Differences in age at diagnosis of ovarian cancer for each BRCA mutation type in Japan: optimal timing to carry out risk-reducing salpingo-oophorectomy

Abstract

Objective BRCA1 and BRCA2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) by age 40 and 45, respectively. However, the carriers have a different way of thinking about their life plan. We aimed to investigate the distribution of age at diagnosis of ovarian cancer (OC) patients to examine the optimal timing of RRSO in the carriers. Methods We examined a correlation between age at diagnosis of OC and common mutation types in 3,517 probands that received BRCA genetic testing. Among them, germline BRCA1 mutation (g BRCA1 m), germline BRCA2 mutation (g BRCA2 m) and germline BRCA wild-type (g BRCA wt) were found in 185, 42 and 241 OC patients, respectively. Results The average age at diagnosis of OC in g BRCA1 m and g BRCA2 m was 51.3 and 58.3 years, respectively, and the difference from g BRCA wt (53.8 years) was significant. The g BRCA2 m carriers did not develop OC under the age of 40. The average age was 50.1 years for L63X and 52.8 years for Q934X in BRCA1 , and 55.1 years for R2318X and 61.1 years for STOP1861 in BRCA2 . The age at diagnosis in L63X or R2318X carriers was relatively younger than other BRCA1 or BRCA2 carriers, however their differences were not significant. With L63X and R2318X carriers, 89.4% (42/47) and 100% (7/7) of women were able to prevent the development of OC, respectively, when RRSO was performed at age 40. Conclusion There appears to be no difference in the age at diagnosis of OC depending on the type of BRCA common mutation. Further analysis would be needed.

The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition

“…In terms of age of cancer onset, the median age at the first onset of breast and ovarian cancers was 52 and 63 years, respectively, for all carriers of the BRCA2 c.7847C>T (p.Ser2616Phe) variant. These findings are consistent with those reported for BRCA2 pathogenic variant carriers in the Japanese population (mean age ± SD = 45.2 ± 11.1 years for breast cancer and 58.3 ± 9.3 years for ovarian cancer), and for the BRCA ‐negative Japanese population (48.8 ± 12.6 years for breast cancer and 53.8 ± 13.2 years for ovarian cancer) 7,28 . From a histopathological perspective, three carriers with breast cancer (III‐3 and III‐6 in Family 1 and II‐1 in Family 3) were subgrouped as having luminal‐type breast cancer, whereas two patients (III‐1 in Family 2 and III‐1 in Family 3) developed triple‐negative breast cancer.…”

“…Subsequently, we further examined the database of the Japanese Organization of Hereditary Breast and Ovarian Cancer (JOHBOC), which is the largest HBOC registration system in Japan, searching for data on this variant registered by August 2019. In the JOHBOC database, 62 hospitals in Japan registered 3517 probands and their relatives who underwent BRCA1/2 genetic testing, as reported previously 6,7 . Almost all genetic testing was conducted at Myriad Genetics Laboratories using BRACAnalysis or at FALCO Biosystems, and the pathogenicity of the identified variants was classified based on the criteria of Myriad Genetics Laboratories.…”

Ovarian cancer onset across differentBRCAmutation types: a view to a more tailored approach forBRCAmutated patients

“…Initially, the hypothesis that the position of the mutation could influence the age at cancer diagnosis was assessed by Rebbeck et al; they hypothesized and demonstrated that the mutation within exon 11 in BRCA1 is predictive of a higher risk of high grade serous ovarian cancer at an earlier age 26. More recently, Sekine et al27 have presented the distribution of the age at diagnosis of ovarian cancer with BRCA mutation in detail and analyzed age by each common mutation type in the Japanese population. They found that age at diagnosis in L63X (common founder variant in BRCA1 gene in the Japanese population) or R2318X (common founder variant BRCA2 gene in the Japanese population) carriers was relatively younger than other BRCA1 or BRCA2 carriers.…”

Risk-reducing decisions regarding germlineBRCApathogenic variant: focusing on the timing of genetic testing and RRSO

“… 22 Sekine et al reported that for all g BRCA1 carriers, the preventive effect was 97% and 92% when RRSO was administered by the age of 35 and 40 years, respectively. 10 Moreover, this effect was reduced to 89% when RRSO was administered after the age of 40.…”