OBJECTIVE: BRCA mutational status is important in the management of ovarian cancer, but there is a lack of evidence supporting genetic testing in Asian populations. This study was performed to investigate the prevalence and prognostic outcomes of BRCA1/2 mutation and variant of unknown significance (VUS) in Korean patients diagnosed with epithelial ovarian cancer (EOC). METHODS: Among patients newly diagnosed with EOC between January 2007 and January 2017, those tested for germline BRCA1/2 mutation were studied, regardless of family history. Overall survival (OS) and progression-free survival (PFS) were compared between the patients with and without BRCA1/2 mutation and VUS. RESULTS: A total of 313 patients underwent BRCA testing: 88 patients had a BRCA1/2 mutation and 48 patients had a BRCA1/2 VUS (28.1% and 15.3%, respectively). There were no significant associations between BRCA1/2 mutation, BRCA1/2 wild-type, or BRCA1/2 VUS with age at diagnosis, histologic distribution, or residual disease status after primary cytoreductive surgery. BRCA1 mutation, including BRCA1 VUS, showed no difference in PFS or OS compared to BRCA1 wild-type. In contrast, BRCA2 mutation showed longer PFS than that of BRCA2 wild-type (P=0.04) or BRCA2 VUS (P=0.02). BRCA2 mutation, including BRCA2 VUS, did not show any difference in OS compared to BRCA2 wild-type. CONCLUSION: BRCA mutation and BRCA VUS had similar clinical characteristics and survival outcomes, except that BRCA2 mutation showed better PFS. The results of this study will help to understand the prognostic significance of BRCA mutation and VUS in Korean patients.
Asian Continental Ancestry Group ; Diagnosis ; Disease-Free Survival ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Testing ; Humans ; Korea ; Ovarian Neoplasms ; Prevalence

PURPOSE: We investigated the clinical relevance and spectrum of BRCA1/2 mutations in Korean ovarian cancer (KoOC) patients. MATERIALS AND METHODS: Two hundred seventy-nine KoOC patients were enrolled from three university hospitals between 2012 and 2017. Their peripheral blood samples were obtained for BRCA1/2 mutation analysis by direct sequencing. Clinicopathological characteristics were retrospectively reviewed, and spectrum analyses of BRCA1/2 mutation were assessed by systematic literature review. RESULTS: Frequency of BRCA1/2 mutations was 16.5% in KoOC patients. BRCA1/2 mutations were significantly associated with family history of breast/ovarian cancer (p<0.001), serous histology (p=0.044), and advanced International Federation of Gynecology and Obstetrics (FIGO) stage (III/IV, p=0.018) but not with early age-of-onset (age < 50, p=0.729). Literature review of BRCA1/2 mutations in KoOC patients found 111 (55 distinct) mutations with high proportion of Korean-specific mutations (24/55, 43.6%). Comparing the spectrum of BRCA1/2 mutation between KoOC and Korean breast cancer (KoBC) patients, the ratio of BRCA1-to-BRCA2 mutations was different, with BRCA1 (78.4%) being predominant in KoOC and BRCA2 in KoBC (59.2%). The most common mutation also differed between the two (c.3627insA of BRCA1 in KoOC and c.7480C>T of BRCA2 in KoBC). CONCLUSION: The clinical relevance of BRCA1/2 mutations in KoOC patients was confirmed but that of early age-of-onset was not. Possible inconsistency in the ratio of BRCA1-to-BRCA2 mutations and the most common mutation between KoOC and KoBC may probably suggest presence of mutation sequence-associated penetrance tendency in hereditary Korean breast and ovarian cancer. These data may provide insights for optimal genetic counseling and prophylactic treatment for at-risk relatives of KoOC patients.
Asian Continental Ancestry Group ; Breast ; Breast Neoplasms ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Counseling ; Germ-Line Mutation ; Gynecology ; Hospitals, University ; Humans ; Obstetrics ; Ovarian Neoplasms ; Penetrance ; Retrospective Studies

