{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:26:48Z","timestamp":1791044808732,"version":"4.1.0"},"reference-count":38,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2024,3,1]]},"abstract":"Importance<\/jats:title>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.<\/jats:p><\/jats:sec>Objective<\/jats:title>To evaluate whether rare germline deleterious protein-truncating variants (PTVs) can be applied to discriminate between IC and SDC while considering mammographic density.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>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.<\/jats:p><\/jats:sec>Exposure<\/jats:title>Germline PTVs in 34 BC susceptibility genes as analyzed by targeted sequencing.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>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.<\/jats:p><\/jats:sec>Results<\/jats:title>All 4121 patients with BC (IC, n\u2009=\u20091229; SDC, n\u2009=\u20092892) were female, with a mean (SD) age of 55.5 (7.1) years. There were 5631 age-matched controls. The PTVs of the ATM<\/jats:italic>, BRCA1<\/jats:italic>, BRCA2<\/jats:italic>, CHEK2<\/jats:italic>, and PALB2<\/jats:italic> genes were more common in patients with IC compared with SDC (OR, 1.48; 95% CI, 1.06-2.05). This association was primarily influenced by BRCA1\/2 <\/jats:italic>and PALB2<\/jats:italic> 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.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>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.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamaoncol.2023.6287","type":"journal-article","created":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T16:34:16Z","timestamp":1706200456000},"page":"372","source":"Crossref","is-referenced-by-count":10,"title":["Investigation of Genetic Alterations Associated With Interval Breast Cancer"],"prefix":"10.1001","volume":"10","author":[{"given":"Juan","family":"Rodriguez","sequence":"first","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 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