内容紹介
Current Clinical Issues and Recent Trends in Hereditary Breast and Ovarian Cancer in Japan―Genetic Testing for HBOC and Risk-Reducing Surgery
Summary
The recognition of hereditary breast and ovarian cancer(HBOC)is gradually spreading in Japan after a famous American actress made it public that she underwent risk-reducing mastectomy(RRM)based on mutation of BRCA1.
HBOC is a cancer susceptibility syndrome involving breast, ovarian, or prostate cancers due to germline mutation of BRCA1 or BRCA2. Although the frequency is low, genomic rearrangement is also found in Japan; therefore, in addition to PCR-direct sequencing, multiplex ligation-dependent probe amplification(MLPA)should be performed in genetic testing for HBOC. Recently, candidate genes other than BRCA1/2, such as RAD51C, PALB2, and BRIP1, have been identified for hereditary breast cancers. Variants of uncertain significance are seen in approximately 4-6% of all genetic testing reports for BRCA1/2. ACMG recommends the use of the term“variant”in addition to a modifier such as pathogenic, benign, and so on, instead of terms such as mutation or polymorphism. The incidence of ovarian cancer is not increased in women from breast cancer-only families that test negative for BRCA1/2 mutations. Therefore, intensive gynecological surveillance may not be needed for these clients.
Basic data such as penetrance and cumulative risks of HBOC in Japanese populations are insufficient for risk assessment in genetic counseling. The Japanese HBOC consortium was established, and as one of the activities of the consortium, the registration project will start to provide essential genetic information in clinical practice.
In Japan risk-reducing surgeries are, albeit gradually, increasingly being performed to potentially protect mutation carriers against HBOC. Risk-reducing salpingo-oophorectomy(RRSO)is effective in the reduction of the incidence of breast cancer, as well as of ovarian cancer. Furthermore, RRSO is associated with improved overall survival in BRCA1/2 mutation carriers. RRM also reduces the risk of breast cancer by more than 90%, but the survival benefit remains unknown. Recently, contralateral RRM has shown improved overall survival in a prospective analysis.
Pathological examination of resected surgical specimens from RRSO revealed that some serous ovarian carcinomas originated from fimbriae of the uterine tube, showing focal p53 overexpression(p53 signature)in the tubal epithelium. Therefore, initial bilateral salpingectomy followed by a delayed oophorectomy may be a proposed alternative to RRSO, but there is no prospective evidence on the efficacy of bilateral salpingectomy.
要旨
遺伝性乳癌卵巣癌(HBOC)は,2013年に米国の女優がBRCA1の遺伝子変異によりリスク低減乳房切除術(RRM)を受けたことを自ら公開したことから,わが国でも広く知られるようになった。HBOCはBRCA1あるいはBRCA2の病的変異に基づく乳癌,卵巣癌をはじめとする癌の易罹患性症候群である。HBOCのBRCA1/2遺伝学的検査に際して,わが国でも遺伝子の再構成(exon単位の欠失,重複)が認められるので,通常のPCR-direct sequenceで変異を認めない症例ではMLPA法も実施しておく必要がある。近年,BRCA1/2以外にも遺伝性乳癌の原因遺伝子が同定された。将来は遺伝性乳癌の原因遺伝子がさらに明らかになり,HBOCの遺伝子検査の内容やHBOCの概念は変わってくる可能性がある。BRCA1/2に変異を認めない場合,乳癌のみの家族歴であれば卵巣癌の発症リスクは高くないので,intensiveな婦人科検診の適応はないと考えられる。また,遺伝子検査実施例の約4～6%で病的意義が不明なuncertain variantsを認める。日本人全体を対象としたHBOCに関する基礎データがないので,現在,日本HBOCコンソーシアムの登録事業によりわが国のHBOCのデータベースを作成して,日常の遺伝カウンセリングで有用な情報を提供できるように準備を進めている。リスク低減手術もわが国で徐々に認識が広まり実施されるようになってきた。リスク低減卵巣卵管切除術(RRSO)は癌の発症率の低下,生存率の改善ともにエビデンスが示されており,米国のガイドラインではBRCA1/2変異陽性者にRRSOを推奨している。一方,RRMは乳癌の発症リスクを下げるのは確実であるが,これまで生存率を改善しているデータは乏しかった。しかし最近,乳癌と反対側の乳房を切除することが生存率の改善に寄与しているというデータが示されている。
目次
Summary
The recognition of hereditary breast and ovarian cancer(HBOC)is gradually spreading in Japan after a famous American actress made it public that she underwent risk-reducing mastectomy(RRM)based on mutation of BRCA1.
