{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:59:22Z","timestamp":1786982362263,"version":"build-2736575974"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Breast Cancer"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    While patients with hereditary breast and ovarian cancer with germline double heterozygosity (GDH) for\n                    <jats:italic>BRCA1<\/jats:italic>\n                    and\n                    <jats:italic>BRCA2<\/jats:italic>\n                    are rare, carcinogenesis in these cases remains unclear. We examined two-hit events of heterochronous bilateral breast cancers in a patient with GDH for\n                    <jats:italic>BRCA1<\/jats:italic>\n                    and\n                    <jats:italic>BRCA2<\/jats:italic>\n                    . A 65-year-old woman developed right breast cancer (triple-negative type) at the age of 49 and left breast cancer (triple-negative type) at 55. Family history indicated that multiple relatives on her mother\u2019s side also developed breast cancer.\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    genetic testing (BRACAnalysis\u00ae) showed that she had variants in both the\n                    <jats:italic>BRCA1<\/jats:italic>\n                    and\n                    <jats:italic>BRCA2<\/jats:italic>\n                    (\n                    <jats:italic>BRCA1<\/jats:italic>\n                    :c.5193\u2009+\u20092dup,\n                    <jats:italic>BRCA2<\/jats:italic>\n                    :c.6952C\u2009&gt;\u2009T\/p.Arg2318Ter). According to the data from the test, the former was interpreted as likely pathogenic at Myriad Inc. Further examination regarding two-hit events in her bilateral breast cancers was obtained by somatic mutation analysis using DNA isolated from cut slide specimens of formalin-fixed and paraffin-embedded tumor samples. We first confirmed the pathogenicity of the\n                    <jats:italic>BRCA2<\/jats:italic>\n                    variant by detecting unusual splicing of\n                    <jats:italic>BRCA2<\/jats:italic>\n                    that entirely skipped exon 19 using cultured T cells of the proband. Loss of heterozygosity in\n                    <jats:italic>BRCA1<\/jats:italic>\n                    was observed in her right breast cancer. On the other hand, a somatic nonsense pathogenic variant in\n                    <jats:italic>BRCA2<\/jats:italic>\n                    (variant allele frequency\u2009=\u200915%) and a two-hit event in\n                    <jats:italic>APC<\/jats:italic>\n                    (VAF\u2009=\u200980%) were also found in her left breast cancer. These data provide evidence of different carcinogenesis between left and right breast cancer. Clinical and pathogenic characteristics of cancers with GDH for\n                    <jats:italic>BRCA1<\/jats:italic>\n                    and\n                    <jats:italic>BRCA2<\/jats:italic>\n                    depend on the genes somatically mutated in wild alleles.\n                  <\/jats:p>","DOI":"10.1007\/s12282-025-01740-4","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T04:59:39Z","timestamp":1751432379000},"page":"1472-1479","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Two-hit events occurred independently in bilateral breast cancers in a germline double heterozygous carrier for BRCA1 and BRCA2"],"prefix":"10.1007","volume":"32","author":[{"given":"Ryoko","family":"Semba","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetaka","family":"Eguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuki","family":"Takatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toko","family":"Hashizume","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Moteki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuma","family":"Maeno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumi","family":"Murakami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichiro","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goro","family":"Kutomi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7544-4536","authenticated-orcid":false,"given":"Masami","family":"Arai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"issue":"4","key":"1740_CR1","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1038\/s10038-017-0355-1","volume":"63","author":"M Arai","year":"2018","unstructured":"Arai M, Yokoyama S, Watanabe C, et al. Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan. J Hum Genet. 