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

Introduction:

Breast cancer is a genetic disease but the known genes explain a minority of cases. RCC1, the Regulator of Chromosome Condensation 1, is important for replication control and proper mitotic spindle formation but has not previously been associated with hereditary cancer.

Methods:

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. We then directly genotyped a Tunisian breast cancer case-control series for the identified RCC1 mutation, and further analysed tumors from six mutation carriers for loss of heterozygosity.

Results:

Exome sequencing identified a novel frameshift mutation RCC1*c.1067_1086del19. 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.

Conclusions:

The results suggest RCC1 as a novel breast cancer susceptibility gene and encourage further search for germline RCC1 mutations in cancer patients from other populations.

This work was funded by the German Ministry of Education and Research and the Tunisian Ministry for Higher Education and Scientific Research (TUNGER-70).