Characteristics of double heterozygosity for BRCA1 and BRCA2 germline mutations in Korean breast cancer patients

Abstract

To investigate clinical, pathological, and familial characteristics of Korean patients with double heterozygosity for BRCA1 and BRCA2 mutations, six breast tumors of five patients who carried deleterious mutations in both of the genes were included. Medical records of the patients were reviewed and genetic testing by direct sequencing was undertaken to detect mutations in BRCA1 and BRCA2. Seven frameshift and three nonsense mutations were identified, and four mutations are novel in the Breast Cancer Information Core. There were no Ashkenazi founder mutations detected. The mean age at diagnosis for breast cancer was 33 years. All six tumors were infiltrating ductal carcinoma and poorly differentiated. Pathologic stage was I or II, and immunohistochemistry showed negative immunoreactivity for estrogen receptor and Her-2/neu in all tumors. Positive immunoreactivity for progesterone receptor was found only in one tumor. Three patients had familial history of breast, ovarian or other cancers. One patient who was diagnosed for breast cancer at the age of 26 had two maternal family members of metachronous bilateral breast cancer. Another patient who experienced metachronous bilateral breast cancer had maternal history of ovarian and esophageal cancer. In summary, Korean patients with double heterozygosity for BRCA1 and BRCA2 were young at diagnosis of breast cancer. Tumors were early stage, high grade, and almost triple-negative phenotype. All familial history of breast, ovary or other cancer was maternal. Close surveillance and accurate risk assessment should be provided for the patients with mutations in the both of the genes.

Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

“…Double heterozygosity for BRCA1 and BRCA2 mutations, as observed in the patient 608, is rare but not unprecedented in the diagnostic setting (0.09%–0.36% of index cases according to Leegte et al. []), although the effects of such mutations may not necessarily be cumulative [Ludwig et al., ; Friedman et al., ; Leegte et al., ; Choi et al., ; Smith et al., ; Steffensen et al., ; Zuradelli et al., ; Lavie et al., ; Heidemann et al., ; Noh et al., ]. On the other hand, co‐occurrence of two extremely rare variants, BRCA1 c.1510C>T and BRCA2 c. c.9371A>T (Table ), in one individual, who is characterized by genomic instability in uninvolved mammary glandular tissue, may indicate nonrandom connection.…”

Association betweenBRCAMutation Status, Pathological Findings, and Magnetic Resonance Imaging Features in Patients with Breast Cancer at Risk for the Mutation

“…Patients with both BRCA1 and BRCA2 germline mutations were classified as having a BRCA1 mutation, because the histopathological features of double heterozygosity tend to be primarily influenced by BRCA1 mutation [18]. A multiple logistic regression analysis was applied to identify factors associated with morphological and enhancement features on MRI.…”

DNA repair systems

“…As carriership of muta ons in BRCA genes is not uncommon, a small propor on of individuals at high risk may carry defects in both their BRCA1 and in BRCA2 genes. The associated risk is similar to the risk in carriers of a defec ve copy of either BRCA1 or BRCA2, albeit the first tumour/s may appear earlier and/or appear in more than one loca on in double heterozygotes [506,507]. For a double heterozygote, the risk of transmission of at least one defec ve allele to their children is higher, about 75% (compared to the 50% risk of transmission in carriers of muta on in one of the two genes).…”