, 2015 ). In addition, the RCC1 ∗ C. 1067_1086del19 mutation found in Tunisian familial breast cancer patients also indicates that RCC1 mutations have carcinogenic potential ( Riahi et al, 2018 ).…”

RCC1 Expression as a Prognostic Marker in Colorectal Liver Oligometastases

“…In our study, RCC1 overexpression was correlated with a worse clinical outcome, but the underlying mechanism was unclear. Riahi et al identified a novel mutation in RCC1 as a breast cancer susceptibility allele through exome sequencing that has exclusively been found in Tunisian breast cancer patients [ 23 ]. In fact, RCC1 blockade is being investigated as a potential therapeutic strategy against aggressive breast tumors [ 24 ].…”

Integrative and Comprehensive Pancancer Analysis of Regulator of Chromatin Condensation 1 (RCC1)

“…On the one hand, as RCC1 methylation downregulates RCC1 expression and promotes the oncogenesis and invasion of STAD, RCC1 shows the potential to regulate DNA replication and inhibit tumors [ 12 ]. On the other hand, RCC1 promotes oncogenesis and drug resistance in a variety of tumors (e.g., in LUAD, OV and others) [ 9 , 10 , 11 , 16 ].…”

“…A genomewide expression profile analysis of cervical cancer showed that the expression of RCC1 in higher staged tumor tissue (FIGO III) was higher than that of normal cervix [ 10 ]. In addition, Riahi et al identified RCC1 as a candidate breast cancer susceptibility gene through exome sequencing and case–control analysis [ 11 ]. These studies indicate that RCC1 may play an important role in the occurrence and development of tumors.…”