Incidence of contralateral and ipsilateral breast cancers and prognosis in BRCA1/2 pathogenic variant carriers based on the Japanese HBOC Consortium registration

Abstract

This study aimed to clarify the breast cancer prognosis in Japanese patients with BRCA1/2 pathogenic variant. We analyzed 2235 women with breast cancer who underwent BRCA1/2 genetic testing between 1996 and 2018 using data from the Japanese hereditary breast and ovarian cancer syndrome registry. The cumulative risk for contralateral and ipsilateral breast cancers and time to death since the first breast cancer were stratified based on the BRCA1/2 variant status. The median follow-up was 3.0 years (0.1-34.1 years) after the first breast cancer. The annual average risks of contralateral breast cancer in BRCA1 and BRCA2 and non-BRCA1/2 pathogenic variant carriers were 4.0%, 2.9%, and 1.9%, respectively (P = 0.001). The annual average risks of ipsilateral breast cancer in the three groups were 2.7%, 1.4%, and 1.1%, respectively (P = 0.06). BRCA1 pathogenic variant carriers had significantly higher risks of contralateral (hazard ratio 1.91, P < 0.001) and ipsilateral (hazard ratio 2.00, P = 0.02) breast cancers than non-BRCA1/2 pathogenic variant carriers. The time to death by the BRCA1/ 2 variant status was not significantly difference (P = 0.28). The prognosis of breast cancer patients who received standard treatment was comparable regardless of the BRCA1/2 variant status.

Prevalence of Pathogenic Germline BRCA1/2 Variants and Their Association with Clinical Characteristics in Patients with Epithelial Ovarian Cancer in a Rural Area of Japan

“…Therefore, the difference in the prevalence of each gene might be explained by genetic drift in the studied population or sampling bias due to the small number of participants. Among the 10 recurrently found g BRCA1/2 -PV (in more than 10 families) in the Japanese Organization Of Hereditary Breast and Ovarian Cancer (JOHBOC) registry in Japan [ 16 , 25 ], only three variants, BRCA1 :c.2800C>T, BRCA2 :c.6952C>T, and BRCA2 :c.9076C>T, were identified in our OC cases. In contrast, three g BRCA2 -PV, two of which were observed in more than one case, found in our study had not been identified in previous studies of Japanese cases with OC [ 6 , 7 ] and BC [ 16 , 24 ].…”

“…Among the 10 recurrently found g BRCA1/2 -PV (in more than 10 families) in the Japanese Organization Of Hereditary Breast and Ovarian Cancer (JOHBOC) registry in Japan [ 16 , 25 ], only three variants, BRCA1 :c.2800C>T, BRCA2 :c.6952C>T, and BRCA2 :c.9076C>T, were identified in our OC cases. In contrast, three g BRCA2 -PV, two of which were observed in more than one case, found in our study had not been identified in previous studies of Japanese cases with OC [ 6 , 7 ] and BC [ 16 , 24 ]. In addition, among these three variants, NM_000059.4:c.3703C>T (p.Gln1235*) and NM_000059.4:c.7922dup (p.Phe2642Ilefs*3) have never been reported previously, suggesting that these are novel pathogenic variants and some g BRCA2 -PV unique to the local area may exist in Tokushima prefecture located on the island of Shikoku, Japan.…”

One origin of founder mutations in Japan

“…The clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2 c.5576_5579del and those of other PVs. The detection rate of BRCA2 c.5576_5579del in the BRCA1/2 genetic testing at each institution was also compared with that in the previous report [15].…”

“…We compared the BRCA1/2carrier frequency in patients among four hospitals. We also compared the frequency of PVs in the observed patients with that observed in Japanese patients reported by Yoshimura, et al [15]. We used a pie chart to compare the proportion of PVs at each hospital.…”

“…In Japan, owing to the development of the HBOC Consortium [14,15], several PVs have been reported to exhibit founder effects, including BRCA1 c.188T > A (p.Leu63*) [14][15][16][17], BRCA2 c.5576_5579del (p.Ile1859fs), BRCA2 c.6952C > T (p.Arg2318*) [15][16][17]. Among them, BRCA2 c.5576_5579del has a higher carrier frequency in the Kinki region than in other regions [17].…”