2024-01-25 カロリンスカ研究所(KI)
◆この研究により、特にBRCA1/2およびPALB2の変異がリスクを増加させ、またこれらの変異を有する患者の生存率が有意に低いことが示されました。これは画期的な知見であり、画像検出と間隔があいて診断されるがんは遺伝子および生物学の両面で異なり、個別化されたスクリーニング戦略に新たな洞察を提供しています。
<関連情報>
- https://news.ki.se/inherited-genetic-mutations-can-predict-interval-breast-cancer
- https://jamanetwork.com/journals/jamaoncology/fullarticle/2814259
間歇性乳がんに関連する遺伝子変異の調査 Investigation of Genetic Alterations Associated With Interval Breast Cancer
Juan Rodriguez, PhD; Felix Grassmann, PhD; Qingyang Xiao, PhD; et al
JAMA Oncology Published:January 25, 2024
DOI:10.1001/jamaoncol.2023.6287
Key Points
Question Can rare germline genetic variants be used to discriminate between interval and screen-detected breast cancer?
Findings In this genetic association study of 4121 patients with cancer and 5631 health controls, protein-truncating variants in the 5 major genes for breast cancer, particularly BRCA1/2 and PALB2 variants, were significantly associated with the occurrence of interval cancer. Women with a diagnosis of interval cancer who were carrying variants in any of these 5 genes experienced lower survival rates compared with women with interval cancer without such variants.
Meaning The results of this study suggest that screen-detected and interval cancers possess distinct genetic profiles; consequently, these findings may provide insights into the identification of individuals at high risk of developing aggressive forms of breast cancer.
Abstract
Importance Breast cancers (BCs) diagnosed between 2 screening examinations are called interval cancers (ICs), and they have worse clinicopathological characteristics and poorer prognosis than screen-detected cancers (SDCs). However, the association of rare germline genetic variants with IC have not been studied.
Objective To evaluate whether rare germline deleterious protein-truncating variants (PTVs) can be applied to discriminate between IC and SDC while considering mammographic density.
Design, Setting, and Participants This population-based genetic association study was based on women aged 40 to 76 years who were attending mammographic screening in Sweden. All women with a diagnosis of BC between January 2001 and January 2016 were included, together with age-matched controls. Patients with BC were followed up for survival until 2021. Statistical analysis was performed from September 2021 to December 2022.
Exposure Germline PTVs in 34 BC susceptibility genes as analyzed by targeted sequencing.
Main Outcomes and Measures Odds ratios (ORs) were used to compare IC with SDC using logistic regression. Hazard ratios were used to investigate BC-specific survival using Cox regression.
Results All 4121 patients with BC (IC, n = 1229; SDC, n = 2892) were female, with a mean (SD) age of 55.5 (7.1) years. There were 5631 age-matched controls. The PTVs of the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes were more common in patients with IC compared with SDC (OR, 1.48; 95% CI, 1.06-2.05) and associated with BRCA1/2 and PALB2 variants. A family history of BC together with PTVs of any of these genes synergistically increased the probability of receiving a diagnosis of IC rather than SDC (OR, 3.95; 95% CI, 1.97-7.92). Furthermore, 10-year BC-specific survival revealed that if a patient received a diagnosis of an IC, carriers of PTVs in any of these 5 genes had significantly worse survival compared with patients not carrying any of them (hazard ratio, 2.04; 95% CI, 1.06-3.92). All of these associations were further pronounced in a subset of patients with IC who had a low mammographic density at prior screening examination.
Conclusions and Relevance The results of this study may be helpful in future optimizations of screening programs that aim to lower mortality as well as the clinical treatment of patients with BC.