Breast cancer is the second most common cancer in Korean women. Germline mutations in the BRCA1 and BRCA2 genes cause hereditary breast cancer and are detected in 15–20% of hereditary breast cancer. We investigated the BRCA1 and BRCA2 mutations in 114 familial breast cancer patients using next-generation sequencing. We confirmed 20 different mutations of BRCA1 and BRCA2 in 25 subjects (21.9%). Two such mutations in eight patients were novel (not reported in any variant database or previous study). Six mutations have been reported as disease-causing mutations in public databases. Seven mutations were found only in a single nucleotide polymorphism database and one mutation has been reported in Korea. The BRCA1/2 mutation frequency was similar to that of other studies on familial breast cancer patients in the Korean population. Further studies should examine more cases and mutations of whole exons.
BRCA1 Protein ; BRCA2 Protein ; Breast Neoplasms ; Breast ; Exons ; Female ; Genes, BRCA2 ; Germ-Line Mutation ; Humans ; Korea ; Mutation Rate ; Polymorphism, Single Nucleotide

No abstract available.
Genes, Tumor Suppressor ; BRCA2 Protein ; BRCA1 Protein ; Ovarian Neoplasms ; Breast Neoplasms

BRCA1 carriers, 50 BRCA2 carriers, and 445 non-carriers. The median follow-up was 84.5 months. Overall, 61 patients (11.3%) developed CBC (24.4% for BRCA1 carriers, 20% for BRCA2 carriers, and 9% for non-carriers). The 10-year cumulative risk for CBC was 23.8% for BRCA1 carriers, 19.1% for BRCA2 carriers, and 9.8% for non-carriers (p = 0.174). Among the 277 patients who underwent breast-conserving surgery, 29 (10.5%) developed IBTR (9.1% for BRCA1 carriers, 16.7% for BRCA2 carriers, and 10.2% for non-carriers). The 10-year cumulative risk for IBTR for BRCA1 carriers, BRCA2 carriers, and non-carriers was 8.7%, 14.1%, and 20%, respectively (p = 0.577). BRCA1 (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.20–7.20; p = 0.019) and BRCA2 (HR, 2.88; 95% CI, 1.13–7.35; p = 0.027) mutations and negative estrogen receptor status (HR, 4.02; 95% CI, 1.60–10.08; p = 0.003) were the significant predictive factors for CBC, while tumor size ≥ 2 cm was predictive of IBTR (HR, 6.11; 95% CI, 2.03–18.33; p = 0.001).CONCLUSION: While BRCA1/2 mutation carriers had a higher risk of developing CBC compared to non-carriers at high-risk of HBOC, the risk of IBTR was similarly high across breast cancer patients irrespective of the BRCA mutation. Further preventive strategies to reduce CBC and IBTR for all patients at high-risk of HBOC should be investigated.]]>
Breast Neoplasms ; Breast ; Cohort Studies ; Estrogens ; Follow-Up Studies ; Genes, BRCA1 ; Genes, BRCA2 ; Hereditary Breast and Ovarian Cancer Syndrome ; Humans ; Mastectomy, Segmental ; Ovarian Neoplasms ; Prospective Studies ; Recurrence ; Risk Factors ; Unilateral Breast Neoplasms

