RAD51C germline mutations in Chinese women with familial breast cancer

Abstract

Germline mutations in high penetrance breast cancer susceptibility genes, BRCA1 and BRCA2, account for only approximately 10% of Chinese familial breast cancers [1], indicating other susceptibility genes related to Chinese familial breast cancer may exist. RAD51C gene (Rasrelated associated with diabetes) is located on chromosome 17q23, a region that was found to be frequently amplified in breast tumors [2, 3]. RAD51C gene is a member of the RAD51 family and plays an essential role in homologous recombination, DNA damage sensitivity, genomic integrity, embryonic development, activation of cell cycle checkpoint kinase 2 (CHK2), and cell cycle arrest in response to DNA damage [4–8]. Recently, a biallelic missense mutation in the RAD51C gene was found in a family from Pakistan with Fanconi anemia-like disorder [9]. In an accompanying article, six monoallelic deleterious mutations in the RAD51C gene were found in 480 BRCA1/2-negative breast/ovarian cancer families from Germany [10]. This study provides the first evidence to show that the RAD51C is a breast cancer susceptibility gene. Thus, the RAD51C gene may deserve to be comprehensively screened as a breast cancer susceptibility gene in other populations. In this study, we screened the entire coding regions and exon–intron boundaries of the RAD51C gene in 273 Chinese women with familial breast cancer who do not carry mutations in BRCA1 and BRCA2 genes by polymerase chain reaction (PCR)-sequencing. Familial breast cancer cases were from the Breast Center, Peking University Cancer Hospital from July 2006 to May 2010. The criteria of familial breast cancer are (1) patients have at least one or more firstor second-degree relatives affected with breast cancer and/or ovarian cancer regardless of age and (2) bilateral breast cancer regardless of age. Four hundreds seventy-five healthy Chinese women serve as controls. Both of the cases and controls are Han Chinese women and reside in the north of China. The whole coding sequences of RAD51C were amplified using nine sets of primers described elsewhere with a minor modification [10]. All fragments were sequenced using BigDye Terminator Cycle Sequencing Kit and ABI 3730 automated sequencer (Applied Biosystems, Foster City, CA). Each mutation was confirmed by duplicate. In total, we detected eight germline sequence variants in the RAD51C gene in the 273 BRCA1/2-negative familial breast cancer cases. Among them, three were non-coding variants and five were coding variants (Table 1). None of them were previously reported. Of the coding variants, one was synomenous and four were non-synomenous. Among the four amino-acid substitution variants, 4C[G (R2G) was located in exon 1, 635G[A (R212H) and 644A[G (D215G) in exon 4, and 882G[C (Q294H) in exon 6. The missense variants R2G, D215G, and Q294H were detected in one index case, whereas R212H was detected in two unrelated cases. We then screened the four missense variants in 475 healthy controls. The variant R212H was found in two healthy individuals, indicating this variant was unlikely to be pathogenic. In contrast, none of the Zhiyuan Pang and Lu Yao contributed equally to this study.