Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan

Abstract

The hereditary breast and ovarian cancer (HBOC) registration system of Japan was established by the Japanese HBOC Consortium. The first trial was registered in 2015 in four institutions to which some registration committee members belonged. We analyzed the information of 830 Japanese pedigrees, who underwent BRCA1/2 genetic testing, including mutation carriers with BRCA1 (N = 127) and BRCA2 (N = 115), and their families. The mutation-positive rate was 19.7%. Variants of uncertain significance were found in 6.5% of all individuals subjected to genetic testing for BRCA1/2. Compared to the United States, Japan had a higher mutation-positive rate in most categories, except for the groups with male breast cancer. Among the intrinsic subtypes of BRCA1-associated breast cancers, 75.8% were triple-negative. The incidence rate of contralateral breast cancer in BRCA1/2 mutation carriers was 0.99%/year. Among 240 mutation carriers, 26 and 62 patients underwent risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), respectively; the respective frequencies of occult cancer were 7.1 and 3.2%. Metachronous breast cancer after RRM or peritoneal cancer after RRSO was not observed during the follow-up period. The nationwide registration system began last year and the system enables followup analysis in Japan.

BRCA1/2mutation status in patients with metachronous breast and ovarian malignancies: clues towards the implementation of genetic counseling

“…Because our study cohort included a limited number of non-serous ovarian malignancies, the prevalence of BRCA mutations was lower in our study (42%) as compared with a previous report showing that 70% of patients with metachronous breast and ovarian cancer carried BRCA mutations [29]. To better guide genetic counseling practice, especially in East Asia where a larger proportion of ovarian cancers are of non-serous type, it is warranted to confirm our finding with a larger sample size, possibly from national or international consortia (e.g., Japanese HBOC consortium and Asian BRCA consortium) [30].…”

Analysis of clinical characteristics in breast cancer patients with the Japanese founder mutation of BRCA1 L63X.

“…This study was approved by the Ethical Review Boards of the Japanese HBOC Consortium and each medical institution. Informed consent has been obtained in principle [16]. The Japanese HBOC consortium was established in 2012, following another study conducted by the Japanese Breast Cancer Society (2010)(2011)(2012) (Figure 2).…”

“…The Japanese HBOC consortium was established in 2012, following another study conducted by the Japanese Breast Cancer Society (2010)(2011)(2012) (Figure 2). We registered patients who underwent genetic testing at these four hospitals [16]. During the registration, the following data were collected: family identification number, birthdate, sex, age at death, development and type of breast cancer and ovarian cancer, history of other cancers, age during first childbirth, age at menarche, age at menopause, cause of death, data about breast cancer (age at onset, location, discovery opportunities, treatments, operative method, operation date, pathological histology, tumor size, nuclear grade, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, and Ki-67 index score), data about ovarian cancer (age at onset, date of treatment initiation, treatment result, location, treatments, operative method, operation date, pathological histology, stage, and nuclear grade), date of genetic testing, result of genetic testing, genotype, prophylactic surgery, and family history (at least till second-degree relatives).…”

“…Furthermore, using data from 651 breast cancer patients in Southern China, one BRCA1 pathogenic variant (c.981_982delAT) and three BRCA2 pathogenic variants (c.3109C>T, c.7436_7805del370, and c.9097_9098insA) were analyzed and reported as Chinese founder mutations [13]. In Japan, only a few reports on founder mutations of HBOC have been published [14][15][16]. The c.188T>A (307T>A) variant, which causes the amino acid change L63X, was reported as the Japanese founder mutation in breast cancer and ovarian cancer.…”

Genome-wide association study (GWAS) of ovarian cancer in Japanese predicted regulatory variants in 22q13.1

“…Most of these studies were conducted in European populations [4][5][6][7][8][9][10], and only two studies included Asian populations [11,12]. Pathogenic variations in the BRCA1 and BRCA2 tumor suppressor genes responsible for most of hereditary breast and ovarian cancer syndromes [13] have been reported in numerous ethnic group including Japanese populations [14]. However, low-penetrance genetic variants still need to be elucidated, especially in Japanese populations.…”