OBJECTIVE: The aim of the present study was to assess the frequency of germline mutations in patients with peritoneal carcinoma (PC) or the fallopian tube carcinoma (FTC), using a multi-gene panel. METHODS: Twenty-six patients diagnosed with either PC or FTC between January 2013 and December 2016 were recruited consecutively. Germline DNA was sequenced using a 6-gene next generation sequencing (NGS) panel following genetic counseling. Surgico-medical information was obtained from hospital records. Genetic variations were detected using the panel and were cross-validated by Sanger direct sequencing. RESULTS: Germline BRCA1/2 mutations were identified in 6 patients (23.1%). Four were detected in patients with PC and 2 were in FTC patients. No mutations were detected in TP53, PTEN, CDH1, or PALB2. We identified 11 variant of uncertain significance (VUS) in 9 patients; 2 in BRCA1, 3 in BRCA2, 2 in TP53, and 4 in CDH1. We also detected a CDH1 c.2164+16->A VUS in 3 patients. CONCLUSION: The prevalence of germline BRCA1/2 mutations in patients with PC or FTC is comparable to that of BRCA1/2 mutations in epithelial ovarian cancer patients.
DNA ; Fallopian Tube Neoplasms ; Fallopian Tubes* ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Counseling ; Genetic Variation ; Germ-Line Mutation ; Hospital Records ; Humans ; Ovarian Neoplasms ; Peritoneal Neoplasms ; Peritoneum* ; Prevalence*

PURPOSE: The characteristic expression of DNA damage response proteins in familial breast cancers with BRCA1, BRCA2, or non-BRCA1/2 mutations has not been analyzed in Chinese patients. Our study aimed to assess the differential expression of microcephalin 1 (BRIT1), ATM serine/threonine kinase (ATM), checkpoint kinase 2 (CHEK2), BRCA1, RAD51 recombinase (RAD51), and poly (ADP-ribose) polymerase 1 (PARP-1) and establish the profile of Chinese familial breast cancers with different mutation status. METHODS: We constructed five tissue microarrays from 183 familial breast cancer patients (31 with BRCA1 mutations; 14 with BRCA2 mutations, and 138 with non-BRCA1/2 mutations). The DNA response and repair markers used for immunohistochemistry analysis included BRIT1, ATM, CHEK2, BRCA1, RAD51, and PARP-1. The expressions of these proteins were analyzed in BRCA1/2 mutated tumors. The association between pathologic characteristics with BRCA1/2 mutation status was also analyzed. RESULTS: In familial breast cancer patients, BRCA1 mutated tumors were more frequent with high nuclear grade, estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 negative, low Ki-67, and positive CK5/6. BRCA1 mutated tumors had lower CHEK2 and higher cytoplasmic BRIT1 expression than BRCA2 and non-BRCA1/2 mutation tumors. BRCA2-associated tumors showed higher CHEK2 and cytoplasmic RAD51 expression than those in other groups. Nuclear PARP-1 expression in BRCA1/2-associated tumors was significantly higher than in non-BRCA1/2 mutation tumors. Moreover, we found quite a few of negative PARP-1 expression cases in BRCA1/2 mutated groups. CONCLUSION: The clinicopathologic findings of BRCA1-associated Chinese familial breast cancers were similar to the results of other studies. Chinese familial breast cancer patients with BRCA1/2 mutations might have distinctive expression of different DNA damage response proteins. The reduced expression of PARP-1 in Chinese BRCA1/2 mutated breast cancer patients could influence the therapeutic outcome of PARP-1 inhibitors.
Asian Continental Ancestry Group* ; Breast Neoplasms* ; Breast* ; Checkpoint Kinase 2 ; Cytoplasm ; DNA Damage* ; DNA Repair ; DNA* ; Estrogens ; Genes, BRCA1 ; Genes, BRCA2 ; Humans ; Immunohistochemistry ; Phosphotransferases ; Rad51 Recombinase ; Receptor, Epidermal Growth Factor