HBOC is a cancer susceptibility syndrome involving breast, ovarian, or prostate cancers due to germline mutation of BRCA1 or BRCA2. Although the frequency is low, genomic rearrangement is also found in Japan; therefore, in addition to PCR-direct sequencing, multiplex ligation-dependent probe amplification(MLPA)should be performed in genetic testing for HBOC. Recently, candidate genes other than BRCA1/2, such as RAD51C, PALB2, and BRIP1, have been identified for hereditary breast cancers. Variants of uncertain significance are seen in approximately 4-6% of all genetic testing reports for BRCA1/2. ACMG recommends the use of the term“variant”in addition to a modifier such as pathogenic, benign, and so on, instead of terms such as mutation or polymorphism. The incidence of ovarian cancer is not increased in women from breast cancer-only families that test negative for BRCA1/2 mutations. Therefore, intensive gynecological surveillance may not be needed for these clients.
Basic data such as penetrance and cumulative risks of HBOC in Japanese populations are insufficient for risk assessment in genetic counseling. The Japanese HBOC consortium was established, and as one of the activities of the consortium, the registration project will start to provide essential genetic information in clinical practice.
In Japan risk-reducing surgeries are, albeit gradually, increasingly being performed to potentially protect mutation carriers against HBOC. Risk-reducing salpingo-oophorectomy(RRSO)is effective in the reduction of the incidence of breast cancer, as well as of ovarian cancer. Furthermore, RRSO is associated with improved overall survival in BRCA1/2 mutation carriers. RRM also reduces the risk of breast cancer by more than 90%, but the survival benefit remains unknown. Recently, contralateral RRM has shown improved overall survival in a prospective analysis.
Pathological examination of resected surgical specimens from RRSO revealed that some serous ovarian carcinomas originated from fimbriae of the uterine tube, showing focal p53 overexpression(p53 signature)in the tubal epithelium. Therefore, initial bilateral salpingectomy followed by a delayed oophorectomy may be a proposed alternative to RRSO, but there is no prospective evidence on the efficacy of bilateral salpingectomy.
要旨
遺伝性乳癌卵巣癌(HBOC)は,2013年に米国の女優がBRCA1の遺伝子変異によりリスク低減乳房切除術(RRM)を受けたことを自ら公開したことから,わが国でも広く知られるようになった。HBOCはBRCA1あるいはBRCA2の病的変異に基づく乳癌,卵巣癌をはじめとする癌の易罹患性症候群である。HBOCのBRCA1/2遺伝学的検査に際して,わが国でも遺伝子の再構成(exon単位の欠失,重複)が認められるので,通常のPCR-direct sequenceで変異を認めない症例ではMLPA法も実施しておく必要がある。近年,BRCA1/2以外にも遺伝性乳癌の原因遺伝子が同定された。将来は遺伝性乳癌の原因遺伝子がさらに明らかになり,HBOCの遺伝子検査の内容やHBOCの概念は変わってくる可能性がある。BRCA1/2に変異を認めない場合,乳癌のみの家族歴であれば卵巣癌の発症リスクは高くないので,intensiveな婦人科検診の適応はないと考えられる。また,遺伝子検査実施例の約4～6%で病的意義が不明なuncertain variantsを認める。日本人全体を対象としたHBOCに関する基礎データがないので,現在,日本HBOCコンソーシアムの登録事業によりわが国のHBOCのデータベースを作成して,日常の遺伝カウンセリングで有用な情報を提供できるように準備を進めている。リスク低減手術もわが国で徐々に認識が広まり実施されるようになってきた。リスク低減卵巣卵管切除術(RRSO)は癌の発症率の低下,生存率の改善ともにエビデンスが示されており,米国のガイドラインではBRCA1/2変異陽性者にRRSOを推奨している。一方,RRMは乳癌の発症リスクを下げるのは確実であるが,これまで生存率を改善しているデータは乏しかった。しかし最近,乳癌と反対側の乳房を切除することが生存率の改善に寄与しているというデータが示されている。