Familial breast and ovarian cancers

Abstract

About 60% of familial breast and ovarian cancers in Japan involve germline mutations of the BRCA1 or BRCA2 ( BRCA1/2) genes. These genes contribute to genetic stability and DNA repair and act as tumor suppressor genes. Mutation analysis of the BRCA1/2 genes has improved our understanding of both common mutation patterns in Japanese patients and the clinicopathological features of BRCA1/2-related cancers. BRCA1-related breast cancers are characterized by poor prognosis, a low rate of estrogen receptor positivity, and histological predominance of solid-tubular carcinoma. BRCA1-related ovarian cancers are associated with a high frequency of serous adenocarcinoma and a good outcome. Further large-scale studies are needed to delineate genotype-phenotype relations and penetrance in BRCA1/2-related breast and ovarian cancers in Japan. The development of systems for clinical genetics in Japan, including genetic counseling, has led to the increased use of genetic testing for the clinical management of BRCA1/2-related cancers. Three options are available for carriers of BRCA1/2 mutations: intensive surveillance, chemoprevention, and prophylactic surgery. Studies done in other countries indicate that prophylactic surgery effectively prevents the development of breast and ovarian cancers in carriers of BRCA1/2 mutations. However, prophylactic mastectomy remains controversial in Japan, and now systematic intensive surveillance is generally performed for the prevention of breast cancer in women at high risk. Early detection of ovarian cancer remains challenging, resulting in increased acceptance of the need for prophylactic oophorectomy in women at risk. This review summarizes experimental and clinical findings about familial breast and ovarian cancers, including data on Japanese patients.

Insertion/deletion polymorphism in the BRCA2 nuclear localization signal

“…This interaction has been shown to regulate Rad51 nucleoprotein filament formation and the nuclear transport of Rad51 (6,29,33,35). Loss of BRCA2 function via mutation leads to genomic instability and tumorigenesis (1,18,27,31).The BRCA2 protein is localized to the nucleus, which is consistent with its role in DNA recombination and repair (4, 26). In human BRCA2, three nuclear localization signals (NLSs) have been identified and named NLS1, NLS2, and NLS3.…”

“…This interaction has been shown to regulate Rad51 nucleoprotein filament formation and the nuclear transport of Rad51 (6,29,33,35). Loss of BRCA2 function via mutation leads to genomic instability and tumorigenesis (1,18,27,31).…”

Germline mutations of BRCA1 in two Korean hereditary breast/ovarian cancer families

“…However, it is still necessary to screen the entire sequences of BRCA1 genes in Asian women. Most studies of BRCA1 mutations in Japan reported many frameshift or non-sense mutations as well as polymorphisms and unclassified variants in BRCA1 gene, but there appears not to be specific Japanese 'hot spots' for BRCA1 mutations (24). A previous study in 21 Korean hereditary breast/ovarian cancer families identified only 5 deleterious mutations in BRCA1 gene; 2 frameshift and 3 non-sense mutations, without polymorphisms or unclassified variants.…”

“…Lanes 1, 2, exon 11.13 PCR products; Lanes 3, 4, exon 11.11 PCR products; Lanes 5, 6, exon 11.14 PCR products; Wt, wild-type; Mt, mutant type. studies (24). According to the BIC database, three variations are all regarded as favor polymorphisms.…”

“…BRCA1-related breast cancers can be associated with a poor prognosis, but BRCA1-related ovarian cancers are associated with a high frequency of serous adenocarcinoma and a good outcome (24). Among patients with FIGO stage III ovarian cancer, the 5-year survival rate of BRCA1-mutation positive patients is reported as 78.6%, as compared with only 30.3% in control patients, with other etiologies for their ovarian cancer (25).…”