PURPOSE: Unclassified variants (UVs) of BRCA1 and BRCA2 genes are not defined as pathogenic for breast cancer, and their clinical significance currently remains undefined. Therefore, this study was conducted to identify potentially pathogenic UVs by comparing their prevalence between breast cancer patients and controls. MATERIALS AND METHODS: A total of 328 breast cancer patients underwent BRCA1/2 genetic screening at the National Cancer Center of Korea. Genetic variants of BRCA genes that were categorized as unclassified according to the Breast Cancer Information Core database were selected based on allelic frequency, after which candidate variants were genotyped in 421 healthy controls. We also examined family members of the study participants. Finally, the effects of amino acid substitutions on protein structure and function were predicted in silico. RESULTS: Genetic tests revealed 33 UVs in BRCA1 and 47 in BRCA2. Among 15 candidates genotyped in healthy controls, c.5339T>C in BRCA1 and c.6029T>G, c.7522G>A in BRCA2 were not detected. Moreover, the c.5339T>C variant in the BRCA1 gene was detected in four patients with a family history of breast cancer. This nonsynonymous variant (Leu1780Pro) in the BRCA1 C-terminal domain was predicted to have an effect on BRCA1 protein structure/function. CONCLUSION: This study showed that comparison of genotype frequency between cases and controls could help identify UVs of BRCA genes that are potentially pathogenic. Moreover, ourfindings suggest that c.5339T>C in BRCA1 might be a pathogenic variant for patients and their families.
Amino Acid Substitution ; BRCA1 Protein ; Breast Neoplasms* ; Breast* ; Computer Simulation ; Genes, BRCA1 ; Genes, BRCA2* ; Genetic Testing ; Genotype ; Humans ; Korea ; Prevalence

Germline mutations in the BRCA1 and BRCA2 genes are strong genetic factors for predispositions to breast, ovarian, and other related cancers. This report describes a family with a history of breast and ovarian cancers that harbored a novel BRCA1 germline mutation. A single nucleotide deletion in intron 20, namely c.5332+4delA, was detected in a 43-year-old patient with breast cancer. This mutation led to the skipping of exon 20, which in turn resulted in the production of a truncated BRCA1 protein that was 1773 amino acids in length. The mother of the proband had died due to ovarian cancer and had harbored the same germline mutation. Ectopically expressed mutant BRCA1 protein interacted with the BARD1 protein, but showed a reduced transcriptional function, as demonstrated by the expression of cyclin B1. This novel germline mutation in the BRCA1 gene caused familial breast and ovarian cancers.
Adult ; Amino Acids ; BRCA1 Protein ; Breast Neoplasms* ; Breast* ; Cyclin B1 ; Exons* ; Genes, BRCA1 ; Genes, BRCA2 ; Germ-Line Mutation* ; Humans ; Introns ; Mothers ; Ovarian Neoplasms

PURPOSE: Germline mutations in the BRCA1 and BRCA2 genes confer increased risks for breast cancers. However, the clinical presentation of breast cancer among women who are carriers of the BRCA1 or BRCA2 (BRCA1/2 carriers) mutations is heterogenous. We aimed to identify the effects of the reproductive histories of women with the BRCA1/2 mutations on the clinical presentation of breast cancer. METHODS: We retrospectively analyzed clinical data on women with proven BRCA1 and BRCA2 mutations who were recruited to the Korean Hereditary Breast Cancer study, from 2007 to 2014. RESULTS: Among the 736 women who were BRCA1/2 mutation carriers, a total of 483 women had breast cancers. Breast cancer diagnosis occurred at significantly younger ages in women who experienced menarche at ≤14 years of age, compared to those who experienced menarche at >14 years of age (37.38±7.60 and 43.30±10.11, respectively, p<0.001). Additionally, the number of full-term pregnancies was significantly associated with the age of diagnosis, especially in women with the BRCA2 mutation. The prevalence of advanced stages (stage II or III vs. stage I) of disease in parous women was higher than in nulliparous women (68.5% vs. 55.2%, p=0.043). This association was more pronounced in women with the BRCA2 mutation (hazard ratio, 2.67; p=0.014). CONCLUSION: Our results suggest that reproductive factors, such as the age of onset of menarche and the presence of parity, are associated with the clinical presentation patterns of breast cancer in BRCA1/2 mutation carriers.
Age of Onset ; Breast Neoplasms* ; Breast* ; Diagnosis ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Germ-Line Mutation ; Humans ; Menarche ; Parity ; Pregnancy ; Prevalence ; Reproductive History ; Retrospective Studies