2018;63(4):447\u201357.","journal-title":"J Hum Genet"},{"issue":"4","key":"1740_CR2","doi-asserted-by":"publisher","first-page":"029","DOI":"10.1093\/jncics\/pkaa029","volume":"4","author":"J Chen","year":"2020","unstructured":"Chen J, Bae E, Zhang L, et al. Penetrance of breast and ovarian cancer in women who carry a BRCA1\/2 Mutation and do not use risk-reducing salpingo-oophorectomy: an updated meta-analysis. JNCI Cancer Spectr. 2020;4(4):029.","journal-title":"JNCI Cancer Spectr."},{"key":"1740_CR3","unstructured":"Ministry of Health LaWoJ. Summary of Statistics of Medical Care Activities in Public Health Insurance. 2022."},{"key":"1740_CR4","first-page":"145","volume":"2023","author":"MAM Inuzuka","year":"2020","unstructured":"Inuzuka MAM, Nakamura S. Registration data of japanese organization of hereditary breast and ovarian cancer till. Pract Guide Hered Breast Ovarian Cancer Springer. 2020;2023:145\u201354.","journal-title":"Pract Guide Hered Breast Ovarian Cancer Springer"},{"issue":"3","key":"1740_CR5","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1097\/CEJ.0000000000000787","volume":"32","author":"H Fujitani","year":"2023","unstructured":"Fujitani H, Eguchi H, Kochi Y, Arai T, Muramatsu M, Okazaki Y. Rare germline variants in pancreatic cancer and multiple primary cancers: an autopsy study. Eur J Cancer Prev. 2023;32(3):286\u201397.","journal-title":"Eur J Cancer Prev"},{"issue":"3","key":"1740_CR6","doi-asserted-by":"publisher","first-page":"333","DOI":"10.3390\/ph17030333","volume":"17","author":"T Ismail","year":"2024","unstructured":"Ismail T, Alzneika S, Riguene E, et al. BRCA1 and its vulnerable c-terminal BRCT domain: structure, function, genetic mutations and links to diagnosis and treatment of breast and ovarian cancer. Pharmaceuticals (Basel). 2024;17(3):333.","journal-title":"Pharmaceuticals (Basel)."},{"issue":"5","key":"1740_CR7","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17(5):405\u201324.","journal-title":"Genet Med"},{"issue":"2","key":"1740_CR8","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.ygyno.2015.11.001","volume":"141","author":"HN Hasmad","year":"2016","unstructured":"Hasmad HN, Lai KN, Wen WX, et al. Evaluation of germline BRCA1 and BRCA2 mutations in a multi-ethnic Asian cohort of ovarian cancer patients. Gynecol Oncol. 2016;141(2):318\u201322.","journal-title":"Gynecol Oncol"},{"issue":"10","key":"1740_CR9","doi-asserted-by":"publisher","first-page":"1962","DOI":"10.3324\/haematol.2018.207241","volume":"104","author":"M Mori","year":"2019","unstructured":"Mori M, Hira A, Yoshida K, et al. Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients. Haematologica. 2019;104(10):1962\u201373.","journal-title":"Haematologica"},{"key":"1740_CR10","unstructured":"Variation ID: 38076 in ClinVar (last accessed: May 13th, 2025)"},{"issue":"1","key":"1740_CR11","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/s13058-016-0768-3","volume":"18","author":"TR Rebbeck","year":"2016","unstructured":"Rebbeck TR, Friebel TM, Mitra N, et al. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. Breast Cancer Res. 2016;18(1):112.","journal-title":"Breast Cancer Res"},{"key":"1740_CR12","unstructured":"Variation ID: 1745927 in ClinVar (last accessed: Jan 9th, 2025)"},{"issue":"3","key":"1740_CR13","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","volume":"176","author":"K Jaganathan","year":"2019","unstructured":"Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, et al. Predicting splicing from primary sequence with deep learning. Cell. 2019;176(3):535-48 e24.","journal-title":"Cell."},{"issue":"3","key":"1740_CR14","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1093\/nar\/gkz1212","volume":"48","author":"R Leman","year":"2020","unstructured":"Leman R, Gaildrat P, Le Gac G, et al. Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico\/in vitro studies: an international collaborative effort. Nucleic Acids Res. 2020;48(3):1600\u20131.","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"1740_CR15","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1038\/ng0197-14","volume":"15","author":"SJ Ramus","year":"1997","unstructured":"Ramus SJ, Friedman LS, Gayther SA, et al. A breast\/ovarian cancer patient with germline mutations in both BRCA1 and BRCA2. Nat Genet. 1997;15(1):14\u20135.","journal-title":"Nat Genet"},{"issue":"3","key":"1740_CR16","doi-asserted-by":"publisher","first-page":"827","DOI":"10.4143\/crt.2021.791","volume":"54","author":"YJ Bang","year":"2022","unstructured":"Bang YJ, Kwon WK, Nam SJ, et al. Clinicopathological Characterization of Double Heterozygosity for BRCA1 and BRCA2 variants in Korean breast cancer patients. 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